<SEC-DOCUMENT>0000874015-22-000079.txt : 20220225
<SEC-HEADER>0000874015-22-000079.hdr.sgml : 20220225
<ACCEPTANCE-DATETIME>20220224173852
ACCESSION NUMBER:		0000874015-22-000079
CONFORMED SUBMISSION TYPE:	10-K
PUBLIC DOCUMENT COUNT:		122
CONFORMED PERIOD OF REPORT:	20211231
FILED AS OF DATE:		20220225
DATE AS OF CHANGE:		20220224

FILER:

	COMPANY DATA:	
		COMPANY CONFORMED NAME:			IONIS PHARMACEUTICALS INC
		CENTRAL INDEX KEY:			0000874015
		STANDARD INDUSTRIAL CLASSIFICATION:	PHARMACEUTICAL PREPARATIONS [2834]
		IRS NUMBER:				330336973
		STATE OF INCORPORATION:			CA
		FISCAL YEAR END:			1231

	FILING VALUES:
		FORM TYPE:		10-K
		SEC ACT:		1934 Act
		SEC FILE NUMBER:	000-19125
		FILM NUMBER:		22673044

	BUSINESS ADDRESS:	
		STREET 1:		2855 GAZELLE COURT
		CITY:			CARLSBAD
		STATE:			CA
		ZIP:			92010
		BUSINESS PHONE:		7609319200

	MAIL ADDRESS:	
		STREET 1:		2855 GAZELLE COURT
		CITY:			CARLSBAD
		STATE:			CA
		ZIP:			92010

	FORMER COMPANY:	
		FORMER CONFORMED NAME:	ISIS PHARMACEUTICALS INC
		DATE OF NAME CHANGE:	19930328
</SEC-HEADER>
<DOCUMENT>
<TYPE>10-K
<SEQUENCE>1
<FILENAME>form10k.htm
<DESCRIPTION>IONIS PHARMACEUTICALS, INC. 10-K 12-31-2021
<TEXT>
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<div>UNITED STATES</div>
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  <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 18pt; font-weight: bold;">SECURITIES AND EXCHANGE COMMISSION</div>

  <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Washington, DC 20549</div>

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  <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 18pt; font-weight: bold;">FORM <ix:nonNumeric name="dei:DocumentType" id="Fact_f34076e33da741fba157b721a4b6b995" contextRef="c20210101to20211231">10-K</ix:nonNumeric></div>

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          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">ANNUAL REPORT PURSUANT TO SECTION 13 OR 15(d) OF THE SECURITIES EXCHANGE ACT OF 1934</div>
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  <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">For the fiscal year ended <ix:nonNumeric name="dei:DocumentPeriodEndDate" id="Fact_b1753b5fa4f349ffaab215d222af530f" contextRef="c20210101to20211231" format="ixt:datemonthdayyearen">December 31, 2021</ix:nonNumeric></div>

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  <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">For the transition period from ___________ to ___________</div>

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    <td style="width: 32.84%; vertical-align: top;">&#160;</td>

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  <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 18pt; font-weight: bold;"><ix:nonNumeric name="dei:EntityRegistrantName" id="Fact_7fc974efee624382872b5cd11c21b58a" contextRef="c20210101to20211231">Ionis Pharmaceuticals, Inc</ix:nonNumeric>.</div>

  <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(Exact name of Registrant as specified in its charter)</div>

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    <td style="width: 48.93%; vertical-align: top;">
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          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(State or other jurisdiction of incorporation or organization)</div>
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    <td style="width: 2.14%; vertical-align: bottom;">&#160;</td>

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          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(IRS Employer Identification No.)</div>
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    <td style="width: 2%; vertical-align: bottom;">&#160;</td>

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    <td style="width: 49%; vertical-align: top;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(Address of Principal Executive Offices)</div>
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    <td style="width: 2%; vertical-align: bottom;">&#160;</td>

    <td style="width: 49%; vertical-align: top;">
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  <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"><ix:nonNumeric name="dei:CityAreaCode" id="Fact_1d5033ad127447cb8c6245cb0d1a7d15" contextRef="c20210101to20211231">760</ix:nonNumeric>-<ix:nonNumeric name="dei:LocalPhoneNumber" id="Fact_19ef73d6a4704ad2a6bc44118c67c751" contextRef="c20210101to20211231">931-9200</ix:nonNumeric></div>

  <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(Registrant&#8217;s telephone number, including area code)</div>

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  <div>&#160;</div>

  <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Securities registered pursuant to Section 12(b) of the Act:</div>

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    <td style="width: 39.77%; vertical-align: bottom; border-bottom: #000000 2px solid;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Title of each class</div>
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    <td style="width: 1.82%; vertical-align: top;">&#160;</td>

    <td style="width: 15.83%; vertical-align: bottom; border-bottom: #000000 2px solid;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Trading symbol</div>
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    <td style="width: 1.39%; vertical-align: bottom;">&#160;</td>

    <td style="width: 41.19%; vertical-align: bottom; border-bottom: #000000 2px solid;">
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    <td style="width: 39.77%; vertical-align: top;">
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    <td style="width: 1.82%; vertical-align: top;">&#160;</td>

    <td style="width: 15.83%; vertical-align: top;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8220;</span><ix:nonNumeric name="dei:TradingSymbol" id="Fact_f289d0833adc47d48ab112ea5425dd24" contextRef="c20210101to20211231">IONS</ix:nonNumeric><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8221;</span></div>
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    <td style="width: 1.39%; vertical-align: top;">&#160;</td>

    <td style="width: 41.19%; vertical-align: top;">
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  <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Securities registered pursuant to Section 12(g) of the Act: <span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">None</span></div>

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    <td style="width: 32.84%; vertical-align: top;">&#160;</td>

    <td style="width: 34.31%; vertical-align: top; border-bottom: #000000 2px solid;">&#160;</td>

    <td style="width: 32.84%; vertical-align: top;">&#160;</td>

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  <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><a id="_Hlk63843037"><!--Anchor--></a>Indicate by check mark if the Registrant is a well-known seasoned issuer, as defined in Rule 405 of
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  <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Indicate by check if the Registrant is not required to file reports pursuant to Section 13 or Section 15(d) of the Act. Yes <span style="font-size: 10pt; font-family: 'Segoe UI Symbol';">&#9744;&#160; </span><ix:nonNumeric name="dei:EntityVoluntaryFilers" id="Fact_9b00987f3f0f4efa811d1d88058496a6" contextRef="c20210101to20211231">No</ix:nonNumeric>&#160;<span style="font-size: 10pt; font-family: 'Segoe UI Symbol';">&#9746;</span></div>

  <div style="text-align: justify; text-indent: 18pt;"><br />
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  <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Indicate by check mark whether the Registrant (1) has filed all reports required to be filed by Section 13 or 15(d) of the Securities
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  <div style="text-align: justify; text-indent: 18pt;"><br />
  </div>

  <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Indicate by check mark whether the registrant has submitted electronically every Interactive Data File required to be submitted pursuant to
    Rule 405 of Regulation S-T (&#167;232.405 of this chapter) during the preceding 12 months (or for such shorter period that the registrant was required to submit such files). <ix:nonNumeric name="dei:EntityInteractiveDataCurrent" id="Fact_77761b52548541cd8636b4977e4ce396" contextRef="c20210101to20211231">Yes</ix:nonNumeric>&#160;<span style="font-size: 10pt; font-family: 'Segoe UI Symbol';">&#9746;&#160; </span>No <span style="font-size: 10pt; font-family: 'Segoe UI Symbol';">&#9744;</span></div>

  <div style="text-align: left; text-indent: 18pt;"><br />
  </div>

  <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Indicate by check mark whether the registrant is a large accelerated filer, an accelerated filer, a non-accelerated filer, a smaller
    reporting company, or an emerging growth company. See the definitions of &#8220;large accelerated filer,&#8221; &#8220;accelerated filer,&#8221; &#8220;smaller reporting company,&#8221; and &#8220;emerging growth company&#8221; in Rule 12b-2 of the Exchange Act.</div>

  <div style="text-align: center;"><br />
  </div>

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  <tr>

    <td style="width: 48.93%; vertical-align: top;">
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        </td>

    <td style="width: 2.14%; vertical-align: bottom;">&#160;</td>

    <td style="width: 48.93%; vertical-align: top;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Accelerated Filer <span style="font-size: 10pt; font-family: 'Segoe UI Symbol';">&#9744;</span></div>
        </td>

  </tr>

  <tr>

    <td style="width: 48.93%; vertical-align: top;">&#160;</td>

    <td style="width: 2.14%; vertical-align: bottom;">&#160;</td>

    <td style="width: 48.93%; vertical-align: top;">&#160;</td>

  </tr>

  <tr>

    <td style="width: 48.93%; vertical-align: top;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Non-accelerated Filer <span style="font-size: 10pt; font-family: 'Segoe UI Symbol';">&#9744;</span></div>
        </td>

    <td style="width: 2.14%; vertical-align: bottom;">&#160;</td>

    <td style="width: 48.93%; vertical-align: top;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Smaller Reporting Company <span style="font-size: 10pt; font-family: 'Segoe UI Symbol';"><ix:nonNumeric name="dei:EntitySmallBusiness" id="Fact_94f2a3b48074424fb8b8ec805d6a1f03" contextRef="c20210101to20211231" format="ixt-sec:boolballotbox">&#x2610;</ix:nonNumeric></span></div>
        </td>

  </tr>

  <tr>

    <td style="width: 48.93%; vertical-align: top;">&#160;</td>

    <td style="width: 2.14%; vertical-align: bottom;">&#160;</td>

    <td style="width: 48.93%; vertical-align: top;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Emerging Growth Company <span style="font-size: 10pt; font-family: 'Segoe UI Symbol';"><ix:nonNumeric name="dei:EntityEmergingGrowthCompany" id="Fact_6effdccfd60146819fd57b1b1656ae59" contextRef="c20210101to20211231" format="ixt-sec:boolballotbox">&#x2610;</ix:nonNumeric></span></div>
        </td>

  </tr>


</table>
  <div style="text-align: center;"><br />
  </div>

  <div style="text-align: justify; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">If an emerging growth company, indicate by check mark if the
      registrant has elected not to use the extended transition period for complying with any new or revised financial accounting standards provided pursuant to Section 13(a) of the Securities Act. </span><span style="font-size: 10pt; font-family: 'Segoe UI Symbol';">&#9744;</span></div>

  <div><br />
  </div>

  <div style="text-align: justify; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Indicate by check mark whether the registrant has filed a report on and attestation to its management assessment of the effectiveness of its internal
    controls over financial reporting under Section 4049b) of the Sarbanes-Oxley Act (15 U.S.C. 7262(b)) by the registered public accounting firm that prepared or issued its audit report <span style="font-size: 10pt; font-family: 'Segoe UI Symbol';"><ix:nonNumeric name="dei:IcfrAuditorAttestationFlag" id="Fact_c2b307bb966544129913e56d9d34c7fd" contextRef="c20210101to20211231" format="ixt-sec:boolballotbox">&#x2612;</ix:nonNumeric></span></div>

  <div><br />
  </div>

  <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 12pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Indicate by check mark whether the Registrant is a shell company
      (as defined in Rule 12b-2 of the Act). Yes </span><span style="font-size: 10pt; font-family: 'Segoe UI Symbol';"><ix:nonNumeric name="dei:EntityShellCompany" id="Fact_b1e3d0a44ab34b92ab3b0372aa886d34" contextRef="c20210101to20211231" format="ixt-sec:boolballotbox">&#x2610;</ix:nonNumeric></span><span style="font-size: 12pt; font-family: 'Segoe UI Symbol';">&#160; </span><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">No </span><span style="font-size: 10pt; font-family: 'Segoe UI Symbol';">&#9746;</span></div>

  <div style="text-align: left; text-indent: 18pt;"><br />
  </div>

  <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">The approximate aggregate market value of the voting common stock held by non-affiliates of the Registrant, based upon the last sale price of
    the common stock reported on The Nasdaq Global Select Market was $<ix:nonFraction name="dei:EntityPublicFloat" id="Fact_89d739e3e11d4548a21d2f8422ed16b4" contextRef="c20210630" unitRef="U001" decimals="0" scale="0" format="ixt:numdotdecimal">4,675,204,973</ix:nonFraction> as of June 30, 2021.*</div>

  <div style="text-align: left; text-indent: 18pt;"><br />
  </div>

  <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">The number of shares of voting common stock outstanding as of February 16, 2022 was <ix:nonFraction name="dei:EntityCommonStockSharesOutstanding" id="Fact_fe6137454bf243b5a7f73b35caa13c25" contextRef="c20220216" unitRef="U002" decimals="INF" scale="0" format="ixt:numdotdecimal">141,688,727</ix:nonFraction>.</div>

  <div><br />
  </div>

  <div style="text-align: center; text-indent: 18pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">DOCUMENTS INCORPORATED BY REFERENCE</div>

  <div><br />
  </div>

  <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Portions of the Registrant&#8217;s definitive Proxy Statement to be filed on or about April 20, 2022 with the Securities and Exchange Commission in
    connection with the Registrant&#8217;s annual meeting of stockholders to be held on June 2, 2022 are incorporated by reference into Part III of this Report.</div>

  <div style="text-align: left; text-indent: 18pt;"><br />
  </div>

  <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; border-collapse: collapse; text-align: left; color: #000000;">


  <tr>

    <td style="width: 30.71%; vertical-align: top; border-bottom: #000000 2px solid;">&#160;</td>

    <td style="width: 69.29%; vertical-align: top;">&#160;</td>

  </tr>


</table>
  <table cellspacing="0" cellpadding="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">


  <tr>

    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">*</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Excludes 23,819,152 shares of common stock held by directors and officers and by stockholders whose beneficial ownership is known by the Registrant to
            exceed 10 percent of the common stock outstanding at June 30, 2021. Exclusion of shares held by any person should not be construed to
            indicate that such person possesses the power, direct or indirect, to direct or cause the direction of the management or policies of the Registrant, or that such person is controlled by or under common control with the Registrant.</div>
        </td>

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</table>
  <div><br />
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    <hr style="border: none; border-bottom: 4px solid black; border-top: 1px solid black; height: 10px; color: #ffffff; background-color: #ffffff; text-align: center; margin-left: auto; margin-right: auto;" /></div>

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  <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">FORWARD-LOOKING STATEMENTS</div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"><!--PROfilePageNumberReset%Num%2%%%--></div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">This report on Form 10-K and the information incorporated herein by reference includes forward-looking
    statements regarding our business and the therapeutic and commercial potential of SPINRAZA (nusinersen), TEGSEDI (inotersen), WAYLIVRA (volanesorsen), eplontersen, olezarsen, donidalorsen, ION363, pelacarsen, tofersen and our technologies and products
    in development. Any statement describing our goals, expectations, financial or other projections, intentions or beliefs, is a forward-looking statement and should be considered an at-risk statement. Such statements are subject to certain risks and
    uncertainties, including those related to the impact of COVID-19 could have on our business, and particularly those inherent in the process of discovering, developing and commercializing medicines that are safe and effective for use as human
    therapeutics, and in the endeavor of building a business around such medicines. Our forward-looking statements also involve assumptions that, if they never materialize or prove correct, could cause our results to differ materially from those expressed
    or implied by such forward-looking statements. Factors that could cause or contribute to such differences include, but are not limited to, those discussed in this report on Form 10-K, including those identified in Item 1A entitled &#8220;Risk Factors&#8221;.
    Although our forward-looking statements reflect the good faith judgment of our management, these statements are based only on facts and factors currently known by us. As a result, you are cautioned not to rely on these forward-looking statements.</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">In this report, unless the context requires otherwise, &#8220;Ionis,&#8221; &#8220;Company,&#8221; &#8220;we,&#8221; &#8220;our,&#8221; and &#8220;us&#8221; refers to Ionis
    Pharmaceuticals, Inc. and its subsidiaries.</div>

  <div><br />
  </div>

  <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Summary of Risk Factors</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">There are a number of risks related to our business and our securities. Below is a summary of material factors that make
    an investment in our securities speculative or risky. Importantly, this summary does not address all of the risks that we face. Additional discussion of the risks summarized in this risk factor summary, as well as other risks that we face, can be found
    in this report on Form 10-K in Item 1A entitled &#8220;Risk Factors.&#8221;:</div>

  <div style="text-align: left;"><br />
  </div>

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    <td style="width: 36pt;"></td>

    <td style="width: 18pt; vertical-align: top; align: right; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: left;">
          <div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;">the impact on our operations and financial condition from the effects of the current COVID-19 pandemic;</div>
        </td>

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    <td style="width: 36pt;"></td>

    <td style="width: 18pt; vertical-align: top; align: right; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: left;">
          <div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;">our ability to generate substantial revenue from the sale of our medicines;</div>
        </td>

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  <table cellspacing="0" cellpadding="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">


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    <td style="width: 36pt;"></td>

    <td style="width: 18pt; vertical-align: top; align: right; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: left;">
          <div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;">our and our partners&#8217; ability to compete effectively;</div>
        </td>

  </tr>


</table>
  <table cellspacing="0" cellpadding="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">


  <tr>

    <td style="width: 36pt;"></td>

    <td style="width: 18pt; vertical-align: top; align: right; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: left;">
          <div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;">the availability of adequate coverage and payment rates for our medicines;</div>
        </td>

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  <table cellspacing="0" cellpadding="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">


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    <td style="width: 36pt;"></td>

    <td style="width: 18pt; vertical-align: top; align: right; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: left;">
          <div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;">our ability to successfully manufacture our medicines;</div>
        </td>

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  <table cellspacing="0" cellpadding="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">


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    <td style="width: 36pt;"></td>

    <td style="width: 18pt; vertical-align: top; align: right; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: left;">
          <div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;">our ability to successfully develop and obtain marketing approvals for our medicines;</div>
        </td>

  </tr>


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  <table cellspacing="0" cellpadding="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">


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    <td style="width: 36pt;"></td>

    <td style="width: 18pt; vertical-align: top; align: right; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: left;">
          <div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;">our ability to secure and maintain effective corporate partnerships;</div>
        </td>

  </tr>


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    <td style="width: 36pt;"></td>

    <td style="width: 18pt; vertical-align: top; align: right; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: left;">
          <div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;">our ability to sustain cash flows and achieve consistent profitability;</div>
        </td>

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    <td style="width: 36pt;"></td>

    <td style="width: 18pt; vertical-align: top; align: right; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: left;">
          <div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;">our ability to protect our intellectual property; and</div>
        </td>

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    <td style="width: 36pt;"></td>

    <td style="width: 18pt; vertical-align: top; align: right; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: left;">
          <div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;">our ability to maintain the effectiveness of our personnel.</div>
        </td>

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  <div><br />
  </div>

  <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">TRADEMARKS</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">&#160;</span>&#8220;Ionis,&#8221; the Ionis
    logo, and other trademarks or service marks of Ionis Pharmaceuticals, Inc. appearing in this report are the property of Ionis Pharmaceuticals, Inc. &#8220;Akcea,&#8221; the Akcea logo, and other trademarks or service marks of Akcea Therapeutics, Inc. appearing in
    this report are the property of Akcea Therapeutics, Inc., Ionis&#8217; wholly owned subsidiary. This report contains additional trade names, trademarks and service marks of others, which are the property of their respective owners. Solely for convenience,
    trademarks and trade names referred to in this report may appear without the &#174; or TM symbols.</div>

  <div><br />
  </div>

  <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">CORPORATE INFORMATION</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We incorporated in California in 1989 and in January 1991 we changed our state of incorporation to Delaware. In December
    2015, we changed our name to Ionis Pharmaceuticals, Inc. from Isis Pharmaceuticals, Inc. Our principal offices are in Carlsbad, California. In December 2014, we formed Akcea Therapeutics, Inc., as a Delaware corporation, with its principal office in
    Boston, Massachusetts. Prior to Akcea&#8217;s initial public offering, or IPO, in July 2017, we owned 100 percent of Akcea&#8217;s stock. In October 2020, we completed a merger transaction with Akcea such that following the completion of the merger, Akcea became
    our wholly owned subsidiary.</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We make available, free of charge, on our website, <span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">www.ionispharma.com</span>, our reports on Forms 10-K, 10-Q, 8-K and amendments thereto, as soon as reasonably practical after we file such materials with the Securities and Exchange Commission, or SEC. Periodically, we
    provide updates about the company in the Newsroom section of the Investors &amp; Media page of our website. Any information that we include on or link to our website is not a part of this report or any registration statement that incorporates this
    report by reference. The SEC maintains an internet site, <span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">www.sec.gov</span>, that contains reports, proxy and information statements that we file
    electronically with the SEC.</div>

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  <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">IONIS PHARMACEUTICALS, INC.</div>

  <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">FORM 10-K</div>

  <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">For the Fiscal Year Ended December 31, 2021</div>

  <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"><a id="toc"><!--Anchor--></a>Table of Contents</div>

  <div><br />
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    <td style="width: 10.51%; vertical-align: top;">
          <div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">PART I</div>
        </td>

    <td style="width: 83.22%; vertical-align: top;">&#160;</td>

    <td style="width: 6.27%; vertical-align: top;">&#160;</td>

  </tr>

  <tr>

    <td style="width: 10.51%; vertical-align: top;">&#160;</td>

    <td style="width: 83.22%; vertical-align: top;">&#160;</td>

    <td style="width: 6.27%; vertical-align: top; border-bottom: #000000 2px solid;">
          <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Page</div>
        </td>

  </tr>

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    <td style="width: 10.51%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Item 1.</div>
        </td>

    <td style="width: 83.22%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Business</div>
        </td>

    <td style="width: 6.27%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">4</div>
        </td>

  </tr>

  <tr>

    <td style="width: 10.51%; vertical-align: top; background-color: #FFFFFF;">
          <div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Item 1A.</div>
        </td>

    <td style="width: 83.22%; vertical-align: top; background-color: #FFFFFF;">
          <div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Risk Factors</div>
        </td>

    <td style="width: 6.27%; vertical-align: top; background-color: #FFFFFF;">
          <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">49</div>
        </td>

  </tr>

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    <td style="width: 10.51%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Item 1B.</div>
        </td>

    <td style="width: 83.22%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Unresolved Staff Comments</div>
        </td>

    <td style="width: 6.27%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">66</div>
        </td>

  </tr>

  <tr>

    <td style="width: 10.51%; vertical-align: top; background-color: #FFFFFF;">
          <div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Item 2.</div>
        </td>

    <td style="width: 83.22%; vertical-align: top; background-color: #FFFFFF;">
          <div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Properties</div>
        </td>

    <td style="width: 6.27%; vertical-align: top; background-color: #FFFFFF;">
          <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">66</div>
        </td>

  </tr>

  <tr>

    <td style="width: 10.51%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Item 3.</div>
        </td>

    <td style="width: 83.22%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Legal Proceedings</div>
        </td>

    <td style="width: 6.27%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">66</div>
        </td>

  </tr>

  <tr>

    <td style="width: 10.51%; vertical-align: top; background-color: #FFFFFF;">
          <div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Item 4.</div>
        </td>

    <td style="width: 83.22%; vertical-align: top; background-color: #FFFFFF;">
          <div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Mine Safety Disclosures</div>
        </td>

    <td style="width: 6.27%; vertical-align: top; background-color: #FFFFFF;">
          <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">66</div>
        </td>

  </tr>

  <tr>

    <td style="width: 10.51%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 83.22%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 6.27%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

  </tr>

  <tr>

    <td style="width: 10.51%; vertical-align: top; background-color: #FFFFFF;">
          <div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">PART II</div>
        </td>

    <td style="width: 83.22%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 6.27%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

  </tr>

  <tr>

    <td style="width: 10.51%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 83.22%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 6.27%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

  </tr>

  <tr>

    <td style="width: 10.51%; vertical-align: top; background-color: #FFFFFF;">
          <div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Item 5.</div>
        </td>

    <td style="width: 83.22%; vertical-align: top; background-color: #FFFFFF;">
          <div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Market for Registrant&#8217;s Common Equity, Related Stockholder Matters and Issuer Purchases of Equity Securities</div>
        </td>

    <td style="width: 6.27%; vertical-align: top; background-color: #FFFFFF;">
          <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">67</div>
        </td>

  </tr>

  <tr>

    <td style="width: 10.51%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Item 6.</div>
        </td>

    <td style="width: 83.22%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Selected Financial Data</div>
        </td>

    <td style="width: 6.27%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">68</div>
        </td>

  </tr>

  <tr>

    <td style="width: 10.51%; vertical-align: top; background-color: #FFFFFF;">
          <div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Item 7.</div>
        </td>

    <td style="width: 83.22%; vertical-align: top; background-color: #FFFFFF;">
          <div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Management&#8217;s Discussion and Analysis of Financial Condition and Results of Operations</div>
        </td>

    <td style="width: 6.27%; vertical-align: top; background-color: #FFFFFF;">
          <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">68</div>
        </td>

  </tr>

  <tr>

    <td style="width: 10.51%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Item 7A.</div>
        </td>

    <td style="width: 83.22%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Quantitative and Qualitative Disclosures About Market Risk</div>
        </td>

    <td style="width: 6.27%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">79</div>
        </td>

  </tr>

  <tr>

    <td style="width: 10.51%; vertical-align: top; background-color: #FFFFFF;">
          <div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Item 8.</div>
        </td>

    <td style="width: 83.22%; vertical-align: top; background-color: #FFFFFF;">
          <div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Financial Statements and Supplementary Data</div>
        </td>

    <td style="width: 6.27%; vertical-align: top; background-color: #FFFFFF;">
          <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">79</div>
        </td>

  </tr>

  <tr>

    <td style="width: 10.51%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Item 9.</div>
        </td>

    <td style="width: 83.22%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Changes in and Disagreements With Accountants on Accounting and Financial Disclosure</div>
        </td>

    <td style="width: 6.27%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">79</div>
        </td>

  </tr>

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    <td style="width: 10.51%; vertical-align: top; background-color: #FFFFFF;">
          <div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Item 9A.</div>
        </td>

    <td style="width: 83.22%; vertical-align: top; background-color: #FFFFFF;">
          <div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Controls and Procedures</div>
        </td>

    <td style="width: 6.27%; vertical-align: top; background-color: #FFFFFF;">
          <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">79</div>
        </td>

  </tr>

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    <td style="width: 10.51%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Item 9B.</div>
        </td>

    <td style="width: 83.22%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Other Information</div>
        </td>

    <td style="width: 6.27%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">82</div>
        </td>

  </tr>

  <tr>

    <td style="width: 10.51%; vertical-align: top; background-color: #FFFFFF;">
          <div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Item 9C.</div>
        </td>

    <td style="width: 83.22%; vertical-align: top; background-color: #FFFFFF;">
          <div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Disclosure Regarding Foreign Jurisdictions that Prevent Inspections</div>
        </td>

    <td style="width: 6.27%; vertical-align: top; background-color: #FFFFFF;">
          <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">82</div>
        </td>

  </tr>

  <tr>

    <td style="width: 10.51%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 83.22%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 6.27%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

  </tr>

  <tr>

    <td style="width: 10.51%; vertical-align: top; background-color: #FFFFFF;">
          <div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">PART III</div>
        </td>

    <td style="width: 83.22%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 6.27%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

  </tr>

  <tr>

    <td style="width: 10.51%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 83.22%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 6.27%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

  </tr>

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    <td style="width: 10.51%; vertical-align: top; background-color: #FFFFFF;">
          <div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Item 10.</div>
        </td>

    <td style="width: 83.22%; vertical-align: top; background-color: #FFFFFF;">
          <div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Directors, Executive Officers and Corporate Governance</div>
        </td>

    <td style="width: 6.27%; vertical-align: top; background-color: #FFFFFF;">
          <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">82</div>
        </td>

  </tr>

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    <td style="width: 10.51%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Item 11.</div>
        </td>

    <td style="width: 83.22%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Executive Compensation</div>
        </td>

    <td style="width: 6.27%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">82</div>
        </td>

  </tr>

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    <td style="width: 10.51%; vertical-align: top; background-color: #FFFFFF;">
          <div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Item 12.</div>
        </td>

    <td style="width: 83.22%; vertical-align: top; background-color: #FFFFFF;">
          <div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Security Ownership of Certain Beneficial Owners and Management and Related Stockholder Matters</div>
        </td>

    <td style="width: 6.27%; vertical-align: top; background-color: #FFFFFF;">
          <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">83</div>
        </td>

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    <td style="width: 10.51%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Item 13.</div>
        </td>

    <td style="width: 83.22%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Certain Relationships and Related Transactions, and Director Independence</div>
        </td>

    <td style="width: 6.27%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">83</div>
        </td>

  </tr>

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    <td style="width: 10.51%; vertical-align: top; background-color: #FFFFFF;">
          <div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Item 14.</div>
        </td>

    <td style="width: 83.22%; vertical-align: top; background-color: #FFFFFF;">
          <div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Principal Accountant Fees and Services</div>
        </td>

    <td style="width: 6.27%; vertical-align: top; background-color: #FFFFFF;">
          <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">83</div>
        </td>

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    <td style="width: 10.51%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 83.22%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 6.27%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

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    <td style="width: 10.51%; vertical-align: top; background-color: #FFFFFF;">
          <div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">PART IV</div>
        </td>

    <td style="width: 83.22%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 6.27%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

  </tr>

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    <td style="width: 10.51%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 83.22%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 6.27%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

  </tr>

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    <td style="width: 10.51%; vertical-align: top; background-color: #FFFFFF;">
          <div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Item 15.</div>
        </td>

    <td style="width: 83.22%; vertical-align: top; background-color: #FFFFFF;">
          <div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Exhibits, Financial Statement Schedules</div>
        </td>

    <td style="width: 6.27%; vertical-align: top; background-color: #FFFFFF;">
          <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">83</div>
        </td>

  </tr>

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    <td style="width: 10.51%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 83.22%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 6.27%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

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    <td style="width: 10.51%; vertical-align: top; background-color: #FFFFFF;">
          <div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Signatures</div>
        </td>

    <td style="width: 83.22%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 6.27%; vertical-align: top; background-color: #FFFFFF;">
          <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">92</div>
        </td>

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</table>
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  </div>

  <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">PART I</div>

  <div><br />
  </div>

  <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Item 1. Business</div>

  <div><br />
  </div>

  <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Overview</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We are a leader in RNA-targeted therapeutics. We believe our medicines, which are based on our novel antisense technology, have the
    potential to pioneer new markets, change standards of care and transform the lives of people with devastating diseases. We currently have three marketed medicines- SPINRAZA, TEGSEDI and WAYLIVRA. We also have a rich late-stage pipeline of medicines,
    primarily focused on our cardiovascular and neurology franchises. Our late-stage pipeline consists of six medicines in Phase 3 development for eight indications.</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Over the past year, we made important progress toward achieving our goal to be a leading fully integrated biotechnology company. We
    advanced our commercial strategy and go-to-market plans for our near-term commercial opportunities, eplontersen, olezarsen and donidalorsen. We entered an agreement with AstraZeneca to jointly develop and commercialize eplontersen. We believe this
    agreement positions eplontersen to maximize value for patients and shareholders while also enabling us to bolster our commercial organization and accelerate our preparations for our near-term product launches.</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We continued to advance and expand our Phase 3 pipeline with the achievement of key enrollment milestones for eplontersen and pelacarsen,
    and the addition of two new Phase 3 programs for olezarsen and donidalorsen, bringing us to 6 medicines in Phase 3 development addressing 8 indications. In 2021, we also reported data from the Phase 3 VALOR study of tofersen in patients with SOD1-ALS.
    While VALOR did not achieve statistical significance in the primary endpoint, signs of reduced disease progression were observed across multiple secondary and exploratory endpoints. Biogen is actively engaged with regulators to determine the next steps
    for tofersen. In addition, Roche recently announced plans to initiate a new Phase 2 study of tominersen in patients with Huntington&#8217;s disease, based on new findings from a post hoc analysis of the Phase 3 GENERATION HD1 study of tominersen.</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Our mid-stage pipeline also continued to perform well, with positive data readouts from several medicines. And we invested in expanding
    the reach of our technology, including obtaining exclusive rights to Bicycle Therapeutic&#8217;s peptide technology targeting transferrin receptor 1 to expand the capabilities of our Ligand Conjugated Antisense, or LICA, technology. We strengthened our
    financial position and focused our resources in support of our highest priority programs through the integration of Akcea Therapeutics and our distribution agreements with Swedish Orphan Biovitrum AB, or Sobi. We accomplished all this and exceeded our
    2021 financial guidance, including achieving revenues of $810 million. And we remain well capitalized with a 2021 year-end cash balance of $2.1 billion.</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><a id="_Hlk54336544"><!--Anchor--></a>&#160;Our multiple sources of revenue and strong balance sheet enable us to invest in our strategic
    priorities to build our commercial pipeline, expand and diversify our technology and deliver new medicines to the market. By continuing to focus on these priorities, we believe we are well positioned to drive future growth and to deliver increasing
    value for patients and shareholders.</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;">Marketed Medicines</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">SPINRAZA is the global foundation-of-care for the treatment of patients of all ages with spinal muscular atrophy, or SMA, a progressive,
    debilitating and often fatal genetic disease. Biogen, our partner responsible for commercializing SPINRAZA worldwide, reported that as of December 31, 2021, over 11,000 patients were on SPINRAZA therapy in markets around the world. From inception
    through December 31, 2021, we have earned more than $1.6 billion in revenues from our SPINRAZA collaboration, including nearly $1.2 b<a id="_Hlk16011662"><!--Anchor--></a>illion in royalties on sales of SPINRAZA.</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">TEGSEDI is a once weekly, self-administered subcutaneous medicine approved in the U.S., Europe, Canada and Brazil for the treatment of
    patients with polyneuropathy caused by hATTR, a debilitating, progressive, and fatal disease. We launched TEGSEDI in the U.S. and the European Union, or EU, in late 2018. In 2021, we began selling TEGSEDI in Europe through our distribution agreement
    with Sobi. Additionally, in the second quarter of 2021, Sobi began distributing TEGSEDI in the U.S. and Canada. In Latin America, PTC Therapeutics International Limited, or PTC, is commercializing TEGSEDI in Brazil and is pursuing access in additional
    Latin American countries through its exclusive license agreement with us.</div>

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  <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">WAYLIVRA is a once weekly, self-administered, subcutaneous medicine that received conditional marketing authorization in May 2019 from the
    European Commission, or EC, as an adjunct to diet in adult patients with genetically confirmed familial chylomicronemia syndrome, or FCS, and at high risk for pancreatitis. We launched WAYLIVRA in the EU in the third quarter of 2019. In 2021, we began
    selling WAYLIVRA in Europe through our distribution agreement with Sobi. Through our exclusive license agreement with PTC, PTC is working to provide access to WAYLIVRA across Latin America, beginning in Brazil. In the third quarter of 2021, the
    National Health Surveillance Agency (Ag&#234;ncia Nacional de Vigil&#226;ncia Sanit&#225;ria), or <a id="_Hlk93133833"><!--Anchor--></a>ANVISA, approved WAYLIVRA in Brazil. In December 2021, PTC submitted an application to ANVISA for approval of WAYLIVRA for the
    treatment of familial partial lipodystrophy, or FPL, in Brazil. If approved, Waylivra will be the first approved treatment for patients with FPL in Brazil.</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Under our distribution agreements with Sobi, we retained the marketing authorizations for TEGSEDI and WAYLIVRA. We will continue to supply
    commercial product to Sobi and manage regulatory and manufacturing processes, as well as relationships with key opinion leaders. We will also continue to lead the TEGSEDI and WAYLIVRA global commercial strategy. In connection with the agreements, we
    restructured our European operations in the first quarter of 2021, and we restructured our North American TEGSEDI operations in the second quarter of 2021.</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;"><a id="_Hlk46213905"><!--Anchor--></a>Medicines in Phase 3 Studies</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We currently have six medicines in Phase 3 studies for eight indications, which include:</div>

  <div style="text-align: justify;"><br />
  </div>

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    <td style="width: 18pt; vertical-align: top; align: right; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Eplontersen: In July 2021, we achieved full enrollment in the NEURO-TTRansform Phase 3 study with data expected mid-2022. Enrollment is ongoing in the CARDIO-TTRansform
            Phase 3 study</div>
        </td>

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    <td style="width: 18pt; vertical-align: top; align: right; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">o</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;">In November 2021, we entered into an agreement with AstraZeneca for eplontersen, under which we will jointly develop and commercialize eplontersen in the U.S. AstraZeneca
            has exclusive rights to commercialize eplontersen in the rest of the world</div>
        </td>

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    <td style="width: 18pt; vertical-align: top; align: right; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Olezarsen: We initiated the Phase 3 CORE study in patients with severe hypertriglyceridemia, or SHTG, in October 2021. Enrollment is ongoing in the BALANCE Phase 3 study
            in patients with FCS</div>
        </td>

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    <td style="width: 18pt; vertical-align: top; align: right; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">o</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Data from the Phase 2 study of olezarsen in patients with moderate hypertriglyceridemia and at high risk for or with established cardiovascular disease were published in
            the <span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">European Heart Journal</span></div>
        </td>

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    <td style="width: 18pt; vertical-align: top; align: right; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Donidalorsen: Based on positive topline data from a Phase 2 study of donidalorsen in patients with hereditary angioedema which we reported in April 2021, we initiated the
            Phase 3 OASIS-HAE study in November 2021</div>
        </td>

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            <div style="text-align: left; margin-left: 54pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">o</div>
          </td>

    <td style="width: auto; vertical-align: top;">
            <div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We reported additional positive results from the Phase 2 study of donidalorsen at the ACAAI annual scientific meeting in November 2021, demonstrating
              rapid and sustained reductions in HAE attacks with favorable safety and tolerability</div>
          </td>

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    <td style="width: 18pt; vertical-align: top; align: right; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;">ION363: In April 2021, we initiated a Phase 3 study in patients with <span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">amyotrophic
              lateral sclerosis, or ALS, with mutations in the fused in sarcoma gene, or FUS, or </span>FUS-ALS, the most common cause of juvenile-onset ALS</div>
        </td>

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    <td style="width: 18pt; vertical-align: top; align: right; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Pelacarsen: In August 2021, Novartis achieved 50 percent enrollment in Novartis&#8217; Lp(a) HORIZON Phase 3 cardiovascular outcome study in patients with established
            cardiovascular disease and elevated <span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">lipoprotein(a), or Lp(a)</span></div>
        </td>

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    <td style="width: 18pt; vertical-align: top; align: right; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Tofersen: In October 2021, Biogen reported that tofersen did not meet the primary clinical endpoint in the Phase 3 VALOR study; however, trends favoring tofersen were
            seen across multiple secondary and exploratory measures of disease activity and clinical function</div>
        </td>

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    <td style="width: 18pt; vertical-align: top; align: right; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">o</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Biogen is actively engaging with regulators, the medical community, patient advocacy groups and other key stakeholders around the world to determine potential next
              steps</div>
        </td>

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    <td style="width: 18pt; vertical-align: top; align: right; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">o</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Given the high unmet medical need, Biogen expanded its ongoing early access program, or EAP, to the broader SOD1-ALS population</div>
        </td>

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    <td style="width: 18pt; vertical-align: top; align: right; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">o</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;">The Phase 3 ATLAS study in patients with presymptomatic SOD1-ALS is ongoing</div>
        </td>

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</table>
  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;">COVID-19</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">As a company focused on improving the health of people around the world, our priority during the COVID-19 pandemic
      is the safety of our employees, their families, the healthcare workers who work with us and the patients who rely on our medicines. We are also focused on maintaining the quality of our studies and minimizing the impact to timelines. While the
      COVID-19 pandemic has impacted some areas of our business, we believe our mitigation efforts and financial strength will enable us to continue to manage through the pandemic and execute on our strategic initiatives. Because the situation is extremely
      fluid, we are continuing to evaluate the impact COVID-19 could have on our business, including the impact on our commercial products and the medicines in our pipeline.</div>

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  <div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic; font-weight: bold;">Our Marketed Medicines &#8211; Potentially Transformational Medicines Bringing Value to Patients Today</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">SPINRAZA </span>&#8211;
    SPINRAZA (nusinersen) injection for intrathecal use is a survival motor neuron-2, or SMN2, directed antisense medicine indicated for the treatment of SMA in pediatric and adult patients.</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">SPINRAZA continues to demonstrate substantial benefit in SMA patients of all ages, supporting its position as a global foundation of care
    for the treatment of SMA. Biogen, our worldwide commercial partner, reported that as of December 31, 2021, there were more than 11,000 patients on SPINRAZA therapy.</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">SMA is characterized by loss of motor neu<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">rons
      in the spinal cord and lower brain stem, People with SMA have a deletion or defect in their </span><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic; color: #000000;">SMN1</span><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> gene and rely on their </span><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic; color: #000000;">SMN2</span><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> gene to produce functional SMN protein, which motor neurons need to maintain motor function and muscle strength. However, the </span><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic; color: #000000;">SMN2</span><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> gene can only produce approximately 10 percent of the SMN protein critical
      for motor neurons, resulting in severe and progressive loss of motor function and strength.</span></div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">The rate and severity of degeneration varies depending on the amount of functional SMN protein a patient can produce. Type
    1, or infantile-onset, SMA is the most severe form of the disease. Type 1 SMA patients produce very little SMN protein and often progress to death or permanent ventilation by the age of 2. Patients with Type 2 or Type 3, or later-onset, SMA produce
    more SMN protein, but also suffer from a progressive loss of muscle strength and function and a reduced life expectancy.</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 35.3pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Biogen continues to expand the body of evidence supporting SPINRAZA&#8217;s durable efficacy and well-established safety
    profile to address the remaining needs of SMA patients of all ages. In the Phase 2/3 DEVOTE study, Biogen is evaluating the safety and potential to achieve increased efficacy with a higher dose of SPINRAZA compared to the currently approved dose. At
    the AAN 2021 Virtual Annual meeting in April 2021, Biogen reported that initial findings from the DEVOTE study suggest no new safety concerns and support continued development of a higher dose of SPINRAZA.</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 35.3pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">In January 2021, Biogen initiated the Phase
      4 RESPOND study evaluating the benefit of SPINRAZA in infants and children with a suboptimal clinical response to the gene therapy, </span>onasemnogene abeparvovec<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">.</span></div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 35.3pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">And in September 2021, Biogen initiated the Phase 3b ASCEND study designed to evaluate the clinical outcomes and assess
    the safety of a higher dose of SPINRAZA in children, teens and adults with later-onset SMA following treatment of risdiplam.</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 35.3pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">Additionally, Biogen continues to conduct
      the Phase 2 NURTURE study, an open-label study investigating the benefit of SPINRAZA when administered before symptom onset in patients genetically diagnosed with SMA, and likely to develop Type 1 or Type 2 SMA. NURTURE was the first study to
      investigate the potential to slow or stop SMA disease progression in presymptomatic SMA patients. In June 2021, Biogen reported data from an interim analysis, showing that all study patients remain alive without the need for permanent ventilation.
      Additionally, at the time of the interim analysis, 92 percent of patients maintained the ability to swallow</span>.</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 35.3pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">The approval of SPINRAZA was based on efficacy and safety data from multiple clinical studies, including two randomized,
    placebo-controlled Phase 3 studies, ENDEAR, in patients with infantile-onset SMA, and CHERISH, in patients with later-onset SMA as well as from SHINE, an open-label extension, or OLE, study for patients with SMA who participated in prior SPINRAZA
    studies.</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 35.3pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">TEGSEDI &#8211; </span>TEGSEDI (inotersen)
    injection is an RNA-targeted medicine indicated for the treatment of polyneuropathy due to hATTR in adults. <span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">TEGSEDI prevents the creation of TTR proteins,
      reducing the amount of amyloid that builds up, which damages organs and issues.</span></div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Polyneuropathy due to hATTR is caused by the accumulation of misfolded mutated TTR protein in the peripheral nerves. Patients with
    polyneuropathy due to hATTR experience ongoing debilitating nerve damage throughout their body resulting in the progressive loss of motor functions, such as walking. These patients also accumulate TTR in other major organs, which progressively
    compromises their function and eventually leads to death within five to fifteen years of disease onset. There are an estimated 40,000 patients with polyneuropathy due to hATTR worldwide.</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 35.3pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">TEGSEDI is commercially available in numerous countries, including the U.S., many European countries, Canada, and Latin America. <span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">In 2021, we began selling TEGSEDI in Europe through our distribution agreement with Sobi. Additionally, in the second quarter of 2021, Sobi began distributing
      TEGSEDI in the U.S. and Canada. In Latin America, PTC through its exclusive license agreement with us, is commercializing TEGSEDI in Brazil and is working to achieve access in additional Latin American countries.</span></div>

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  </div>

  <div style="text-align: justify; text-indent: 35.3pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">The approvals of TEGSEDI were based on efficacy and safety data from the Phase 3 NEURO-TTR study in patients with hATTR amyloidosis with
    stage 1 and stage 2 polyneuropathy. <span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">We also conducted an OLE study in patients with hATTR treated with TEGSEDI to evaluate the long-term efficacy and safety
      profile of TEGSEDI. </span>We reported interim data from the study that demonstrated continued efficacy in patients after two years. Results also showed that patients who started treatment earlier achieved greater long-term disease stabilization
    compared to those who switched from placebo to TEGSEDI in the OLE study.</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">WAYLIVRA &#8211; </span>WAYLIVRA (volanesorsen)
    is an antisense medicine indicated as an adjunct to diet in adult patients with genetically confirmed FCS and at high risk for pancreatitis, in whom response to diet and triglyceride lowering therapy has been inadequate. <span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">WAYLIVRA reduces triglyceride levels by inhibiting the production of apolipoprotein C-III, or apoC-III, a protein that is a key regulator of triglyceride levels.</span></div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 35.3pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">FCS is a rare, genetic disease estimated to affect 3,000 to 5,000 people worldwide and characterized by extremely elevated triglyceride
    levels. FCS can lead to many chronic health issues including severe, recurrent abdominal pain, fatigue, high risk of life-threatening pancreatitis and abnormal enlargement of the liver or spleen. In addition, people with FCS are often unable to work,
    adding to their disease burden. In severe cases, patients can have bleeding into the pancreas, serious tissue damage, infection, and cyst formation, as well as damage to other vital organs such as the heart, lungs, and kidneys.</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">WAYLIVRA is commercially available in multiple European countries and in Brazil. <span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">In 2021, we began selling WAYLIVRA in Europe through our distribution agreement with Sobi. In Latin America, PTC through its exclusive license agreement with us, is commercializing WAYLIVRA in Brazil and is
      working to achieve access in additional Latin American countries.</span></div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">WAYLIVRA&#8217;s conditional marketing authorization in the EU and approval in Brazil we<span style="background-color: #FBFBFB; font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">re based </span>on efficacy and safety data from <span style="background-color: #FBFBFB; font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">the Phase 3
      APPROACH study, the ongoing APPROACH OLE study and supported by results from the Phase 3 COMPASS study.</span></div>

  <div><br />
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  <div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Drug Discovery and Development</div>

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  <div style="text-align: justify; text-indent: 35.3pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic; font-weight: bold;">Introduction to Drug Discovery</div>

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  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Proteins are essential working molecules in a cell. Almost all human diseases result from inappropriate protein
    production, improper protein activity or loss of a protein. Antisense medicines can modify the production of proteins by targeting RNAs. In this way, antisense medicines can inhibit the production of a disease-causing protein, modify the protein
    produced or increase the production of a protein that, when absent, causes diseases. Antisense medicines can also treat diseases by targeting and reducing RNAs that may be causing diseases (so called &#8220;toxic RNAs&#8221;). RNAs are naturally occurring
    molecules in the body that primarily act as messengers that carry the information the cell needs to produce proteins from the deoxyribonucleic acid, or DNA, to the protein making complex in the cell. When antisense medicines bind to the specific RNAs
    of a particular gene, they will ultimately alter the production of the protein encoded in the target gene or, in the case of disease-causing RNAs, degrade the toxic RNAs.</div>

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  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic; font-weight: bold;">Our Pipeline</div>

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  <div style="text-align: justify; text-indent: 35.3pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We are a leader in the discovery and development of RNA-targeted therapeutics. We are focused on pioneering new markets
    and changing standards of care with a focus on cardiovascular and neurological diseases. Additionally, we are developing a number of medicines that are outside these areas. We also have an emerging specialty rare disease pipeline comprised of medicines
    which we believe represent a compelling opportunity for us. We are developing our medicines for systemic and local delivery (e.g., subcutaneous, intrathecal, intraocular, oral and aerosol). We plan to continue adding new investigational medicines to
    our pipeline in the future.</div>

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  <div style="text-align: justify; text-indent: 35.3pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We have built a rich pipeline of medicines designed to treat many serious diseases. To select the best candidates, we
    efficiently screen many targets in parallel and apply our rational approach to selecting disease targets. With our expertise in discovering and characterizing novel antisense medicines, our scientists can optimize the properties of our antisense
    medicines against each particular target. We have created LICA technology, which we designed to enhance the effective uptake and activity of our medicines in particular tissues. With our LICA technology we attach specific chemical structures or
    molecules to our antisense medicines. With our first LICA conjugate, a complex sugar-like molecule called N-acetylgalactosamine, or GalNAc, we have shown an increase in medicinal potency of 20-30-fold for liver targets, compared to non-conjugated
    antisense medicines. Many of the medicines in our pipeline are LICA medicines, including four LICA medicines currently in Phase 3 studies: eplontersen, olezarsen, donidalorsen and pelacarsen. We have utilized our chemistry advancements to expand the
    therapeutic and commercial opportunities of our pipeline. Our antisense technology, along with our manufacturing and analytical processes that are the same across our medicines, shorten our timeline from initial concept to the first human dose, when
    compared to early development timelines for other drug modalities like small molecule and monoclonal antibody medicines.</div>

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  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">The table below lists the medicines in our clinical pipeline. We categorize patient studies to establish a medicine&#8217;s
    safety profile as Phase 1/2 and those studies in healthy volunteers as Phase 1. The table includes the disease indication, a partner (if the medicine is partnered), and the development status of each medicine. We have included descriptions for each of
    our medicines in Phase 2 and Phase 3 development below.</div>

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  <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">*China Only</div>

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  <div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic; font-weight: bold;">Our Phase 3 Medicines</div>

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  <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We currently have six medicines in Phase 3 studies for eight indications: eplontersen, olezarsen, donidalorsen, ION363, pelacarsen and
    tofersen.</div>

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  <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold; color: #000000;">Eplontersen (TTR) </span><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">&#8211; </span>Eplontersen (formerly<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold; color: #000000;">&#160;</span><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">IONIS-TTR-L</span><sub style="color: #000000;">Rx</sub><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">) is an
      investigational LICA medicine we designed </span>to inhibit the production of TTR protein. We are developing eplontersen as a monthly self-administered subcutaneous injection to treat all types of ATTR. ATTR amyloidosis is a systemic, progressive
    and fatal disease in which patients experience multiple overlapping clinical manifestations caused by the inappropriate formation and aggregation of TTR amyloid deposits in various tissues and organs, including peripheral nerves, heart, intestinal
    tract, eyes, kidneys, central nervous system, thyroid and bone marrow. The progressive accumulation of TTR amyloid deposits in these tissues and organs leads to organ failure and eventually death.</div>

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    <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Polyneuropathy due to hATTR is caused by the accumulation of misfolded mutated TTR protein in the peripheral nerves. Patients with
      polyneuropathy due to hATTR experience ongoing debilitating nerve damage throughout their body resulting in the progressive loss of motor functions, such as walking. These patients also accumulate TTR in other major organs, which progressively
      compromises their function and eventually leads to death within five to fifteen years of disease onset. There are an estimated 40,000 patients with polyneuropathy due to hATTR worldwide.</div>

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    <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">ATTR cardiomyopathy is caused by the accumulation of misfolded TTR protein in the cardiac muscle. Patients experience ongoing
      debilitating heart damage resulting in progressive heart failure, which results in death within 3 to 5 years from disease onset. ATTR cardiomyopathy includes both the genetic and wild-type form of the disease. There are an estimated 300,000 to
      500,000 patients with ATTR cardiomyopathy worldwide.</div>

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    <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Often patients with the polyneuropathy form of TTR amyloidosis will have TTR build up in the heart and experience cardiomyopathy
      symptoms. Similarly, patients with the cardiomyopathy form of TTR amyloidosis may often have TTR build up in their peripheral nerves and experience nerve damage and progressive difficulty with motor functions.</div>

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  <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">In November 2019, we initiated the NEURO-TTRansform Phase 3 study of eplontersen in patients with polyneuropathy caused by hATTR
    amyloidosis. NEURO-TTRansform is <span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">a global, multi-center, randomized, open-label study designed to evaluate the efficacy, safety and tolerability of
      eplontersen. The NEURO-TTRansform study is fully enrolled with 168 patients. </span>We expect data from the NEURO-TTRansform study in mid-2022. <span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">The current
      study will be compared to the historical placebo arm from the TEGSEDI (inotersen) NEURO-TTR Phase 3 study. The NEURO-TTRansform study includes multiple primary endpoints, including the percent change from baseline in serum TTR concentration </span>modified
    Neuropathy Impairment Score +7, or mNIS+7, a measure of neuropathic disease progression<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> and in </span>the Norfolk Quality of Life Questionnaire-Diabetic
    Neuropathy, or Norfolk QoL-DN.</div>

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  <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">In January 2020, we initiated the CARDIO-TTRansform Phase 3 cardiovascular outcome study of eplontersen in patients with ATTR
    cardiomyopathy. CARDIO-TTRansform i<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">s </span>a global, multi-center, randomized, double-blind, placebo-controlled study in up to 750 patients designed to
    evaluate the efficacy, safety and tolerability of eplontersen. The CARDIO-TTRansform study includes<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> co-</span>primary outcome measures of cardiovascular death
    and frequency of cardiovascular clinical events.</div>

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  <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">In September 2019, we reported results from the Phase 1 study with eplontersen in healthy volunteers at the Heart Failure Society of
    America Annual Meeting. In this study, subjects treated with eplontersen achieved dose-dependent reductions of TTR protein of up to 94 percent and eplontersen had a favorable safety and tolerability profile supportive of continued development.</div>

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  <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">In January 2022, the FDA granted an Orphan Medicine Designation for eplontersen.</div>

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  <div style="text-align: justify; text-indent: 35.3pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">In December 2021, we entered into an agreement with AstraZeneca to jointly develop and commercialize eplontersen in the
    U.S. AstraZeneca obtained exclusive rights to commercialize eplontersen outside the U.S, except for certain Latin American countries.</div>

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  <div style="text-align: justify; text-indent: 35.3pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Olezarsen (ApoC-III)</span><sub style="font-weight: bold;">&#160;</sub><span style="font-size: 12pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">&#8211; </span>Olezarsen (formerly IONIS-APOCIII-L<sub>Rx</sub>) is an investigational LICA medicine we designed to inhibit
    the production of apoC-III for patients who are at risk of disease due to elevated triglyceride levels. ApoC-III is a protein produced in the liver that regulates triglyceride metabolism in the blood. People with severely elevated triglycerides, such
    as people with FCS, are at high risk for acute pancreatitis and an increased risk of CVD. It is estimated that there are between 3,000 to 5,000 patients with FCS worldwide and more than three million patients with severely high triglycerides in the
    U.S.</div>

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  <div style="text-align: justify; text-indent: 35.3pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">In December 2020, we initiated our first Phase 3 study of olezarsen, BALANCE, in patients with FCS. BALANCE is a global,
    multi-center, randomized, double-blind, placebo-controlled study enrolling up to 60 patients (age 18 and over) designed to assess the efficacy, safety and tolerability of olezarsen. The primary endpoint is percent change from baseline in fasting
    triglyceride levels at six months compared to placebo.</div>

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  <div style="text-align: justify; text-indent: 35.3pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">In November 2021, we </span>initiated a
    second Phase 3 study of olezarsen, CORE, in patients with SHTG. CORE is a global, multi-center, randomized, double-blind, placebo-controlled study enrolling up to 450 patients designed to assess the efficacy, safety and tolerability of olezarsen. The
    CORE study will compare olezarsen to placebo in patients with triglyceride levels equal to or greater than 500 mg/dL who are on currently available therapies for elevated triglycerides. The primary endpoint of the study is the percent change in fasting
    triglycerides from baseline at month 6.</div>

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  <div style="text-align: justify; text-indent: 35.3pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">In January 2020, we reported positive
      results from a Phase 2 clinical study in patients</span> with hypertriglyceridemia and at high risk of or with established CVD. Olezarsen achieved statistically significant, dose-dependent reductions in fasting triglycerides compared to placebo at
    all dose levels. Additionally, at the highest monthly dose, 91 percent of patients achieved serum triglycerides of &#8804; 150 mg/dL, the recognized threshold for cardiovascular risk, compared to less than 5 percent of patients in the placebo group.
    Olezarsen also achieved statistical significance in numerous key secondary endpoints, including significant reductions in apoC-III, very low-density lipoprotein cholesterol, or VLDL-C, and remnant cholesterol, and a statistically significant increase
    in high-density lipoprotein cholesterol, or HDL-C. Olezarsen had a favorable safety and tolerability profile supportive of continued development.</div>

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  <div style="text-align: justify; text-indent: 35.3pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Donidalorsen (PKK)</span>&#160;<span style="font-size: 12pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">&#8211; </span>Donidalorsen (formerly IONIS-PKK-L<sub>Rx</sub>) is an investigational LICA medicine we designed to inhibit the production of prekallikrein, or PKK,
    to treat people with HAE. HAE is a rare genetic disease that is characterized by rapid and painful attacks of inflammation in the hands, feet, limbs, face, abdomen, larynx, and trachea and can be fatal if swelling occurs in the larynx. PKK plays an
    important role in the activation of inflammatory mediators associated with acute attacks of HAE. By inhibiting the production of PKK, donidalorsen could be an effective prophylactic approach to preventing or reducing the severity of HAE attacks. It is
    estimated that there are more than 20,000 patients with HAE in the U.S. and EU.</div>

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  <div style="text-align: justify; text-indent: 35.3pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">In November 2021, we initiated the Phase 3 study of donidalorsen, OASIS-HAE, in patients with HAE. OASIS-HAE is a multi-center,
    randomized, double-blind placebo-controlled study in up to 84 patients designed to assess the efficacy, safety and tolerability of olezarsen. The primary endpoint is the time-normalized number of investigator-confirmed HAE attacks per month from Week 1
    to Week 25.</div>

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  <div style="text-align: justify; text-indent: 35.3pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">In March 2021, we reported positive results
      from a Phase 2</span> clinical study of donidalorsen in patients with HAE. Patients received either donidalorsen 80mg or placebo subcutaneously once monthly for 17 weeks. The Phase 2 study met its primary and secondary endpoints, achieving
    significant reductions in the number of attacks suffered by patients with HAE compared to placebo. The study demonstrated a mean reduction of 90 percent in the number of monthly HAE attacks in weeks one to 17 of the study (p &lt;0.001) and a mean
    reduction of 97 percent in the number of monthly HAE attacks in weeks five to 17 (p=0.003). In weeks five to 17, 92 percent of patients treated with donidalorsen were attack-free compared to 0 percent in the placebo group (p &lt;0.001). Additionally,
    in November 2021 we reported additional data from the Phase 2 study, including that donidalorsen demonstrated an overall reduction in moderate to severe attacks starting with the second dose. For the final month of the study, all donidalorsen treated
    patients were attack-free. Donidalorsen had a favorable safety and tolerability profile supportive of continued development.</div>

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  <div style="text-align: justify; text-indent: 35.3pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">In September 2020, results from the Phase 1 study of donidalorsen in healthy volunteers and a compassionate-use study of
    IONIS-PKK<sub>Rx</sub> and donidalorsen in patients living with severe angioedema were published in <span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">The</span>&#160;<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">New England Journal of Medicine</span>. In the study, we observed that the medicines reduced plasma prekallikrein activity levels and showed evidence of clinical efficacy in reducing the number of
    breakthrough attacks per month in patients over the course of the treatment, including complete resolution in a patient.</div>

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  <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">ION363 (FUS)</span> &#8211; ION363 is an
    investigational antisense medicine we designed to reduce the production of the FUS protein to treat people with ALS caused by mutations in the FUS gene. Because antisense-mediated reduction of mutant FUS protein in a FUS-ALS mouse model demonstrated
    the ability to prevent motor neuron loss, it is hypothesized that reduction of FUS protein will reverse or prevent disease progression in FUS-ALS patients. It is estimated that there are approximately 350 patients with FUS-ALS in G7 countries
    (comprised of Canada, France, Germany, Italy, Japan, the United Kingdom and the U.S.).</div>

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  <div style="text-align: justify; text-indent: 35.3pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">In April 2021, we initiated a Phase 3 study of ION363 in patients with FUS-ALS. The Phase 3 trial of ION363 is a global, multi-center,
    randomized, double-blind, placebo-controlled study enrolling up to 64 patients designed to assess the efficacy, safety and tolerability of ION363. Part 1 of the trial will consist of patients randomized to receive a multi-dose regimen of ION363 or
    placebo for 29 weeks, followed by Part 2, which will be an open-label period in which all patients in the trial will receive ION363 for 73 weeks. The primary endpoint is change from baseline as measured by the ALSFRS-R Total Score, time of rescue or
    discontinuation from Part 1 and entering Part 2 due to a deterioration in function, and Ventilation Assistance-free survival, or VAFS.</div>

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  <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold; color: #000000;">Pelacarsen (Apo(a)) </span>(TQJ230)<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"> &#8211; </span><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">Pelacarsen (formerly </span>IONIS-APO(a)-L<sub>Rx</sub>)<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold; color: #000000;">&#160;</span><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">is an investigational LICA antisense
      medicine we designed to inhibit the production of apolipoprotein(a), or Apo(a), in the liver to offer a direct approach for reducing Lp(a). Elevated Lp(a) is recognized as an independent, genetic cause of CVD. Lp(a) levels are determined at birth and
      lifestyle modification, including diet and exercise, do not impact Lp(a) levels. Inhibiting the production of Apo(a) in the liver reduces the level of Lp(a) in blood, potentially slowing down or reversing cardiovascular disease in people with
      hyperlipoproteinemia(a), a condition in which individuals have levels of Lp(a) greater than 50 mg/dL, the recognized threshold for risk of CVD. We believe antisense technology is well suited to address hyperlipoproteinemia(a) because antisense
      technology specifically targets the RNA that codes for all forms of the Apo(a) molecule. Furthermore, we believe addressing elevated Lp(a) is the next important horizon in CVD risk reduction. It is estimated that there are more than eight million
      people living with CVD and elevated levels of Lp(a).</span></div>

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  <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">In December 2019,<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">&#160;</span>Novartis initiated
    the Phase 3 study of pelacarsen, Lp(a) HORIZON, in <span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">patients with </span>elevated Lp(a) levels and a prior cardiovascular event. Lp(a) HORIZON is <span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">a global, multi-center, randomized, double-blind, placebo-controlled cardiovascular outcomes study in more than 8,000 patients designed to assess the efficacy,
      safety and tolerability of pelacarsen</span>. <span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">Patients will be treated with </span>80 mg of pelacarsen administered monthly by subcutaneous injection. <span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">The primary endpoint in Lp(a) HORIZON is the time to occurrence of first major adverse cardiovascular event, or MACE. </span>In August 2021, we announced that the
    Lp(a) HORIZON study had reached 50 percent enrollment.</div>

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  <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">In November 2018, we reported results of the Phase 2 study of pelacarsen in patients with hyperlipoproteinemia(a) at the American Heart
    Association, or AHA, annual meeting. In the Phase 2 study, we observed statistically significant and dose dependent reductions from baseline in Lp(a) levels. Approximately 98 percent of patients who received the highest dose in the study demonstrated a
    reduction in Lp(a) levels to below 50 mg/dL. Pelacarsen had a favorable safety and tolerability profile supportive of continued development.</div>

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  <div style="text-align: justify; text-indent: 35.3pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">In February 2019, Novartis exercised its option to license pelacarsen. As a result, Novartis is responsible for global
    development, regulatory and commercialization activities, and costs for pelacarsen.</div>

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  <div style="text-align: justify; text-indent: 35.3pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Tofersen (SOD1) </span>(BIIB067)<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"> &#8211; </span>Tofersen (formerly IONIS-SOD1<sub>Rx</sub>) is an investigational antisense medicine we designed to inhibit the production of superoxide dismutase 1,
    or SOD1, which is a well understood genetic cause of ALS. SOD1-<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">ALS is a rare, fatal, neurodegenerative disorder caused by a mutation in the </span><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic; color: #000000;">SOD1</span><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> gene leading to a progressive loss of
      motor neurons. As a result, people with SOD1-ALS experience increasing muscle weakness, loss of movement, difficulty breathing and swallowing and eventually succumb to the disease. Current treatment options for people with SOD1-ALS are extremely
      limited, with no medicines that significantly slow disease progression. Tofersen is one of four medicines we have in development to treat ALS. </span>It is estimated that there are approximately 1,400 patients with SOD1-ALS in G7 countries.</div>

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  <div style="text-align: justify; text-indent: 35.3pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">In October 2021, Biogen announced topline results of the Phase 3 VALOR study of tofersen in patients with SOD1-ALS
    designed to assess the efficacy, safety and tolerability of tofersen. While tofersen did not meet the primary endpoint of change from baseline to 28 weeks in the ALSFRS-R, trends favoring tofersen were seen across multiple secondary and exploratory
    measures of disease activity and clinical function. As a result, Biogen is actively engaged with regulators to determine next steps for the program. Additionally, in October 2021, Biogen announced that it would expand eligibility for its ongoing EAP to
    all people with SOD1-ALS, where permitted.</div>

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  <div style="text-align: justify; text-indent: 35.3pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#160;In April 2021, Biogen initiated a second Phase 3 study of tofersen, ATLAS, in presymptomatic individuals with a SOD1
    genetic mutation and biomarker evidence of disease activity. ATLAS is a multi-center, randomized, double-blind, placebo-controlled study enrolling up to 150 subjects designed to assess the efficacy, safety and tolerability of tofersen in presymptomatic
    individuals with a SOD1 genetic mutation and biomarker evidence of disease activity.</div>

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  <div style="text-align: justify; text-indent: 35.3pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Biogen conducted a Phase 1/2 study that demonstrated proof of biology and proof of concept. At the highest dose tested, treatment with
    tofersen over a three month period resulted in a statistically significant lowering of SOD1 protein levels in the cerebrospinal fluid, or CSF, and positive numerical trends across three efficacy endpoints compared to placebo, including slowing of
    clinical decline as measured by the ALSFRS-R. Tofersen had a favorable safety and tolerability profile supportive of continued development.</div>

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  <div style="text-align: justify; text-indent: 35.3pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">In December 2018, Biogen exercised its option to license tofersen, as a result, Biogen is responsible for global
    development, regulatory and commercialization activities, and costs for tofersen.</div>

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  <div style="text-align: left; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic; font-weight: bold;">Our Cardiovascular Medicines in Development</div>

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  <div style="text-align: justify; text-indent: 35.3pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">According to the World Health Organization, or WHO, CVD remains the number one cause of death globally. An estimated 17.9 million people
    died from CVD in 2019, representing approximately 30 percent of all deaths globally. Our cardiovascular medicines target the major risk factors of cardiovascular disease, including cholesterol, triglycerides, and hypertension.</div>

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  <div style="text-align: justify; text-indent: 35.3pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Eplontersen </span>&#8211; See the medicine
    description under &#8220;Our Phase 3 Medicines&#8221; section above.</div>

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  <div style="text-align: justify; text-indent: 35.3pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Olezarsen </span>&#8211; See the medicine
    description under &#8220;Our Phase 3 Medicines&#8221; section above.</div>

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  <div style="text-align: justify; text-indent: 35.3pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Pelacarsen </span>&#8211; See
    the medicine description under &#8220;Our Phase 3 Medicines&#8221; section above.</div>

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  <div style="text-align: justify; text-indent: 35.3pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold; color: #000000;">ION449 (PCSK9) </span>(AZD8233)<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> &#8211; ION449 (formerly IONIS-AZ4-2.5-L</span><sub style="color: #000000;">-Rx</sub><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">) </span>is an investigational LICA medicine we designed to reduce the production of proprotein convertase subtilisin/kexin type 9, or PCSK9, in the liver. PCSK9 is integrally involved in the regulation of LDL-cholesterol. Genetic studies
    have shown that individuals with life-long reductions of LDL-C due to reduced function of PCSK9 have substantially reduced risk of CVD.</div>

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  <div style="text-align: justify; text-indent: 35.3pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">In November 2020, AstraZeneca initiated the Phase 2b study of ION449 in patients with LDL-C levels between 70 and 190<span style="font-size: 12pt; font-family: 'Times New Roman', Times, serif;">&#160;</span>mg/dl and receiving statin therapy. The study is a randomized, double-blind, placebo-controlled clinical study in approximately 110 patients to assess the efficacy, safety
    and tolerability of ION449. The primary objective is to assess the effect of different doses of ION449 on LDL-C compared to placebo at Week 12 in patients taking baseline statin therapy. The study will evaluate three dose levels of ION449 versus
    placebo, all administered once a month by subcutaneous injection.</div>

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  <div style="text-align: justify; text-indent: 35.3pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">In November 2021, we reported positive results from the Phase 1 study of ION449 in patients with dyslipidemia. Participants were treated
    with multiple ascending subcutaneous doses and ION449 demonstrated dose-dependent mean reductions in circulating plasma PCSK9 and LDL-C levels and had a favorable safety and tolerability profile supportive of continued development.</div>

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  <div style="text-align: justify; text-indent: 35.3pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">In October 2020, we reported positive results from the Phase 1 study of ION449 in healthy volunteers. Participants were treated with a
    single subcutaneous dose and ION449 demonstrated dose-dependent mean reductions in circulating plasma PCSK9 and LDL-C levels and had a favorable safety and tolerability profile supportive of continued development.</div>

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  <div style="text-align: justify; text-indent: 35.3pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We licensed ION449 to AstraZeneca under our cardiovascular, renal and metabolic diseases collaboration. As a result,
    AstraZeneca is responsible for global development, regulatory and commercialization activities, and costs for ION449.</div>

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  <div style="text-align: justify; text-indent: 35.3pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Fesomersen (FXI)</span>
    (BAY2976217) &#8211; Fesomersen (formerly IONIS-FXI-L<sub>Rx</sub>) is an investigational LICA medicine we designed to inhibit the production of Factor XI. Factor XI is a clotting factor produced in the liver that is important in the growth of blood clots.
    Thrombosis, characterized by the formation of a blood clot inside blood vessels, can cause heart attacks and strokes. People who are deficient in Factor XI have a lower incidence of thromboembolic events with minimal increase in bleeding risk. Although
    currently available anticoagulants reduce the risk of thrombosis, physicians associate these anticoagulants with increased bleeding, which can be fatal. By inhibiting Factor XI production, we believe that fesomersen can be used broadly as an
    anti-thrombotic in many different therapeutic settings for which additional safe and well tolerated anti-thrombotic medicines are needed.</div>

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  <div style="text-align: justify; text-indent: 35.3pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">In August 2020, Bayer initiated the RE-THINc Phase 2b study of fesomersen in patients with end-stage renal disease, or
    ESRD, on hemodialysis. RE-THINc is a randomized, blinded, placebo-controlled study in approximately 290 patients to assess the efficacy, safety and tolerability of fesomersen. The study is designed to evaluate multiple monthly doses administered
    subcutaneously. The primary endpoint is incidence of major bleeding and clinically relevant non-major bleeding.</div>

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  <div style="text-align: justify; text-indent: 35.3pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We conducted a Phase 1, blinded, randomized, placebo-controlled, dose-escalation study of fesomersen in healthy
    volunteers. In this study, fesomersen produced significant reductions in FXI activity and FXI antigen, without evidence of increased bleeding and had a favorable safety and tolerability profile supportive of continued development.</div>

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  <div style="text-align: justify; text-indent: 35.3pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">In February 2017, we licensed fesomersen to Bayer. As a result, Bayer is responsible for global development, regulatory and
    commercialization activities, and costs for fesomersen.</div>

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  <div style="text-align: justify; text-indent: 35.3pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">IONIS-AGT-L</span><sub style="font-weight: bold;">Rx</sub>&#160;<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">&#8211;</span> IONIS-AGT-L<sub>Rx</sub> is an investigational LICA medicine we designed to inhibit the production of
    angiotensinogen to decrease blood pressure in people with treatment resistant hypertension, or TRH. Despite the availability of antihypertensive agents, TRH is still a major contributor to cardiovascular and renal disease. Approximately 140 million
    adults globally and approximately 10 million adults in the U.S. have resistant hypertension, defined as failure to achieve a blood pressure goal of 140/90 (systolic/diastolic) despite the use of three or more antihypertensive medications. People with
    TRH have been found to have a three-fold higher chance of having fatal and non-fatal cardiovascular events relative to those with controlled hypertension.</div>

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  <div style="text-align: justify; text-indent: 35.3pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We are also studying IONIS-AGT-L<sub>Rx</sub> in patients with chronic heart failure with reduced ejection fraction.
    Heart failure, or HF, afflicts approximately 6.5 million patients in the United States, or U.S., and 26 million worldwide. As the population ages, HF incidence is increasing, and more than 550,000 patients are diagnosed with HF each year. HF is
    responsible for more hospitalizations than all forms of cancer combined and is the most common diagnosis in hospital patients 65 years and older. Every year over 1 million patients are hospitalized for HF in the U.S. and Europe, accounting for 6.5
    million hospital days. High rates of hospitalizations with frequent readmission (almost 25 percent of patients with HF are readmitted within 30 days) along with other direct and indirect costs, also place an enormous economic burden on healthcare
    systems. Despite new advances in medical therapy, the residual risk for patients with HF is still high.</div>

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  <div style="text-align: justify; text-indent: 35.3pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">In January 2021, we initiated a Phase 2b clinical study of IONIS-AGT-L<sub>Rx</sub> in patients with hypertension
    uncontrolled with three or more antihypertensive medications, including angiotensin-converting enzyme, or ACE, inhibitors or angiotensin II receptor blockers, or ARBs. The study is a randomized, double-blinded, placebo-controlled study in approximately
    150 patients to assess the efficacy, safety and tolerability of IONIS-AGT-L<sub>Rx</sub>. We designed the study to evaluate multiple doses administered subcutaneously. The primary endpoint is the change in systolic blood pressure, or SBP, from
    baseline.</div>

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  <div style="text-align: justify; text-indent: 35.3pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">In September 2021, we initiated a Phase 2 clinical study of IONIS-AGT-L<sub>Rx</sub> in patients with chronic HF with
    reduced ejection fraction. The study is a randomized, double-blind, placebo-controlled study in approximately 75 patients to assess the safety, tolerability, and efficacy of IONIS-AGT-L<sub>Rx</sub>. We designed the study to evaluate multiple doses
    administered subcutaneously. The primary endpoint is the percent change in plasma AGT concentration from baseline.</div>

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  <div style="text-align: justify; text-indent: 35.3pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We evaluated IONIS-AGT-L<sub>Rx</sub> in two randomized, double-blinded, placebo-controlled Phase 2 studies. The first study was in
    people with mild hypertension and the second was in people with TRH who were on two or three antihypertensive medications, including ACE inhibitors or ARBs.<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #333333;">
      IONIS-AGT-L</span><sub style="color: #333333;">Rx</sub><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #333333;"> significantly reduced AGT levels compared with placebo in both studies. Although not
      powered for this endpoint, trends were noted in blood pressure reduction and </span><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">IONIS-AGT-L</span><sub style="color: #000000;">Rx</sub><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> had a favorable safety and tolerability profile supportive of continued development.</span></div>

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  <div style="text-align: left; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic; font-weight: bold;">Our Neurological Medicines in Development</div>

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  <div style="text-align: justify; text-indent: 35.3pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Our neurological medicines address a broad range of diseases in major regions of the brain and in the central nervous system, or CNS,
    cell types. Our antisense medicines aim to address both large and rare patient populations. We are currently investigating potential disease-modifying treatments for common neurological diseases including Alzheimer&#8217;s disease and Parkinson&#8217;s disease. We
    also have multiple investigational medicines in clinical trials for rare neurological diseases, including ALS and hATTR polyneuropathy. According to the National Institute of Neurological Disorders and Stroke, or NINDS, at the National Institutes of
    Health, or NIH, a third of the 7,000 known rare diseases are neurological disorders or thought to include a neurological component.</div>

  <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#160;<img width="721" height="332" src="image09.jpg" alt="graphic" /></div>

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  <div style="text-align: justify; text-indent: 35.3pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Eplontersen </span>&#8211; See the medicine
    description under &#8220;Our Phase 3 Medicines&#8221; section above.</div>

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  <div style="text-align: justify; text-indent: 35.3pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">ION363</span> &#8211; See the medicine
    description under &#8220;Our Phase 3 Medicines&#8221; section above.</div>

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  <div style="text-align: justify; text-indent: 35.3pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Tofersen </span>&#8211; See the medicine
    description under &#8220;Our Phase 3 Medicines&#8221; section above.</div>

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  <div style="text-align: justify; text-indent: 35.3pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">ION373 (GFAP)</span> &#8211; ION373 is an
    investigational antisense medicine targeting glial fibrillary acidic protein, or GFAP, mRNA we designed to inhibit the production of GFAP. We are developing ION373 as a potential therapy for Alexander disease, or AxD. AxD is a rare progressive and
    fatal neurological disease that affects the myelin sheath which protects nerve fibers. AxD is caused by a gain-of-function mutation in the GFAP gene and is characterized by progressive deterioration, including loss of skills and independence, generally
    leading to death in childhood or early adulthood.</div>

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  <div style="text-align: justify; text-indent: 35.3pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Two major types of AxD have been defined. Type I onset typically occurs before 4 years of age and patients can experience head
    enlargement, seizures, limb stiffness, delayed or declining cognition, and lack of growth. Type II onset typically occurs after the age of 4 and symptoms can include difficulty speaking, swallowing, and making coordinated movements. AxD is most often
    fatal. There are treatments that can relieve symptoms, but there is no disease modifying therapy yet available to patients.</div>

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  <div style="text-align: justify; text-indent: 35.3pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">In April 2021, we initiated a pivotal study of ION373 in patients with AxD. The Phase 2/3 study of ION373 is a multi-center,
    double-blind, placebo-controlled, multiple-ascending dose study in up to 58 patients with AxD designed to assess the efficacy, safety and tolerability of ION373. Patients will receive ION373 or placebo for a 60-week period, after which all patients in
    the study will receive ION373 for a 60-week open-label treatment period. The primary endpoint is the change from baseline in the 10-Meter Walk Test, or 10MWT.</div>

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  <div style="text-align: justify; text-indent: 35.3pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">IONIS-C9</span><sub style="font-weight: bold;">Rx</sub> (BIIB078) &#8211; IONIS-C9<sub>Rx</sub> is an investigational antisense medicine we designed to selectively inhibit the production of the mutated chromosome 9 open reading frame 72, or <span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">C9ORF72</span>, gene. A mutation in this gene results in an inherited form of ALS, referred to as C9ORF72-ALS, or C9-ALS, the most prevalent genetic cause of ALS worldwide. This
    mutation can lead to rapid progressive loss of motor neurons and is a fatal disease characterized by muscle weakness, loss of movement, and difficulty breathing and swallowing. IONIS-C9<sub>Rx</sub> is one of four medicines we have in development to
    treat ALS.</div>

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  <div style="text-align: justify; text-indent: 35.3pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">In August 2018, Biogen initiated a Phase 1/2 clinical study of IONIS-C9<sub>Rx</sub> in adult patients with C9-ALS. The
    Phase 1/2 study is a global, multi-center, randomized, double-blinded, placebo-controlled study designed to assess&#160; safety, tolerability and activity of multiple ascending doses of IONIS-C9<sub>Rx</sub> administered intrathecally.</div>

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  <div style="text-align: justify; text-indent: 35.3pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">IONIS-C9<sub>Rx</sub> is being developed under our 2013 Strategic Neurology collaboration with Biogen.</div>

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  <div style="text-align: justify; text-indent: 35.3pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">IONIS-MAPT</span><sub style="font-weight: bold;">Rx</sub> (BIIB080) &#8211; IONIS-MAPT<sub>Rx</sub> is an investigational antisense medicine we designed to selectively inhibit production of the microtubule-associated protein tau, or tau, protein in the brain. We are developing
    IONIS-MAPT<sub>Rx</sub> to treat people with Alzheimer&#8217;s disease, or AD, and potentially other neurodegenerative disorders characterized by the deposition of abnormal tau protein in the brain, such as certain forms of frontotemporal degeneration, or
    FTD, and progressive supranuclear palsy, or PSP.</div>

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  <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">AD and FTD are characterized predominantly by memory impairment and behavioral changes, resulting in a person&#8217;s inability to independently
    perform daily activities. PSP is characterized by problems with walking and control of movement, sleep disorder and loss of memory and ability to reason. AD generally occurs late in life and may progress to death in five to 20 years after the onset of
    the disease. FTD and PSP have a more rapid disease progression. In the U.S., there are approximately five million people living with AD, approximately 55,000 people living with FTD and approximately 20,000 people living with PSP.</div>

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  <div style="text-align: justify; text-indent: 35.3pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">In July 2021, we and Biogen reported positive topline data from our Phase 1/2 study of IONIS-MAPT<sub>Rx</sub> in
    patients with mild Alzheimer&#8217;s disease at the Alzheimer&#8217;s Association International Conference, or AAIC. The Phase 1/2 study was a blinded, randomized, placebo-controlled, dose-escalation of IONIS-MAPT<sub>Rx</sub> to evaluate the safety and activity
    of once-monthly intrathecal injections of IONIS-MAPT<sub>Rx</sub> in patients with mild AD. The study showed that IONIS-MAPT<sub>Rx</sub> met its primary objective of safety and tolerability in patients with mild Alzheimer&#8217;s disease. The study
    demonstrated robust time and dose dependent lowering of tau protein in cerebrospinal fluid over the three-month treatment period and sustained reductions during the six-month post-treatment period and IONIS-MAPT<sub>Rx </sub>had a favorable safety and
    tolerability profile supportive of continued development.</div>

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  <div style="text-align: justify; text-indent: 35.3pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">In December 2019, Biogen exercised its option to license IONIS-MAPT<sub>Rx</sub>. We were responsible for completing the Phase 1/2 study
    in patients with mild AD and a one-year long-term extension study. Biogen has responsibility for global development, regulatory and commercialization activities, and costs for IONIS-MAPT<sub>Rx</sub>.</div>

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  <div style="text-align: justify; text-indent: 35.3pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">ION859 (LRRK2) </span>(BIIB094) &#8211;
    ION859 is an investigational antisense medicine we designed to inhibit the production of the Leucine Rich Repeat Kinase 2, or LRRK2, protein as a potential therapy for Parkinson&#8217;s disease, or PD. The most common genetic mutations in PD are found in the
    LRRK2 protein. It is believed that increased LRRK2 protein activity could be one of the key drivers for developing PD. PD is a progressive neurodegenerative disease characterized by loss of neurons in the motor system. Patients with PD can experience
    tremors, loss of balance and coordination, stiffness, slowing of movement, changes in speech and in some cases cognitive decline. PD is ultimately fatal. There are treatments that can relieve symptoms, but there is no disease modifying therapy.</div>

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  <div style="text-align: justify; text-indent: 35.3pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">In August 2019, Biogen initiated a Phase 1/2 study evaluating ION859 in adult patients with PD. The Phase 1/2 study is a global,
    multi-center, randomized, double-blinded, placebo-controlled study designed to assess the safety, tolerability and activity of multiple ascending doses of ION859 administered intrathecally.</div>

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  <div style="text-align: justify; text-indent: 35.3pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">ION859 is being developed under our 2013 Strategic Neurology collaboration with Biogen.</div>

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  <div style="text-align: justify; text-indent: 35.3pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">ION464 (SNCA)</span> (BIIB101) &#8211; ION464
    is an investigational antisense medicine we designed to inhibit the production of the alpha-synuclein protein as a potential therapy for PD, Multiple System Atrophy, or MSA, and related synucleinopathies. Alpha-synuclein protein abnormally accumulates
    in the brains of PD and MSA patients and is thought to be one of the key drivers of these diseases. It is believed that decreasing the production of the alpha-synuclein protein will reduce the toxic effects of gain-of-function mutations.</div>

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  <div style="text-align: justify; text-indent: 35.3pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">In July 2020, we initiated a Phase 1/2 study evaluating ION464 in patients with MSA. The current study is a multi-center, randomized,
    double-blinded, placebo-controlled study designed to assess the safety and tolerability of multiple doses of ION464 administered intrathecally.</div>

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  <div style="text-align: justify; text-indent: 35.3pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">ION464 is being developed under our 2013 Strategic Neurology collaboration with Biogen.</div>

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  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">ION541 (ATXN2) </span>(BIIB105)
    &#8211; ION541 is an investigational antisense medicine we designed to reduce the production of the ataxin-2, or ATXN2, protein for the potential treatment of ALS. The reduction of ATXN2 has been shown to decrease aggregation of TDP-43, a toxic RNA binding
    protein found in most patients with ALS, including the approximately 90 percent of the ALS population with no known family history of ALS. ION541 is one of four medicines we have in development to treat ALS.</div>

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  <div style="text-align: justify; text-indent: 35.3pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">In October 2020, Biogen initiated a Phase 1/2 clinical study evaluating ION541 in this broad ALS population. The current
    study is a randomized, blinded, placebo-controlled study designed to assess the safety, tolerability, and pharmacokinetics of multiple ascending doses of ION541 administered intrathecally.</div>

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  <div style="text-align: justify; text-indent: 35.3pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">ION541 is being developed under our 2013 Strategic Neurology collaboration with Biogen.</div>

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  <div style="text-align: justify; text-indent: 35.3pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">ION582 (UBE3A)</span> (BIIB121) &#8211; ION582
    is an investigational antisense medicine we designed to inhibit the expression of the UBE3A transcript, or UBE3A-ATS for the potential treatment of Angelman Syndrome, or AS. AS is a rare, genetic neurological disease caused by the loss of function of
    the maternally inherited <span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">UBE3A</span> gene. Angelman syndrome typically presents in infancy and is characterized by intellectual disability, balance
    issues, motor impairment, and debilitating seizures. Some patients are unable to walk or speak. Some symptoms can be managed with existing drugs; however, there is no disease modifying therapy. It is estimated that there are more than 60,000 patients
    with AS in the U.S. and EU.</div>

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  <div style="text-align: justify; text-indent: 35.3pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">In December 2021, we initiated the Phase 1/2 study, HALOS, of ION582 in patients with Angelman syndrome. The study is an open label
    dose-escalation study enrolling up to 44 participants to assess the safety, tolerability and activity of multiple ascending doses of ION582.</div>

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  <div style="text-align: justify; text-indent: 35.3pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">ION582 is being developed under our 2012 Neurology collaboration with Biogen.</div>

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  <div style="text-align: justify; text-indent: 35.3pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Tominersen (HTT)</span><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> (</span>RG6042<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">) &#8211; </span>Tominersen (formerly IONIS-HTT<sub>Rx</sub>)
    is an investigational antisense medicine we designed to target the underlying cause of Huntington&#8217;s disease, or HD, by reducing the production of all forms of the huntingtin protein, or HTT, including its mutated variant, or mHTT. HD is an inherited
    genetic brain disorder that results in the progressive loss of both mental faculties and physical control. It is caused by the expansion of the CAG trinucleotide sequence in the HTT gene. The resulting mutant HTT protein is toxic and gradually destroys
    neurons. Symptoms usually appear between the ages of 30 and 50 and worsen over a 10 to 25-year period. Ultimately, the weakened individual succumbs to pneumonia, heart failure or other complications. Presently, there is no effective treatment or cure
    for the disease, and currently available medicines only mask the patient&#8217;s symptoms but do not slow down the underlying loss of neurons.</div>

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  <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">In January 2022, Roche announced plans to initiate a new Phase 2 trial to evaluate tominersen in patients with HD based on findings from a
    post-hoc analysis of the Phase 3 GENERATION HD1 study. The findings from the post-hoc analysis suggested tominersen may benefit younger adult patients with lower disease burden. As a result, Roche is in the early stages of designing a Phase 2 clinical
    trial to explore different doses of tominersen in this patient population.</div>

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  <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Roche conducted the Phase 3 study, GENERATION HD1,of tominersen in patients with HD. The Phase 3 study was a randomized, multicenter,
    double-blind, placebo-controlled study that recruited 791 participants from 18 countries around the world. In March 2021, Roche announced that dosing would be stopped in the study following a recommendation from the independent data monitoring
    committee, or iDMC, based on an overall benefit/risk assessment. The study is ongoing without dosing to allow participants to be followed for safety and clinical outcomes. Roche anticipates the study will complete in March/April 2022.</div>

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  <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Roche is also conducting the GEN-EXTEND study, an OLE study for participants coming from any prior Roche HD study. The study is ongoing
    without dosing to allow participants to be followed for safety and clinical outcomes. Roche anticipates the study will complete in March/April 2022. In parallel with the OLE, Roche initiated a natural history study in a similar patient population to
    the OLE aimed at further understanding the natural progression of HD.</div>

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  <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We completed a randomized, placebo-controlled, dose escalation, Phase 1/2 clinical study of tominersen in patients with early-stage HD. In
    this study, we observed dose-dependent reductions of mHTT among patients treated with tominersen and a favorable safety and tolerability profile supporting continued development. <span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">The data from this study were published in </span><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic; color: #000000;">The New England Journal of Medicine</span><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> in May 2019.</span></div>

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  <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">The European Medicines Agency, or EMA, granted PRIority MEdicines scheme, or PRIME, designation to tominersen. EMA PRIME status is granted
    to medicines that may offer a major therapeutic advantage over existing treatments, or benefit patients without treatment options. The FDA and EMA granted Orphan Medicine Designation for tominersen to treat people with HD.</div>

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  <div style="text-align: justify; text-indent: 35.3pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">In December 2017, Roche exercised its option to license tominersen. As a result, Roche is responsible for global
    development, regulatory and commercialization activities, and costs for tominersen.</div>

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  <div style="text-align: justify; text-indent: 35.3pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">IONIS-DNM2-2.5</span><sub style="font-weight: bold;">Rx</sub> (DYN101) &#8211; IONIS-DNM2-2.5<sub>Rx</sub> is an investigational antisense medicine we designed to inhibit the production of Dynamin 2, or DNM2, protein for the treatment of centronuclear myopathy, or CNM. CNM is a
    group of rare, potentially fatal disorders of the skeletal muscle cells. It is characterized by muscle weakness, decreased muscle tone and muscle atrophy, ranging from severe to mild, and potentially life-threatening. DNM2 reduction demonstrated
    improved muscle mass and muscle force, and extended lifespan in animal models of the most severe form of CNM.</div>

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  <div style="text-align: justify; text-indent: 35.3pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">In November 2019, Dynacure initiated a Phase 1/2 clinical study evaluating IONIS-DNM2-2.5<sub>Rx</sub> in patients with CNM. The current
    study is an open-label study designed to assess the safety and tolerability of multiple doses of IONIS-DNM2-2.5<sub>Rx</sub> administered intravenously.</div>

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  <div style="text-align: justify; text-indent: 35.3pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">In the fourth quarter of 2017, we licensed IONIS-DNM2-2.5<sub>Rx</sub> to Dynacure. As a result, Dynacure is responsible
    for global development, regulatory and commercialization activities, and costs for IONIS-DNM2-2.5<sub>Rx</sub>.</div>

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  <div style="text-align: justify; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic; font-weight: bold;">Specialty Rare Medicines in Development</div>

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  <div style="text-align: justify; text-indent: 35.3pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Our emerging specialty rare disease pipeline is comprised of medicines that are outside of our cardiovascular and
    neurological franchises, but we believe could represent a compelling opportunity for us.</div>

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  <div style="text-align: justify; text-indent: 35.3pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Sapablursen (TMPRSS6)</span>
    &#8211; Sapablursen (formerly IONIS-TMPRSS6-L<sub>Rx</sub>) is an investigational LICA medicine we designed to target the TMPRSS6 gene to modulate the production of hepcidin, which is the key regulator of iron homeostasis. By modulating hepcidin expression,
    sapablursen has the potential to positively impact diseases characterized by iron excess, such as &#946;-thalassemia, and iron deficiency, such as polycythemia vera, or PV.</div>

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  <div style="text-align: justify; text-indent: 35.3pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#946;-thalassemia is a rare, genetic and potentially fatal form of chronic anemia resulting in hepcidin deficiency, severely
    reduced red blood cell production and iron toxicity. In some cases, iron accumulates in major organs, such as the heart and liver, which can be fatal. The current standard-of-care involves symptom management, including blood transfusions and iron
    chelation. There are no approved disease-modifying treatments for &#946;-thalassemia.</div>

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  <div style="text-align: justify; text-indent: 35.3pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">PV is a rare, non-genetic and potentially fatal disease caused by overproduction of red blood cells. This overproduction
    leads to a thickening of the blood, which increases patients&#8217; risk of life-threatening blood clots, including in the lungs, heart and brain. Patients with PV also experience severe iron deficiency due to hepcidin overexpression. The current
    standard-of-care for PV involves symptom management. There are no approved disease-modifying treatments for PV.</div>

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  <div style="text-align: justify; text-indent: 35.3pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#160;In August 2020, we initiated a Phase 2 study evaluating sapablursen in patients with non-transfusion dependent, or
    NTDT, &#946;-thalassemia intermedia. The Phase 2 study is multi-center, randomized, open-label study in approximately 36 patients we designed assess the efficacy, safety, and tolerability of sapablursen administered monthly subcutaneously. The primary
    endpoint is the percentage of participants with a greater than or equal to 1.0 g/dl increase from baseline in hemoglobin at week 27.</div>

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  <div style="text-align: justify; text-indent: 35.3pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">In January 2022 we initiated a Phase 2 study evaluating sapablursen in patients with Phlebotomy Dependent Polycythemia
    Vera, or PD-PV. The Phase 2 study is a multi-center, randomized, open-label study in approximately 40 patients designed to assess the efficacy, safety and tolerability of sapablursen. The primary endpoint is Change in the frequency of phlebotomy
    comparing baseline with the last 20 weeks of the 37-week treatment period.</div>

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  <div style="text-align: justify; text-indent: 35.3pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">In December 2018, we presented positive data from our Phase 1 study of sapablursen in healthy volunteers at the American
    Society of Hematology Annual Meeting. The Phase 1 study demonstrated dose-dependent reductions of serum iron and serum transferrin saturation with sapablursen. Additionally, we observed an increase in serum hepcidin and predicted changes in hemoglobin
    and sapablursen had a favorable safety and tolerability profile supportive of continued development.</div>

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  <div style="text-align: justify; text-indent: 35.3pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Cimdelirsen (GHR) </span>&#8211;
    Cimdelirsen (formerly IONIS-GHR-L<sub>Rx</sub>) is an investigational LICA medicine we designed to inhibit the production of growth hormone receptor, or GHr, to decrease the circulating level of insulin-like growth factor-1, or IGF-1. Elevated levels
    of IGF-1 results in acromegaly, a chronic, slowly progressing and potentially fatal disease. Patients with acromegaly experience multiple chronic conditions, such as type 2 diabetes, hypertension, and respiratory complications and premature death.
    Current treatments to block IGF-1 are often unsuccessful. Drug treatments to normalize IGF-1 levels are also available but are associated with potentially serious side effects.</div>

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  <div style="text-align: justify; text-indent: 35.3pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">In January 2021, we initiated a Phase 2
      study of c</span>imdelirsen evaluating cimdelirsen as a monotherapy <span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">in patients with acromegaly. The Phase 2 study is a multi-center, randomized, open label
      study in approximately 40 patients to assess the efficacy, safety and tolerability of </span>cimdelirsen<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">.</span> The primary endpoint is the percent change
    from baseline in IGF-1 to week 27.</div>

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  <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">We completed a Phase 2 study evaluating
      cimdelirsen as an add-on therapy in patients with uncontrolled acromegaly despite stable therapy with long-acting somatostatin receptor ligands, or SRL. Based on the results of this Phase 2 study and a preliminary analysis of the ongoing open-label
      study, proof of mechanism was achieved with a strong indication of proof of concept supporting the continued development of cimdelirsen. Due to enrollment difficulties associated with the COVID-19 pandemic, the study closed early, resulting in
      smaller cohort sizes than planned. While no longer powered to assess the primary endpoint (percentage of IGF- lowering at Day 141) in accordance with the protocol, the study did permit placebo-controlled evaluation of safety and efficacy. </span>Cimdelirsen
    <span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">had a favorable safety and tolerability profile supportive of continued development.</span></div>

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  <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">We also </span>completed a Phase 1, blinded,
    placebo-controlled, dose-escalation study of cimdelirsen in healthy volunteers. In this study, cimdelirsen demonstrated a favorable safety and tolerability profile supporting continued development.</div>

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  <div style="text-align: justify; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic; font-weight: bold;"><a id="_Hlk33777473"><!--Anchor--></a>Other Medicines in Development</div>

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  <div style="text-align: justify; text-indent: 35.3pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We continue to advance other medicines in
      clinical development targeting metabolic diseases, infectious diseases, renal diseases, </span>ophthalmic diseases and cancer<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">.</span></div>

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  <div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">*China Only</div>

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  <div style="text-align: justify; text-indent: 35.3pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold; color: #000000;">ION224</span><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">&#160;</span><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold; color: #000000;">(DGAT)</span><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> &#8211; </span>ION224 is an investigational LICA medicine designed to reduce the production of DGAT2, or diacylglycerol acyltransferase 2, to treat patients with nonalcoholic steatohepatitis,
    or NASH. NASH is a common liver disease characterized by liver steatosis, inflammation and scarring and can lead to increased risk of cardiovascular disease, liver cancer, need for liver transplantation and early death. DGAT2 is an enzyme that
    catalyzes the final step in triglyceride synthesis in the liver. Reducing the production of DGAT2 should therefore decrease triglyceride synthesis in the liver. In animal studies, antisense inhibition of DGAT2 significantly improved liver steatosis,
    lowered blood lipid levels and reversed diet-induced insulin resistance.</div>

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  <div style="text-align: justify; text-indent: 35.3pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">NASH is sometimes considered a &#8220;silent&#8221; liver disease because people with early-stage NASH feel well, even though they are starting to
    accumulate fat in their livers and may not be aware that they have the disease. However, NASH can develop into more severe diseases such as liver cirrhosis and liver failure. Currently, liver transplant is the only therapeutic option for patients with
    liver cirrhosis. In addition, NASH has been shown to be a major risk factor for the development of liver cancer.</div>

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  <div style="text-align: justify; text-indent: 35.3pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Nonalcoholic fatty liver disease, or NAFLD, describes the full spectrum of liver disease progression from fatty liver to NASH to
    cirrhosis to hepatocellular carcinoma. NASH epidemiology studies have estimated 13 to 32 percent of the global population has NAFLD, 1.5 to 6.5 percent have NASH, and approximately 9 percent of NASH patients progress to advanced liver disease. There
    are currently no commercially available medications to treat NASH.</div>

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  <div style="text-align: justify; text-indent: 35.3pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">In June 2021, we initiated a Phase 2 study of ION224 in patients with <span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">confirmed non-alcoholic steatohepatitis. The Phase 2 study is </span>a multi-center, randomized, double-blind, placebo-controlled clinical study enrolling approximately 150 patients<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> designed to assess the efficacy, safety and tolerability of multiple </span>subcutaneous<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">
      doses of ION224 on NASH histologic improvement.</span></div>

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  <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Bepirovirsen (HBV) </span>(GSK3228836)<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"> &#8211; </span>Bepirovirsen (formerly IONIS-HBV<sub>Rx</sub>) is an investigational antisense medicine we designed to inhibit the production of viral proteins
    associated with hepatitis B virus, or HBV. These include proteins associated with infection and replication, including the hepatitis B surface antigen, or HBsAg, which is present in both acute and chronic infections and is associated with a poor
    prognosis in people with chronic HBV infection.</div>

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  <div style="text-align: justify; text-indent: 35.3pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">HBV infection is a serious health problem that can lead to significant and potentially fatal health conditions,
    including cirrhosis, liver failure and liver cancer. Chronic HBV infection is one of the most common persistent viral infections in the world. Currently available therapies, although effective in reducing circulating HBV in the blood, do not
    effectively inhibit HBV antigen production and secretion, which are associated with poor prognosis and increased risk of liver cancer.</div>

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  <div style="text-align: justify; text-indent: 35.3pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">GSK is conducting a broad Phase 2 program for bepirovirsen. The B-Clear study is a Phase 2b randomized, double-blinded,
    placebo-controlled study in approximately 440 patients with chronic HBV. The primary endpoint is the percentage of patients achieving HBV surface antigen and HBV DNA less than the lower limit of quantitation. <span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">Additionally, GSK is conducting</span> two open label Phase 2 studies and a long-term follow up study in patients with chronic HBV.</div>

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  <div style="text-align: justify; text-indent: 35.3pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">In November 2019, GSK reported results of the Phase 2a study of bepirovirsen<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">&#160;</span>in patients with chronic HBV infection at the American Association for the Study of Liver Diseases annual meeting. In the Phase 2a study, bepirovirsen demonstrated target engagement with dose
    dependent declines in HBsAg with up to 3-log reductions in HBsAg at one month, including two patients who achieved reductions in HBsAg and HBV DNA below levels of detection. Additionally, bepirovirsen <span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">had a favorable safety and tolerability profile supportive of continued development.</span></div>

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  <div style="text-align: justify; text-indent: 35.3pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">In August 2019, GSK exercised its option to license our HBV program following the positive Phase 2 results described above. As a result,
    GSK is responsible for global development, regulatory and commercialization activities, and costs for the HBV program.</div>

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  <div style="text-align: justify; text-indent: 35.3pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">IONIS-FB-L</span><sub style="font-weight: bold;">Rx</sub> &#8211; <span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">IONIS-FB-L</span><sub style="color: #000000;">Rx</sub><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> is an investigational LICA medicine we designed to inhibit the production of complement factor B, or FB. Genetic association studies have shown that overaction of this cascade has been associated with the development
      of several complement-mediated diseases, including IgA nephropathy, or IgAN, and dry age-related macular degeneration, or AMD.</span></div>

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  <div style="text-align: justify; text-indent: 35.3pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">IgAN is one of the most common causes of inflammation that impairs the filtering ability of kidneys and is an important
    cause of chronic kidney disease and renal failure. Also known as Berger&#8217;s disease, IgAN is characterized by deposits of IgA in the kidneys, resulting in inflammation and tissue damage.</div>

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  <div style="text-align: justify; text-indent: 35.3pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">AMD is the leading cause of central vision loss in developed countries. It is estimated that the disease will affect
    more than three million people in the U.S. by 2026. AMD is believed to be a systemic disease with local disease manifestation at the aging retinal macula. AMD gradually destroys vision in the center of the visual field due to progressive damage of the
    retina. Geographic atrophy, or GA, is an advanced form of AMD and accounts for approximately fifteen percent of all patients with cases of AMD.</div>

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  <div style="text-align: justify; text-indent: 35.3pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">In September 2019, we initiated a Phase 2
      study of IONIS-FB-L</span><sub style="color: #000000;">Rx</sub><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> in patients with IgA nephropathy. The Phase 2 study is a single-arm, open-label study
      designed to assess the efficacy, safety and tolerability of IONIS-FB-L</span><sub style="color: #000000;">Rx</sub><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> administered subcutaneously in adults with
      primary IgA nephropathy.</span> The primary endpoint is the percent reduction in 24-hour urine protein excretion from baseline to week 29.</div>

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  <div style="text-align: justify; text-indent: 35.3pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">In May 2017, we reported data from a Phase
      1 study evaluating IONIS-FB-L</span><sub style="color: #000000;">Rx</sub><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> in 54 healthy volunteers. The Phase 1 study was a randomized, placebo-controlled,
      dose-escalation study. Subjects were treated with a single dose of IONIS-FB-L</span><sub style="color: #000000;">Rx</sub><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> achieved dose-dependent reductions
      in plasma FB of up to 50 percent. Treatment with multiple doses of IONIS-FB-L</span><sub style="color: #000000;">Rx</sub><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> during a six-week period resulted
      in greater reductions in circulating FB levels. IONIS-FB-L</span><sub style="color: #000000;">Rx</sub><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> had a favorable safety and tolerability profile
      supportive of continued development.</span></div>

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  <div style="text-align: justify; text-indent: 35.3pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">In June 2019, we initiated a Phase 2 study
      evaluating IONIS-FB-L</span><sub style="color: #000000;">Rx</sub><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> in patients with GA secondary to age-related macular degeneration. The study is a
      randomized, masked, placebo-controlled study designed to assess the efficacy, safety and tolerability of multiple ascending doses of IONIS-FB-L</span><sub style="color: #000000;">Rx</sub><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> administered subcutaneously in adults with GA.</span> The primary endpoint is the absolute change from baseline in GA area at week 49.</div>

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  <div style="text-align: justify; text-indent: 35.3pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">IONIS-FB-L<sub>Rx</sub> is being developed under our collaboration with Roche.</div>

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  <div style="text-align: justify; text-indent: 35.3pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">IONIS-GCGR</span><sub style="font-weight: bold;">Rx</sub> &#8211; IONIS-GCGR<sub>Rx</sub> is an investigational antisense medicine designed to inhibit the production of the glucagon receptor, or GCGR, to treat patients with type 2 diabetes. GCGR is a receptor for the hormone
    glucagon. Glucagon is a hormone that opposes the action of insulin and stimulates the liver to produce glucose, particularly in type 2 diabetes. In patients with advanced diabetes, uncontrolled glucagon action can lead to significant increase in blood
    glucose level. In addition, reducing GCGR produces more active glucagon-like peptide, or GLP-1, a hormone that preserves pancreatic function and enhances insulin secretion.</div>

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  <div style="text-align: justify; text-indent: 35.3pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Diabetes is a chronic disease in which the blood glucose levels are too high. Although glucose is an important source of energy for your
    body and is vital to your health, uncontrolled increases in glucose can lead to serious health problems, such as diabetes. Diabetes is separated into type 1 and type 2. In type 1 diabetes, the body does not make insulin. In type 2 diabetes, the more
    common type, the body does not respond properly to insulin and, therefore, blood glucose levels are not adequately controlled.</div>

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  <div style="text-align: justify; text-indent: 35.3pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">In October 2019, Suzhou-Ribo initiated a Phase 2 clinical study evaluating IONIS-GCGR<sub>Rx</sub> in patients with type 2 diabetes.</div>

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  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">ION357 (RHO) (</span>QR-1123)
    <span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">&#8211; </span>ION357 (formerly IONIS-RHO-2.5<sub>Rx</sub>), is an investigational antisense medicine we designed to treat patients with a genetic form of
    autosomal dominant retinitis pigmentosa by inhibiting the production of the rhodopsin P23H mutant protein in the eye while allowing normal protein to be expressed.</div>

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  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Retinitis pigmentosa, or RP, is a group of rare inherited eye disorders causing photoreceptor degeneration that leads to
    progressive vision loss. Photoreceptors are cells in the eye&#8217;s retina responsible for converting light into signals that are sent to the brain. Photoreceptors provide us our color and night vision. Affected patients first experience defective dark
    adaptation during adolescence or young adulthood, followed by loss of peripheral visual field. Patients eventually have limited residual central vision, which ultimately leads to complete blindness around the age of 60.</div>

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  <div style="text-align: justify; text-indent: 35.3pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">In November 2019, ProQR initiated a Phase 1/2 clinical study evaluating <span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">ION357</span> in patients with RP. The Phase 1/2 study is a randomized, masked, placebo-controlled study designed to assess the safety, tolerability and activity of <span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">ION357</span> in adult patients with RP.</div>

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  <div style="text-align: justify; text-indent: 35.3pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">In the fourth quarter of 2018, we licensed ION357 to ProQR. As a result, ProQR is responsible for global development,
    regulatory and commercialization activities, and costs for ION357.</div>

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  <div style="text-align: justify; text-indent: 35.3pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">ION736 (FOXP3)</span>
    (AZD8701) &#8211; ION736, is an investigational antisense medicine designed to reduce the production of Forkhead Box P3, or FOXP3, for the treatment of patients with cancer. FOXP3 is a protein involved in the function of immuno-suppressive T regulatory cells
    (Tregs). Tregs, which are found at high levels in various types of cancers, often predict poor survival and poor response to immune checkpoint therapeutics. Preclinical studies have demonstrated that FOXP3 downregulation resulted in an increased immune
    response and anti-tumor activity. Moreover, the combination of antisense inhibition of FOXP3 with other immuno-oncology drugs led to enhanced anti-tumor activity.</div>

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  <div style="text-align: justify; text-indent: 35.3pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">In August 2020, AstraZeneca initiated a first-in-human open label study of ION736 in patients with select advanced solid
    tumors. The study is a multi-center, open label multi-arm study in approximately 123 patients designed to evaluate the efficacy, safety and tolerability of ION736 administered intravenously as monotherapy and in combination with durvaluamb (MEDI4736)
    in patients with advanced solid tumors.</div>

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  <div style="text-align: justify; text-indent: 35.3pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">In the second quarter of 2020, we licensed ION736 to AstraZeneca. As a result, AstraZeneca is responsible for global
    development, regulatory and commercialization activities, and costs for ION736.</div>

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  <div style="text-align: justify; text-indent: 35.3pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">IONIS-AR-2.5</span><sub style="font-weight: bold;">Rx</sub><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"> &#8211;</span> IONIS-AR-2.5<sub>Rx</sub> is an investigational antisense medicine we designed to treat people with prostate
    cancer by reducing the production of all known forms of androgen receptor, or AR, including variants of the <span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">AR</span> gene. Prostate cancer is the second
    leading cause of cancer deaths in American men. Prostate cancer growth, proliferation and progression are all androgen-dependent and AR function is involved in disease progression at all stages of prostate cancer. For patients diagnosed with metastatic
    prostate cancer, current treatments largely involve opposing the action of androgens by blocking the androgen receptor or removing circulating androgens. Resistance to current therapies is frequent.</div>

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  <div style="text-align: justify; text-indent: 35.3pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">An open-label, dose-escalation, Phase 1/2 clinical study of IONIS-AR-2.5<sub>Rx</sub> was completed in people with
    advanced tumors for which the androgen receptor pathway is potentially a contributing factor. The study was primarily conducted in prostate cancer patients, and it showed durable responses in a number of those patients. IONIS-AR-2.5<sub>Rx</sub> had a
    safety and tolerability profile supportive of continued development.</div>

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  <div style="text-align: justify; text-indent: 35.3pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">In March 2017, we licensed IONIS-AR-2.5<sub>Rx</sub> to Suzhou-Ribo to develop and commercialize the medicine in China.
    In the third quarter of 2021, we entered into a license agreement with Flamingo Therapeutics for the development and commercialization of certain programs from Ionis&#8217; oncology pipeline, including IONIS-AR-2.5<sub>Rx </sub>outside of China.</div>

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  <div style="text-align: justify; text-indent: 35.3pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Danvatirsen (STAT3) &#8211; </span>Danvatirsen
    (formerly IONIS-STAT3-2.5<sub>Rx</sub>) is an investigational antisense medicine we designed to inhibit the production of signal transducer and activator of transcription 3, or STAT3, to treat people with cancer. STAT3 is a protein involved in the
    translation of key factors critical for tumor cell growth and survival. STAT3 is over-active in a variety of cancers, including brain, lung, breast, bone, liver, and multiple myeloma. Overactivity in STAT3 prevents cancer cell death and promotes tumor
    cell growth.</div>

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  <div style="text-align: justify; text-indent: 35.3pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">In October 2018, we reported data from a Phase 1/2 study of danvatirsen in combination with durvalumab in recurrent
    metastatic head and neck cancer. The combination treatment resulted in seven percent of patients achieving a complete tumor response and 23 percent achieving either a partial or complete tumor response. This response rate is estimated to be double that
    with durvalumab alone, based on previous studies in this difficult to treat patient population. Danvatirsen had a safety and tolerability profile supportive of continued development.</div>

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  <div style="text-align: justify; text-indent: 35.3pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">In the third quarter of 2021, we entered into a license agreement with Flamingo Therapeutics for the development and
    commercialization of certain programs from Ionis&#8217; oncology pipeline, including danvatirsen.</div>

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  <div style="text-align: justify; text-indent: 35.3pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic; font-weight: bold;">Phase 1 Medicines in Clinical Development</div>

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  <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Our early-stage pipeline is comprised of medicines to treat a number of diseases, including from our cardiovascular franchise. It includes
    medicines based on our latest technology advancements. As we continue to add new investigational medicines to our pipeline, we believe these medicines have the potential to expand our mid and late-stage pipelines.</div>

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  <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#160;<img width="571" height="317" src="image08.jpg" alt="graphic" /></div>

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  <div style="text-align: justify; text-indent: 35.3pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Antisense Technology</div>

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  <div style="text-align: justify; text-indent: 35.3pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Our antisense technology is an innovative platform for discovering first-in-class and/or best-in-class medicines.
    Antisense medicines target RNA, the intermediary that conveys genetic information from a gene to the protein synthesis machinery in the cell. By targeting RNA instead of proteins, we can use antisense technology to increase, decrease or alter the
    production of specific proteins. The unique properties of antisense technology provide several advantages over other drug discovery technologies.</div>

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  <div style="text-align: left; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">These advantages include:</div>

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    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Direct intervention in the disease process at the genetic level by targeting RNA: antisense technology represents a direct route from gene to drug. The
            explosion in genomic information and RNA biology has led to the discovery of many new disease-causing proteins and RNAs and has created new opportunities that are uniquely accessible by antisense technology.</div>
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    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Precise specificity: we design antisense medicines to target a single RNA, minimizing the possibility of binding to unintended targets, which can cause
            unwanted side effects.</div>
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    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Good drug properties: antisense medicines distribute well throughout the body. They also have a long half-life, in the range of weeks to months, which
            means patients and/or healthcare providers can dose our medicines weekly, monthly or even less frequently depending on the medicine and target tissue.</div>
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    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

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          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Ability to combine with other medicines: because antisense medicines do not interact with the enzymes that metabolize or break down other medicines,
            physicians can use our medicines in combination with other medicines.</div>
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    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Broad applications to multiple disease targets, multiple tissues and multiple mechanisms: there are virtually no &#8220;undruggable&#8221; targets with antisense
            technology.</div>
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    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Efficient discovery and early development: because of the efficiency of our antisense technology, our drug discovery and early development costs and
            success rates compare favorably to small molecule or antibody drug discovery and development.</div>
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  <div style="text-align: justify; text-indent: 35.3pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We develop antisense medicines we believe will pioneer new markets and change standards of care. Our areas of focus
    include cardiovascular and neurological diseases.</div>

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  <div style="text-align: justify; text-indent: 35.3pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic; font-weight: bold;">Technology Overview</div>

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  <div style="text-align: justify; text-indent: 35.3pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We use our core technology platform to discover and develop medicines that affect targets in the body at the genetic
    level. Genes contain the information necessary to produce proteins. A gene is made up of nucleotides containing the nucleoside bases: adenine, thymine, guanine, and cytosine, commonly known as A, T, G and C, which are linked together to form a
    two-stranded structure that resembles a twisted ladder, known as DNA. The nucleotides on one side of the ladder bind weakly to complementary nucleotides on the other strand according to specific rules; for example, A pairs with T and G pairs with C,
    creating the ladder&#8217;s rungs (Figure 1). Scientists call this highly specific nucleotide pairing hybridization. The sequence or order of these nucleotides establishes the cell&#8217;s recipes for making proteins. Each protein&#8217;s instructions reside in a
    corresponding segment of DNA known as a gene.</div>

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  <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Figure 1: Illustration of DNA.</div>

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  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">The instructions for making a protein are transcribed from a gene, or DNA, into a different genetic molecule called
    messenger RNA. This process starts with the partial uncoiling of the two complementary strands of the DNA. One strand acts as a template and information stored in the DNA template strand is copied into a complementary RNA (Figure 2) by an enzyme called
    RNA polymerase, or RNAP. Messenger RNA, or mRNA, are mature, fully processed RNA that code for proteins.</div>

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  <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Figure 2: Transcription of information contained in a gene, or DNA, to RNA.</div>

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  <div style="text-align: justify; text-indent: 35.3pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Ribosomes, the cell&#8217;s factories for manufacturing proteins, translate mRNA into proteins. The ribosome reads the encoded
    information, the mRNA&#8217;s nucleotide sequence, and in doing so, strings together amino acids to form a specific protein (Figure 3).</div>

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  <div style="text-align: center;"><img width="497" height="427" src="image10.jpg" alt="graphic" /></div>

  <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Figure 3: Translation of the protein-coding information contained in mRNA to protein.</div>

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  <div style="text-align: justify; text-indent: 35.3pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We primarily use our antisense technology to interrupt the cell&#8217;s protein production process by preventing the mRNA
    instructions from reaching the ribosome, thus inhibiting the production of the protein. We can also design antisense medicines to increase protein production for diseases caused by the lack of a particular protein or modify the processing (or splicing)
    of the mRNA, which can alter the composition of the protein. The mRNA sequence of nucleotides that carries the information for protein production is called the &#8216;sense&#8217; strand. Scientists call the complementary nucleotide chain that binds specifically
    to the sense strand the &#8220;antisense&#8221; strand. We use the information contained in mRNA to design chemical structures, that we call antisense oligonucleotides, or ASOs, or antisense medicines, which resemble DNA and RNA and are the complement of RNA. Our
    antisense medicines bind with high selectivity to the mRNA they were designed to target. Since each mRNA codes for a specific protein, we can design antisense medicines that selectively inhibit the disease-causing member of a protein family without
    interfering with other members of the protein family that might be necessary for normal cellular or bodily functions. This unique specificity means that antisense medicines may be less toxic than traditional medicines because we can design them to
    minimize the impact on unintended targets.</div>

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  <div style="text-align: justify; text-indent: 35.3pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We have developed the majority of the medicines in our pipeline using our advanced screening methods to produce medicines with what we
    believe have strong safety and tolerability profiles. We continue to advance our antisense technology to create even more potent medicines that we can use in more tissues and against more targets. These advances allow us to expand the mechanisms
    through which we can use our medicines and provide us with greater opportunities to use our antisense medicines to treat a greater number of diseases and reach more patients. Today our medicines and those entering our pipeline utilize our key
    technology advances, including our Generation 2.5 and our LICA technology.</div>

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  <div style="text-align: justify; text-indent: 35.3pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Generation 2.5 chemistry, used in several medicines in our pipeline, enables up to 10-fold greater potency compared to
    our medicines using our earlier chemistries. This increased potency enables broad distribution throughout the body and target engagement to multiple tissues including liver, kidney, lung, muscle, adipose, adrenal gland, peripheral nerves and tumor
    tissues.</div>

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  <div style="text-align: justify; text-indent: 35.3pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">LICA is a chemical technology we developed that involves attaching a molecule called a ligand that binds with receptors
    on the surfaces of cells in a highly specific manner. Because these receptors are often found only on certain cell types, LICA allows us to increase effective delivery of our antisense medicines with higher specificity to certain cell types that
    express these receptors relative to non-conjugated antisense medicines. As of December 2021, we have an integrated assessment of data from multiple LICA medicines and clinical programs which demonstrates that our LICA technology for liver targets can
    increase potency by 20-30-fold over our non-LICA antisense medicines.</div>

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  <div style="text-align: justify; text-indent: 35.3pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">In addition to the increase in potency, our LICA platform has consistently demonstrated favorable safety and
    tolerability. Pelacarsen exemplifies these improvements. We designed this medicine to reduce the production of Apo(a) protein in the liver to offer a direct approach for reducing Lp(a). Pelacarsen was the first medicine to selectively and robustly
    reduce Lp(a) levels below threshold levels associated with CVD in nearly all patients and demonstrated a favorable safety and tolerability profile in the Phase 2 study. The study included more than 280 patients, with 98 percent of patients in the high
    dose group achieving levels below 50 mg/dL, the recognized risk threshold for CVD.</div>

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  <div style="text-align: justify; text-indent: 35.3pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We can also combine our LICA technology with our Generation 2.5 chemistry, further increasing potency. In addition to
    the LICA technology for liver targets, we are also developing LICA conjugation technology that we can use to target other tissues, such as pancreas and muscle, and initial results in animals are promising.</div>

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  <div style="text-align: justify; text-indent: 35.3pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic; font-weight: bold;">Antisense Targets and Mechanisms</div>

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  <div style="text-align: justify; text-indent: 35.3pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">There are more than a dozen different antisense mechanisms that we can utilize with our antisense technology. The
    majority of the medicines in our pipeline bind to mRNAs and inhibit the production of disease-causing proteins. However, our antisense technology is broadly applicable to many different antisense mechanisms, including modulation of RNA splicing, RNA
    interference, or RNAi, and enhancing protein translation to increase protein production.</div>

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  <div style="text-align: justify; text-indent: 35.3pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">When using antisense technology to inhibit the production of disease-causing proteins or reduce levels of harmful RNAs,
    our antisense medicines bind to the target RNA via highly specific nucleotide pairing, or hybridization, and recruit a cellular enzyme called ribonuclease H1, or RNase H1, to degrade the target RNA. The antisense medicine itself remains intact during
    this process, so it can remain active against additional target RNA molecules and repeatedly trigger their degradation (Figure 4). Examples of our antisense medicines that use the RNase H1 mechanism to reduce disease protein production include,
    TEGSEDI, WAYLIVRA, eplontersen, olezarsen, donidalorsen, ION363, pelacarsen, tofersen and others.</div>

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  <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Figure 4: Antisense medicine using the RNase H mechanism of action.</div>

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  <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">SPINRAZA is an example of an antisense medicine that modulates RNA splicing to increase protein production of the SMN protein (Figure 5),
    which is critical to the health and survival of nerve cells in the spinal cord that are responsible for neuro-muscular function. The SMN protein is deficient in people with SMA.</div>

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  <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Figure 5: Antisense medicine altering splicing of the SMN2 mRNA.</div>

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  <div style="text-align: justify; text-indent: 35.3pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We are also making progress in designing antisense medicines to target long, non-coding RNAs, or lncRNAs and RNAs that
    possess a toxic function in human diseases. Many of these RNAs, such as lncRNAs, do not make proteins but often cause disease by regulating the function of other genes or proteins. In 2014, we published a paper in <span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Nature</span> in which we were the first to show that targeted reduction of a lncRNA with an antisense compound can ameliorate certain cognitive deficits in a mouse model of Angelman
    syndrome, or AS. In 2021, we initiated the HALOS study, a Phase 1/2a study of ION582 in patients with AS.</div>

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  <div style="text-align: justify; text-indent: 35.3pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Because the efficiency of our core technology platform can support multiple target-based antisense research programs, we
    can develop antisense medicines to target a broad range of diseases, efficiently producing a large and broad proprietary portfolio of medicines. We are currently pursuing antisense drug discovery programs focused on neurological, cardiovascular, and
    other diseases.</div>

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  <div style="text-align: left; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic; font-weight: bold;">Collaborative Arrangements</div>

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  <div>
    <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We have established alliances with a cadre of leading global pharmaceutical companies. Our partners include the
      following companies, among others: AstraZeneca, Bayer, Biogen, GSK, Novartis, and Roche. Through our partnerships, we have earned both commercial revenue and a broad and sustaining base of R&amp;D revenue in the form of license fees, upfront payments
      and milestone payments. In 2021, we recognized $810 million in revenue, the majority of which was from our partnered medicines and programs. We have the potential to earn more than $24 billion in future milestone payments, licensing fees and other
      payments from our current partnerships. In addition, we are eligible to receive up to mid-20 percent royalties under certain partnerships. Below, we include the significant terms of our collaboration agreements. For additional details, including
      other financial information, see Note 6, <span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Collaborative Arrangements and Licensing Agreements,</span> in the Notes to the Consolidated Financial
      Statements.</div>

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  <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Strategic Partnership</div>

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    <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;">Biogen</div>

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  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We have several strategic collaborations with Biogen focused on using antisense technology to advance the treatment of
    neurological disorders. These collaborations combine our expertise in creating antisense medicines with Biogen&#8217;s expertise in developing therapies for neurological disorders. We developed and licensed to Biogen SPINRAZA, our approved medicine to treat
    people with SMA. We and Biogen are currently developing nine investigational medicines to treat neurodegenerative diseases under these collaborations, including medicines in development to treat people with ALS, SMA, AS, Alzheimer&#8217;s disease<sub>&#160;</sub>and
    Parkinson&#8217;s disease. In addition to these medicines, our collaborations with Biogen include a substantial research pipeline that addresses a broad range of neurological diseases. From inception through December 2021, we have received $3.2 billion from
    our Biogen collaborations.</div>

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  <div>
    <div style="text-align: left; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic; font-weight: bold;">Spinal Muscular Atrophy Collaborations</div>

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    <div style="text-align: left; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;">SPINRAZA</div>

    <div><br />
    </div>

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  <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">In January 2012, we entered into a
      collaboration agreement with Biogen to develop and commercialize SPINRAZA, an RNA-targeted therapy for the treatment of SMA.</span>&#160;<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">From inception through
      December 2021, we generated more than $</span>1.6<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">
      billion in total revenue under our SPINRAZA collaboration, including nearly $1.2 billion in revenue from SPINRAZA royalties and more than $435 million in R&amp;D revenue. We are receiving tiered royalties ranging from 11 percent to 15 percent on
      sales of SPINRAZA. We have exclusively in-licensed patents related to SPINRAZA from Cold Spring Harbor Laboratory and the University of Massachusetts. We pay Cold Spring Harbor Laboratory and the University of Massachusetts a low single digit royalty
      on net sales of SPINRAZA. Biogen is responsible for global development, regulatory and commercialization activities and costs for SPINRAZA.</span></div>

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  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;"><a id="_Hlk94884711"><!--Anchor--></a>New antisense medicines for the treatment of SMA</div>

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  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">In December 2017, we entered into a collaboration agreement with Biogen to identify new antisense medicines for the
    treatment of SMA. Biogen has the option to license therapies arising out of this collaboration following the completion of preclinical studies. Upon licensing, Biogen will be responsible for global development, regulatory and commercialization
    activities and costs for such therapies. Under the collaboration agreement, we received a $25 million upfront payment in December 2017. In December 2021, we earned a $60 million license fee payment when Biogen exercised its option to license ION306. <span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Biogen is solely responsible for the costs and expenses related to the development, manufacturing and potential future commercialization of ION306 following the option exercise.</span></div>

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  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We will receive development and regulatory milestone payments from Biogen if new medicines advance towards marketing
    approval. In total over the term of our collaboration, we are eligible to receive up to $1.2 billion in license fees, milestone payments and other payments, including up to $555 million if Biogen advances ION306. In addition, we are eligible to receive
    tiered royalties from the mid-teens to mid-20 percent range on net sales from any product that Biogen successfully commercializes under this collaboration.</div>

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  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic; font-weight: bold;">Neurology Collaborations</div>

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  <div style="text-align: left; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;">2018 Strategic Neurology</div>

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  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">In April 2018, we and Biogen entered into a strategic collaboration to develop novel antisense medicines for a broad range
    of neurological diseases and entered into a Stock Purchase Agreement, or SPA. As part of the collaboration, Biogen gained exclusive rights to the use of our antisense technology to develop therapies for these diseases for 10 years. We are responsible
    for the identification of antisense drug candidates based on selected targets. Biogen is responsible for conducting IND-enabling toxicology studies for the selected medicine. Biogen will have the option to license the selected medicine after it
    completes the IND-enabling toxicology study. If Biogen exercises its option to license a medicine, it will assume global development, regulatory and commercialization responsibilities and costs for that medicine.</div>

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  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">In June 2018, we received $1 billion from Biogen, comprised of $625 million to purchase our stock at an approximately 25
    percent cash premium and $375 million in an upfront payment. We are eligible to receive up to $270 million in milestone payments for each medicine that achieves marketing approval. In addition, we are eligible to receive tiered royalties up to the 20
    percent range on net sales from any product that Biogen successfully commercializes under this collaboration. We are currently advancing nine programs under this collaboration and through December 2021, we have generated nearly $1.1 billion in
    payments, including $23 million in milestone payments generated in 2021 when Biogen advanced three programs under this collaboration.</div>

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  <div style="text-align: left; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;">2013 Strategic Neurology</div>

  <div><br />
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  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">In September 2013, we and Biogen entered into a long-term strategic relationship focused on applying antisense technology
    to advance the treatment of neurodegenerative diseases. As part of the collaboration, Biogen gained exclusive rights to the use of our antisense technology to develop therapies for neurological diseases and has the option to license medicines resulting
    from this collaboration. We will usually be responsible for drug discovery and early development of antisense medicines and Biogen will have the option to license antisense medicines after Phase 2 proof-of-concept. In October 2016, we expanded our
    collaboration to include additional research activities we will perform. If Biogen exercises its option to license a medicine, it will assume global development, regulatory and commercialization responsibilities and costs for that medicine. We are
    currently advancing six investigational medicines in development under this collaboration, including a medicine for Parkinson&#8217;s disease, three medicines for ALS, a medicine for multiple system atrophy and a medicine for an undisclosed target. In
    December 2018, Biogen exercised its option to license our most advanced ALS medicine, tofersen, and as a result Biogen is now responsible for global development, regulatory and commercialization activities and costs for tofersen.</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Under the terms of the agreement, we received an upfront payment of $100 million and are eligible to receive milestone
    payments, license fees and royalty payments for all medicines developed under this collaboration, with the specific amounts dependent upon the modality of the molecule advanced by Biogen. For each antisense molecule that is chosen for drug discovery
    and development under this collaboration, we are eligible to receive up to approximately $260 million in a license fee and milestone payments. In addition, we are eligible to receive tiered royalties up to the mid-teens on net sales from any product
    that Biogen successfully commercializes under this collaboration. Through December 2021, we have generated over $280 million under this collaboration, including $10 million we received from Biogen in 2021 when Biogen advanced ION541, an investigational
    medicine targeting ATXN2 to treat patients with ALS.</div>

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    </div>

  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;">2012 Neurology</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">In December 2012, we and Biogen entered into a collaboration agreement to develop and commercialize novel antisense
    medicines to treat neurodegenerative diseases. We are responsible for the development of each of the medicines through the completion of the initial Phase 2 clinical study for such medicine. Biogen has the option to license a medicine from each of the
    programs through the completion of the first Phase 2 study for each program. Under this collaboration, we are currently advancing IONIS-MAPT<sub>Rx</sub> for Alzheimer&#8217;s disease and ION582 for AS. If Biogen exercises its option to license a medicine,
    it will assume global development, regulatory and commercialization responsibilities and costs for that medicine. In December 2019, Biogen exercised its option to license IONIS-MAPT<sub>Rx</sub> and as a result Biogen is now responsible for global
    development, regulatory and commercialization activities and costs for IONIS-MAPT<sub>Rx</sub>.</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Under the terms of the agreement, we received an upfront payment of $30 million. Over the term of the collaboration, we
    are eligible to receive up to $210 million in a license fee and milestone payments per program, plus a mark-up on the cost estimate of the Phase 1 and 2 studies. In addition, we are eligible to receive tiered royalties up to the mid-teens on net sales
    from any product that Biogen successfully commercializes under this collaboration. Through December 2021, we have generated over $165 million under our collaboration, including $10 million we received from Biogen for advancing ION582 during 2021.</div>

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  <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Joint Development and Commercialization Arrangement</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;">AstraZeneca</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;">Eplontersen Collaboration</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">In December 2021, we entered into a joint development and commercialization agreement with AstraZeneca to develop and
    commercialize eplontersen for the treatment of ATTR. We are jointly developing and preparing to commercialize eplontersen with AstraZeneca in the U.S. AstraZeneca obtained exclusive rights to commercialize eplontersen outside the U.S., except certain
    countries in Latin America. Under the terms of the agreement, we received a $200 million upfront payment. We are eligible to receive up to $485 million in development and approval milestones, and up to $2.9 billion in sales-related milestone payments.
    In addition, we are eligible to receive up to mid-20 percent royalties for sales in the U.S. and tiered royalties up to the high teens for sales outside the U.S.</div>

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  <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">The collaboration also includes
      territory-specific development, commercial and medical affairs cost-sharing provisions. AstraZeneca will pay 55 percent of the costs associated with the ongoing global Phase 3 development program. As we will continue to lead the Phase 3 development
      program, we will recognize as revenue the 55 percent of cost-share funding AstraZeneca is responsible for in the same period we incur the related development expenses. As AstraZeneca is responsible for the majority of the commercial and medical
      affairs costs in the U.S. and all costs associated with bringing eplontersen to market outside the U.S., we will recognize cost-share funding we receive from AstraZeneca related to these activities as a reduction of our commercial and medical affairs
      expenses. Through December 2021, we have generated $200 million in payments under this collaboration</span><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">.</span></div>

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  <div style="text-align: justify; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Research and Development Partners</div>

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  <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;">AstraZeneca</div>

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  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">In addition to our collaboration for eplontersen, we have two other collaborations with AstraZeneca. One is focused on the
    treatment of cardiovascular, renal and metabolic diseases and the other is focused on the treatment of oncology diseases. We and AstraZeneca are currently developing six medicines under these collaborations. From inception through December 2021, we
    have generated nearly $425 million from our AstraZeneca research and development collaborations.</div>

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  <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;">Cardiovascular, Renal and Metabolic Diseases Collaboration</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">In July 2015, we and AstraZeneca formed a collaboration to discover and develop antisense therapies for treating
    cardiovascular, renal and metabolic diseases. Under our collaboration, AstraZeneca has licensed five medicines from us. AstraZeneca is responsible for global development, regulatory and commercialization activities and costs for each of the medicines
    it has licensed.</div>

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  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Under the terms of the agreement, we received a $65 million upfront payment. We are eligible to receive license fees and
    milestone payments of up to more than $5.5 billion as medicines under this collaboration advance. In addition, we are eligible to receive tiered royalties up to the low teens on net sales from any product that AstraZeneca successfully commercializes
    under this collaboration agreement. Through December 2021, we have generated over $280 million in payments, including $40 million we earned in 2021 for two targets that AstraZeneca is advancing for a metabolic disease.</div>

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    <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;">Oncology Collaboration</div>

    <div><br />
    </div>

  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">In December 2012, we entered into a collaboration agreement with AstraZeneca to discover and develop antisense medicines
    to treat cancer. We and AstraZeneca also established an oncology research program. In 2020, AstraZeneca licensed ION736, an investigational medicine in development targeting FOXP3 for the treatment of cancer. AstraZeneca is responsible for global
    development, regulatory and commercialization activities and costs for ION736.</div>

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    </div>

  </div>

  <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">Under the terms of this agreement, we
      received $31 million in upfront payments. We are eligible to receive license fees and milestone payments of up to more than $265 million as this collaboration advances. In addition, we are eligible to receive tiered royalties up to the low teens on
      net sales from any product that AstraZeneca successfully commercializes under this collaboration agreement. Through December 2021, we have generated over $140 million in payments under this collaboration, including $13 million we earned in 2020 when
      AstraZeneca licensed ION736</span>.</div>

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  <div>
    <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;">Bayer</div>

  </div>

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    </div>

  </div>

  <div>
    <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">In May 2015, we entered into an exclusive license agreement with Bayer to develop and commercialize IONIS-FXI<sub>Rx</sub>
      for the prevention of thrombosis and we received a $100 million upfront payment. In February 2017, we amended our agreement with Bayer to advance IONIS-FXI<sub>Rx</sub> and to initiate development of fesomersen (formerly IONIS-FXI-L<sub>Rx</sub>),
      which Bayer licensed. In conjunction with the amendment, we received a $75 million payment. In October 2019, Bayer decided to advance fesomersen following positive clinical results. Bayer is now responsible for all global development, regulatory and
      commercialization activities and costs for the FXI program. We are eligible to receive additional milestone payments as the FXI program advances toward the market. Over the term of the collaboration, we are eligible to receive up to $385 million in
      license fees, milestone payments and other payments. In addition, we are eligible to receive tiered royalties in the low to high 20 percent range on gross margins of both medicines combined. Through December 2021, we have generated over $190 million
      under this collaboration.</div>

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  <div>
    <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;">GSK</div>

    <div><br />
    </div>

  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">In March 2010, we entered into an alliance with GSK using our antisense drug discovery platform to discover and develop
    new medicines against targets for serious and rare diseases, including infectious diseases and some conditions causing blindness. Under the collaboration, we received upfront payments of $35 million. Our collaboration with GSK covers bepirovirsen<sub>,</sub>
    an investigational antisense medicine we designed to reduce the production of viral proteins associated with HBV infection. In 2019, following positive Phase 2 results, GSK licensed our HBV program. GSK is responsible for all global development,
    regulatory and commercialization activities and costs for the HBV program.</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Under our agreement, if GSK successfully develops bepirovirsen and achieves pre-agreed sales targets, we could receive
    license fees and milestone payments of more than $260 million. In addition, we are eligible to receive tiered royalties up to the mid-teens on net sales from any product that GSK successfully commercializes under this alliance. Through December 2021,
    we have generated over $185 million in payments under our collaboration.</div>

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  <div>
    <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;">Novartis</div>

  </div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">In January 2017, we initiated a collaboration
      with Novartis to develop and commercialize pelacarsen. </span>We received a $75 million upfront payment in February 2017. <span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">In February 2019, Novartis
      licensed pelacarsen</span> and we earned a $150 million license fee. Novartis is responsible for conducting and funding future development and regulatory activities for pelacarsen, including a global Phase 3 cardiovascular outcomes study, which
    Novartis initiated in December 2019.<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">&#160;</span>In connection with Novartis&#8217; license of pelacarsen, we and Novartis established a more definitive framework under
    which the companies would negotiate the co-commercialization of pelacarsen in selected markets. Included in this framework is an option by which Novartis could solely commercialize pelacarsen in exchange for Novartis paying us increased sales milestone
    payments based on sales of pelacarsen.</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Under the collaboration, we are eligible to receive up to $675 million in milestone payments related to pelacarsen. We are also eligible
    to receive tiered royalties in the mid-teens to low 20 percent range on net sales of pelacarsen. Through December 2021, w<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">e have generated nearly $425 million
      under our collaboration including an upfront payment, license fee, milestone payments and other payments from this collaboration, including a $25 million milestone payment we earned in 2021 when Novartis achieved 50 percent enrollment in the Lp(a)
      HORIZON Phase 3 cardiovascular outcome study of pelacarsen.</span></div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">In conjunction with this collaboration, we entered into a SPA with Novartis. As part of the SPA, Novartis purchased 1.6
    million shares of our common stock for $100 million in the first quarter of 2017.</div>

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  <div style="text-align: left; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;">Roche</div>

  <div>
    <div><br />
    </div>

  </div>

  <div style="text-align: left; margin-left: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;">Huntington&#8217;s Disease</div>

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  </div>

  <div>
    <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">In April 2013, we formed an alliance with Hoffman-La Roche Inc. and F. Hoffmann-La Roche Ltd., collectively Roche, to
      develop treatments for HD based on our antisense technology. Under the agreement, we discovered and developed tominersen, an investigational medicine targeting HTT protein. We developed tominersen through completion of our Phase 1/2 clinical study in
      people with early stage HD. In December 2017, upon completion of the Phase 1/2 study, Roche exercised its option to license tominersen<sub>&#160;</sub>and is now responsible for the global development, regulatory and commercialization activities and costs
      for tominersen. In March 2021, Roche discontinued dosing in the Phase 3 GENERATION HD1 study of tominersen in patients with manifest Huntington&#8217;s disease based on the results of a pre-planned review of data from the Phase 3 study conducted by an
      unblinded Independent Data Monitoring Committee. In January 2022, Roche announced it is actively preparing to initiate a new Phase 2 study of tominersen in patients with HD. Post-hoc analyses from the GENERATION HD1 study suggested tominersen may
      benefit younger adult patients with lower disease burden.</div>

    <div><br />
    </div>

    <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Under the terms of the agreement, we received an upfront payment of $30 million in April 2013. We are eligible to
      receive up to $365 million in a license fee and milestone payments as tominersen advances. In addition, we are eligible to receive up to $136.5 million in milestone payments for each additional medicine successfully developed. We are also eligible to
      receive tiered royalties up to the mid-teens on net sales from any product resulting from this alliance. Through December 2021, we have generated $150 million under our collaboration.</div>

  </div>

  <div><br />
  </div>

  <div style="text-align: left; margin-left: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;">IONIS-FB-L<sub>Rx</sub> for Complement-Mediated Diseases</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">In October 2018, we entered into a collaboration agreement with Roche to develop IONIS-FB-L<sub>Rx</sub> for the treatment
    of complement-mediated diseases. We are currently conducting Phase 2 studies in two disease indications for IONIS-FB-L<sub>Rx</sub>, one for the treatment of patients with GA, the advanced stage of dry AMD, and a second for the treatment of patients
    with IgA nephropathy. Roche has the option to license IONIS-FB-L<sub>Rx</sub> at the completion of these studies. Upon licensing, Roche will be responsible for global development, regulatory and commercialization activities and costs.</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Under the terms of this agreement, we received a $75 million upfront payment in October 2018. We are eligible to receive
    more than $680 million including a license fee and milestone payments. In addition, we are also eligible to receive tiered royalties from the high teens to twenty percent on net sales. Through December 2021, we have generated over $75 million under our
    collaboration.</div>

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  <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Commercialization Partnerships</div>

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  <div style="text-align: left; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;">Swedish Orphan Biovitrum AB (Sobi)</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We began commercializing TEGSEDI and WAYLIVRA in Europe in January 2021 and TEGSEDI in North America in April 2021 through
    distribution agreements with Sobi. Under our agreements, we are responsible for supplying finished goods inventory to Sobi and Sobi is responsible for selling each medicine to the end customer. In exchange, we earn a distribution fee on net sales from
    Sobi for each medicine.</div>

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  </div>

  <div style="text-align: left; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;">PTC Therapeutics</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">In August 2018, we entered into an exclusive
      license agreement with PTC Therapeutics to commercialize TEGSEDI and WAYLIVRA in Latin America and certain Caribbean countries. Under the license agreement, we are eligible to receive royalties from PTC in the mid-</span>20 percent<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> range on net sales for each medicine. </span>In
    December 2021, we started receiving royalties from PTC for TEGSEDI sales<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">.</span></div>

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    </div>

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  <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Technology Enhancement Collaboration</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;">Bicycle License Agreement</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">In December 2020, we entered into a collaboration agreement with Bicycle and obtained an option to license its peptide
    technology to potentially increase the delivery capabilities of our LICA medicines. In July 2021, we paid $42 million when we exercised our option to license Bicycle&#8217;s technology, which included an equity investment in Bicycle. As part of our stock
    purchase, we entered into a lockup agreement with Bicycle that restricts our ability to trade our Bicycle shares for one year. In 2021, we recorded a $7 million equity investment for the shares we received in Bicycle. We recognized the remaining $35
    million as R&amp;D expense in 2021. From inception through December 2021, we have paid Bicycle $47 million under this collaboration agreement.</div>

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    <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Other Agreements</div>

  </div>

  <div>
    <div><br />
    </div>

    <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;">Alnylam Pharmaceuticals, Inc.</div>

    <div><br />
    </div>

    <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Under the terms of our agreement with Alnylam, we co-exclusively (with ourselves) licensed to Alnylam our patent estate
      relating to antisense motifs and mechanisms and oligonucleotide chemistry for double-stranded RNAi therapeutics, with Alnylam having the exclusive right to grant platform sublicenses for double-stranded RNAi.&#160; In exchange for such rights, Alnylam
      gave us a technology access fee, participation in fees from Alnylam&#8217;s partnering programs, as well as future milestone and royalty payments from Alnylam. We retained exclusive rights to our patents for single-stranded antisense therapeutics and for a
      limited number of double-stranded RNAi therapeutic targets and all rights to single-stranded RNAi, or ssRNAi, therapeutics. In turn, Alnylam nonexclusively licensed to us its patent estate relating to antisense motifs and mechanisms and
      oligonucleotide chemistry to research, develop and commercialize single-stranded antisense therapeutics, ssRNAi therapeutics, and to research double-stranded RNAi compounds. We also received a license to develop and commercialize double-stranded RNAi
      therapeutics targeting a limited number of therapeutic targets on a nonexclusive basis. Additionally, in 2015, we and Alnylam entered into an alliance in which we cross-licensed intellectual property. Under this alliance, we and Alnylam each obtained
      exclusive license rights to four therapeutic programs. Alnylam granted us an exclusive, royalty-bearing license to its chemistry, RNA targeting mechanism and target-specific intellectual property for oligonucleotides against four targets, including
      FXI and Apo(a) and two other targets. In exchange, we granted Alnylam an exclusive, royalty-bearing license to our chemistry, RNA targeting mechanism and target-specific intellectual property for oligonucleotides against four other targets. Alnylam
      also granted us a royalty-bearing, non-exclusive license to new platform technology arising from May 2014 through April 2019 for single-stranded antisense therapeutics. In turn, we granted Alnylam a royalty-bearing, non-exclusive license to new
      platform technology arising from May 2014 through April 2019 for double-stranded RNAi therapeutics.</div>

    <div><br />
    </div>

    <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">In the fourth quarter of 2020, we completed an arbitration process with Alnylam. The arbitration panel awarded us $41
      million for payments owed to us by Alnylam related to Alnylam&#8217;s agreement with Sanofi Genzyme. We recognized the $41 million payment from Alnylam as R&amp;D revenue in the fourth quarter of 2020.</div>

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    </div>

    <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;">The Ludwig Institute; Center for Neurological Studies</div>

  </div>

  <div>
    <div><br />
    </div>

  </div>

  <div>
    <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We have a collaboration with the Ludwig Institute, the Center for Neurological Studies and researchers to discover and
      develop antisense medicines for ALS and other neurodegenerative diseases. Under this agreement, we agreed to pay the Ludwig Institute and the Center for Neurological Studies modest milestone payments and royalties on any antisense medicines resulting
      from the collaboration.</div>

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  <div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Manufacturing</div>

  <div style="text-align: justify;"><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We manufacture most of the drug product we use for our research and development activities ourselves. We have also
    manufactured API and commercial supply for our approved medicines. We have dedicated significant resources to develop ways to improve manufacturing efficiency and capacity. Since we can use variants of the same nucleotide building blocks and the same
    type of equipment to produce our oligonucleotide medicines, we found that the same techniques we used to efficiently manufacture one oligonucleotide medicine could help improve the manufacturing processes for our other antisense medicines. By
    developing several proprietary chemical processes to scale up our manufacturing capabilities, we have greatly reduced the cost of producing oligonucleotide medicines. For example, we have significantly reduced the cost of raw materials through improved
    yield efficiency, while at the same time increasing our capacity to make our medicines. Through both our internal research and development programs and collaborations with outside vendors we may achieve even greater efficiency and further cost
    reductions.</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Our manufacturing facility is located in a 26,800 square foot building in Carlsbad, California. We purchased this building
    in 2017. In addition, we have a 25,800 square foot building that houses support functions for our manufacturing activities. We lease this facility under a lease that has a term ending in August 2026 with an option to extend the lease for an additional
    five-year period. Our manufacturing facility is subject to periodic inspections by the FDA and foreign equivalents to ensure that it is operating in compliance with current Good Manufacturing Practices, or cGMP, requirements.</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">As part of our collaborations we may agree to manufacture clinical trial materials and/or commercial supply for our
    partners. For example, in the past we have manufactured clinical supply materials for AstraZeneca, Bayer, Biogen, GSK and Novartis and commercial supply materials for Biogen.</div>

  <div style="text-align: justify; text-indent: 36pt;"><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We believe we have sufficient manufacturing capacity at our own facility or at contract manufacturing organizations, or
    CMOs, to meet our current internal research, development and potential commercial needs, as well as our obligations under existing agreements with our partners for research, development and commercial material. As we continue to advance our wholly
    owned medicines through Phase 3 development, we will begin to manufacture process performance qualification batches and pre-approval inspection batches of our Phase 3 medicines that may be used for regulatory submissions and, pending regulatory
    approval, commercial sale. We believe our current network of CMO partners are capable of providing sufficient quantities to meet anticipated commercial demands. Additionally, we continue to evaluate relationships with additional suppliers to increase
    overall capacity and diversify our supply chain. While we believe that there are alternate sources of supply that can satisfy our commercial requirements, it is possible that identifying and establishing relationships with such sources, if necessary,
    could result in significant delay or material additional costs. We also could experience a disruption in supply from our current CMO partners.</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">CMOs are subject to the FDA&#8217;s cGMP requirements and other rules and regulations prescribed by foreign regulatory
    authorities. We depend on our CMO partners for continued compliance with cGMP requirements and applicable foreign standards.</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Specifically, we have the following in place for our approved medicines, SPINRAZA, TEGSEDI and WAYLIVRA and our medicines
    in Phase 3 development: eplontersen, olezarsen, donidalorsen, ION363, pelacarsen and tofersen.</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;">SPINRAZA</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Biogen is responsible for SPINRAZA drug supply.</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;">TEGSEDI and WAYLIVRA</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">For TEGSEDI&#8217;s commercial drug supply, we are using CMOs to produce custom raw materials, active pharmaceutical ingredient,
    or API, and finished goods. For WAYLIVRA&#8217;s commercial drug supply, we have manufactured custom raw materials and API. We are using CMOs to produce the finished goods for WAYLIVRA. Our CMO partners have extensive technical expertise and cGMP experience.
    We believe our we and our current network of CMO partners are capable of manufacturing sufficient quantities to meet anticipated commercial demands.</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;">Eplontersen</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Our CMO partner supplied the API and the finished drug product for eplontersen&#8217;s Phase 3 program. Pursuant to our collaboration with
    AstraZeneca, we will manufacture and supply eplontersen through a CMO for the ongoing clinical trials and process qualifications. AstraZeneca is responsible for commercial supply.</div>

  <div><br />
  </div>

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  <div><br />
  </div>

  <div style="text-align: left; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;">Olezarsen, Donidalorsen, ION363</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">We have supplied the API and the finished
      drug product for </span>olezarsen, donidalorsen and ION363 that we believe will be <span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">sufficient through the completion of the Phase 3 programs for each
      medicine. We plan to leverage our relationships with CMOs to procure long-term raw material and drug supplies at competitive prices in the future.</span></div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;">Pelacarsen</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We supplied the API and the finished drug product for pelacarsen&#8217;s Phase 3 study. Pursuant to our collaboration with
    Novartis, Novartis is responsible for any further pelacarsen drug supply.</div>

  <div><br />
  </div>

  <div style="text-align: left; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;">Tofersen</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We manufactured the first batch of API for tofersen in 2015 to support the first in human studies under our collaboration
    agreement with Biogen. Pursuant to our collaboration with Biogen, Biogen is responsible for tofersen drug supply. Biogen has an oligonucleotide synthesis manufacturing facility that gives it the capability to manufacture tofersen for all subsequent
    clinical studies and potential commercialization, including supplying the API for the current Phase 3 study.</div>

  <div><br />
  </div>

  <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Patents and Proprietary Rights</div>

  <div style="text-align: justify;"><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Our success depends, in part, on our ability to obtain patent protection for our products in the U.S. and other countries.
    We own or have exclusively licensed a substantial patent estate with numerous issued patents worldwide protecting our products and, more generally, our platform for development and commercialization of oligonucleotide therapeutics. We focus our
    resources on patents and new patent applications that drive value for our company.</div>

  <div style="text-align: left; text-indent: 36pt;"><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We own or control patents that provide exclusivity for products in our pipeline and patents that provide exclusivity for
    our core technology in the field of antisense more generally. Our core technology patents include claims to chemically modified nucleosides and oligonucleotides as well as antisense medicine designs utilizing these chemically modified nucleosides.
    These core claims are independent of specific therapeutic target, nucleic acid sequence, or clinical indication. We also own a large number of patents claiming antisense compounds having nucleic acid sequences complementary to therapeutic target
    nucleic acids, independent of the particular chemical modifications incorporated into the antisense compound. Most importantly, we seek and obtain issued patent claims to specifically protect each of our medicines. For example, we file and seek to
    obtain claims covering each drug&#8217;s nucleic acid sequence and precise drug design. In sum, we maintain our competitive advantage in the field of antisense technology by protecting our core platform technology and by creating multiple layers of patent
    protection for each of our specific medicines in development.</div>

  <div><br />
  </div>

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  <tr>

    <td style="width: 75.89%; vertical-align: bottom; border-bottom: #000000 2px solid;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Type of Patent Claim</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">(Broadly Applicable to Specific)</div>
        </td>

    <td style="width: 0.81%; vertical-align: top;">&#160;</td>

    <td style="width: 23.29%; vertical-align: bottom;">&#160;</td>

  </tr>

  <tr>

    <td style="width: 75.89%; vertical-align: top;">
          <div style="text-align: left; text-indent: -18pt; margin-left: 52.8pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">&#9679;</span>&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">Chemically Modified Nucleosides and Oligonucleotides (target and sequence independent)</span></div>
          <div style="text-align: left; text-indent: -18pt; margin-left: 52.8pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">&#9679;</span>&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">Antisense Drug Design Motifs (target and sequence independent)</span></div>
          <div style="text-align: left; text-indent: -18pt; margin-left: 52.8pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">&#9679;</span>&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">Therapeutic Methods (sequence and chemistry independent)</span></div>
          <div style="text-align: left; text-indent: -18pt; margin-left: 52.8pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">&#9679;</span>&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">Antisense Sequence (chemistry independent)</span></div>
          <div style="text-align: left; text-indent: -18pt; margin-left: 52.8pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">&#9679;</span>&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;<span style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Drug Composition</span></div>
        </td>

    <td style="width: 0.81%; vertical-align: top;">&#160;</td>

    <td style="width: 23.29%; vertical-align: top;">
          <div style="text-align: left;"><img width="115" height="129" src="image12.jpg" alt="graphic" /></div>
        </td>

  </tr>


</table>
  <div><br />
  </div>

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    <div class="DSPFPageFooter">
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  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"><span style="text-decoration: underline;">Chemically Modified Nucleosides and Oligonucleotides</span></div>

  <div style="text-align: justify; text-indent: 36pt;"><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">The most broadly applicable of our patents are those that claim modified nucleosides and oligonucleotides comprising the
    modified nucleosides that we incorporate into our antisense medicines to increase their therapeutic efficacy. Nucleosides and chemically modified nucleosides are the basic building blocks of our antisense medicines. Therefore claims that cover any
    oligonucleotide incorporating one of our proprietary modified nucleosides can apply to a wide array of antisense mechanisms of action as well as several therapeutic targets. Of particular note are our patents covering our proprietary 2&#8217;-O-(2-methoxy)
    ethyl, or &#8220;MOE,&#8221; modified nucleosides, incorporated into many of our second-generation development compounds, as well as our constrained-ethyl nucleosides, or &#8220;cEt&#8221; nucleosides incorporated into our Generation 2.5 compounds. The following are some of
    our patents in this category in key jurisdictions (U.S., Europe and Japan):</div>

  <div><br />
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    <td style="width: 16.86%; vertical-align: bottom; border-bottom: #000000 2px solid;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Jurisdiction</div>
        </td>

    <td style="width: 1.67%; vertical-align: bottom;">&#160;</td>

    <td style="width: 11.11%; vertical-align: bottom; border-bottom: #000000 2px solid;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Patent No.</div>
        </td>

    <td style="width: 1.67%; vertical-align: bottom;">&#160;</td>

    <td style="width: 27.72%; vertical-align: bottom; border-bottom: #000000 2px solid;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Title</div>
        </td>

    <td style="width: 1.67%; vertical-align: bottom;">&#160;</td>

    <td style="width: 12.82%; vertical-align: bottom; border-bottom: #000000 2px solid;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Expiration</div>
        </td>

    <td style="width: 1.67%; vertical-align: bottom;">&#160;</td>

    <td style="width: 24.82%; vertical-align: bottom; border-bottom: #000000 2px solid;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Description of Claims</div>
        </td>

  </tr>

  <tr>

    <td style="width: 16.86%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">United States</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 11.11%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">7,101,993</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 27.72%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">OLIGONUCLEOTIDES CONTAINING 2&#8217;-O-MODIFIED PURINES</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 12.82%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">2023</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 24.82%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Certain MOE nucleosides and oligonucleotides containing these nucleotides</div>
        </td>

  </tr>

  <tr>

    <td style="width: 16.86%; vertical-align: top; background-color: #FFFFFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">United States</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 11.11%; vertical-align: top; background-color: #FFFFFF;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">7,399,845</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 27.72%; vertical-align: top; background-color: #FFFFFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">6-MODIFIED BICYCLIC NUCLEIC ACID ANALOGS</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 12.82%; vertical-align: top; background-color: #FFFFFF;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">2027</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 24.82%; vertical-align: top; background-color: #FFFFFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">cEt nucleosides and oligonucleotides containing these nucleoside analogs</div>
        </td>

  </tr>

  <tr>

    <td style="width: 16.86%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">United States</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 11.11%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">7,741,457</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 27.72%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">6-MODIFIED BICYCLIC NUCLEIC ACID ANALOGS</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 12.82%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">2027</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 24.82%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">cEt nucleosides and oligonucleotides containing these nucleoside analogs</div>
        </td>

  </tr>

  <tr>

    <td style="width: 16.86%; vertical-align: top; background-color: #FFFFFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">United States</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 11.11%; vertical-align: top; background-color: #FFFFFF;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">8,022,193</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 27.72%; vertical-align: top; background-color: #FFFFFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">6-MODIFIED BICYCLIC NUCLEIC ACID ANALOGS</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 12.82%; vertical-align: top; background-color: #FFFFFF;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">2027</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 24.82%; vertical-align: top; background-color: #FFFFFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Oligonucleotides containing cEt nucleoside analogs</div>
        </td>

  </tr>

  <tr>

    <td style="width: 16.86%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Europe</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 11.11%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">1984381</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 27.72%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">6-MODIFIED BICYCLIC NUCLEIC ACID ANALOGS</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 12.82%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">2027</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 24.82%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">cEt nucleosides and oligonucleotides containing these nucleoside analogs</div>
        </td>

  </tr>

  <tr>

    <td style="width: 16.86%; vertical-align: top; background-color: #FFFFFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Europe</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 11.11%; vertical-align: top; background-color: #FFFFFF;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">2314594</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 27.72%; vertical-align: top; background-color: #FFFFFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">6-MODIFIED BICYCLIC NUCLEIC ACID ANALOGS</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 12.82%; vertical-align: top; background-color: #FFFFFF;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">2027</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 24.82%; vertical-align: top; background-color: #FFFFFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Oligonucleotides containing cEt nucleoside analogs and methods of use</div>
        </td>

  </tr>

  <tr>

    <td style="width: 16.86%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Japan</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 11.11%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">5342881</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 27.72%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">6-MODIFIED BICYCLIC NUCLEIC ACID ANALOGS</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 12.82%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">2027</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 24.82%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">cEt nucleosides and oligonucleotides containing these nucleoside analogs</div>
        </td>

  </tr>

  <tr>

    <td style="width: 16.86%; vertical-align: top; background-color: #FFFFFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">United States</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 11.11%; vertical-align: top; background-color: #FFFFFF;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">7,569,686</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 27.72%; vertical-align: top; background-color: #FFFFFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">COMPOUNDS AND METHODS FOR SYNTHESIS OF BICYCLIC NUCLEIC ACID ANALOGS</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 12.82%; vertical-align: top; background-color: #FFFFFF;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">2027</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 24.82%; vertical-align: top; background-color: #FFFFFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Methods of synthesizing cEt nucleosides</div>
        </td>

  </tr>


</table>
  <div><br />
  </div>

  <div style="text-align: left; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"><span style="text-decoration: underline;">Antisense Drug Design Motifs</span></div>

  <div style="text-align: justify; text-indent: 36pt;"><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We also have patents that claim oligonucleotides comprising antisense drug design motifs, or patterns of nucleoside
    modifications at specified positions in the oligonucleotide. Patent claims covering our antisense drug design motifs are independent of nucleic acid sequence, so they cover oligonucleotides having the recited motif, regardless of cellular target or
    clinical indication. The claimed motifs generally confer properties that optimize oligonucleotides for a particular antisense mechanism of action, such as ribonuclease H (RNase H), RNAi, or splicing. We have designed oligonucleotides incorporating
    motifs, which we refer to as chimeric compounds or gapmers, to exploit the RNase H mechanism to achieve target RNA reduction. Almost all of our medicines in clinical development, including TEGSEDI and WAYLIVRA, but excluding SPINRAZA, contain this
    gapmer antisense drug design motif. We own a U.S. patent that covers all of our second-generation MOE gapmer antisense medicines until March of 2023.</div>

  <div><br />
  </div>

  <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" class="DSPFPageBreakArea">
    <div class="DSPFPageFooter">
      <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span class="DSPFPageNumber">34</span></div>

    </div>

    <div style="page-break-after:always;" class="DSPFPageBreak">
      <hr style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;" /></div>


  </div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">In addition, we have patent claims to antisense drug design motifs incorporating bicyclic nucleosides, which include both
    locked nucleic acids, or &#8220;LNA&#8221; and cEt. In Europe, we have been granted claims drawn to certain gapmer oligonucleotides with bicyclic nucleosides, which include locked nucleic acids in the wings. We have also successfully obtained issued patent claims
    covering our Generation 2.5 gapmer antisense drug design motifs that incorporate our cEt modified nucleosides. The following patents are some examples of our issued patents in this category in key jurisdictions (U.S., Europe and Japan):</div>

  <div><br />
  </div>

  <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; border-collapse: collapse; text-align: left; color: #000000;">


  <tr>

    <td style="width: 16.86%; vertical-align: bottom; border-bottom: #000000 2px solid;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Jurisdiction</div>
        </td>

    <td style="width: 1.67%; vertical-align: bottom;">&#160;</td>

    <td style="width: 11.11%; vertical-align: bottom; border-bottom: 2px solid rgb(0, 0, 0);">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Patent No.</div>
        </td>

    <td style="width: 1.67%; vertical-align: bottom;">&#160;</td>

    <td style="width: 27.72%; vertical-align: bottom; border-bottom: #000000 2px solid;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Title</div>
        </td>

    <td style="width: 1.67%; vertical-align: bottom;">&#160;</td>

    <td style="width: 12.82%; vertical-align: bottom; border-bottom: #000000 2px solid;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Expiration</div>
        </td>

    <td style="width: 1.67%; vertical-align: bottom;">&#160;</td>

    <td style="width: 24.82%; vertical-align: bottom; border-bottom: 2px solid rgb(0, 0, 0);">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Description of Claims</div>
        </td>

  </tr>

  <tr>

    <td style="width: 16.86%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">United States</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 11.11%; vertical-align: top; background-color: rgb(204, 238, 255);">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">7,015,315</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 27.72%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">GAPPED OLIGONUCLEOTIDES</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 12.82%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">2023</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 24.82%; vertical-align: top; background-color: rgb(204, 238, 255);">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Gapmer oligonucleotides having 2&#8217;-O-alkyl-O-alkyl nucleosides</div>
        </td>

  </tr>

  <tr>

    <td style="width: 16.86%; vertical-align: top; background-color: #FFFFFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">United States</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 11.11%; vertical-align: top; background-color: rgb(255, 255, 255);">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">7,750,131</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 27.72%; vertical-align: top; background-color: #FFFFFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">5&#8217;-MODIFIED BICYCLIC NUCLEIC ACID ANALOGS</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 12.82%; vertical-align: top; background-color: #FFFFFF;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">2027</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 24.82%; vertical-align: top; background-color: rgb(255, 255, 255);">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Oligonucleotides having 5&#8217;-methyl BNA nucleosides</div>
        </td>

  </tr>

  <tr>

    <td style="width: 16.86%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Europe</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 11.11%; vertical-align: top; background-color: rgb(204, 238, 255);">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">2092065</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 27.72%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">ANTISENSE COMPOUNDS</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 12.82%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">2027</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 24.82%; vertical-align: top; background-color: rgb(204, 238, 255);">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Gapmer oligonucleotides having 2&#8217;-modifed and LNA nucleosides</div>
        </td>

  </tr>

  <tr>

    <td style="width: 16.86%; vertical-align: top; background-color: #FFFFFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Europe</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 11.11%; vertical-align: top; background-color: rgb(255, 255, 255);">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">2410053</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 27.72%; vertical-align: top; background-color: #FFFFFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">ANTISENSE COMPOUNDS</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 12.82%; vertical-align: top; background-color: #FFFFFF;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">2027</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 24.82%; vertical-align: top; background-color: rgb(255, 255, 255);">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Gapmer oligonucleotides having wings comprised of 2&#8217;-MOE and bicyclic nucleosides</div>
        </td>

  </tr>

  <tr>

    <td style="width: 16.86%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Europe</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 11.11%; vertical-align: top; background-color: rgb(204, 238, 255);">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">2410054</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 27.72%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">ANTISENSE COMPOUNDS</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 12.82%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">2027</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 24.82%; vertical-align: top; background-color: rgb(204, 238, 255);">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Gapmer oligonucleotides having a 2&#8217;-modifed nucleoside in the 5&#8217;-wing and a bicyclic nucleoside in the 3&#8217;-wing</div>
        </td>

  </tr>

  <tr>

    <td style="width: 16.86%; vertical-align: top; background-color: #FFFFFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Japan</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 11.11%; vertical-align: top; background-color: rgb(255, 255, 255);">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">5665317</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 27.72%; vertical-align: top; background-color: #FFFFFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">ANTISENSE COMPOUNDS</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 12.82%; vertical-align: top; background-color: #FFFFFF;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">2027</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 24.82%; vertical-align: top; background-color: rgb(255, 255, 255);">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Gapmer oligonucleotides having wings comprised of 2&#8217;-MOE and bicyclic nucleosides</div>
        </td>

  </tr>

  <tr>

    <td style="width: 16.86%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">United States</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 11.11%; vertical-align: top; background-color: rgb(204, 238, 255);">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">9,550,988</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 27.72%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">ANTISENSE COMPOUNDS</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 12.82%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">2028</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 24.82%; vertical-align: top; background-color: rgb(204, 238, 255);">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Gapmer oligonucleotides having BNA nucleosides and 2&#8217;-MOE nucleosides</div>
        </td>

  </tr>

  <tr>

    <td style="width: 16.86%; vertical-align: top; background-color: #FFFFFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">United States</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 11.11%; vertical-align: top; background-color: rgb(255, 255, 255);">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">10,493,092</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 27.72%; vertical-align: top; background-color: #FFFFFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">ANTISENSE COMPOUNDS</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 12.82%; vertical-align: top; background-color: #FFFFFF;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">2028</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 24.82%; vertical-align: top; background-color: rgb(255, 255, 255);">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Gapmer oligonucleotides having BNA nucleosides and 2&#8217;-MOE nucleosides and/or 2&#8217;-OMe nucleosides</div>
        </td>

  </tr>

  <tr>

    <td style="width: 16.86%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Europe</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 11.11%; vertical-align: top; background-color: rgb(204, 238, 255);">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">3067421</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 27.72%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">OLIGOMERIC COMPOUNDS COMPRISING BICYCLIC NUCLEOTIDES AND USES THEREOF</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 12.82%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">2032</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 24.82%; vertical-align: top; background-color: rgb(204, 238, 255);">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Gapmer oligonucleotides having at least one bicyclic, one 2&#8217;-modified nucleoside and one 2&#8217;-deoxynucleoside</div>
        </td>

  </tr>


</table>
  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"><span style="text-decoration: underline;">LIgand-Conjugated Antisense (LICA) Technology</span></div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We also have patent claims to new chemistries created to enhance targeting of antisense medicines to specific tissues and
    cells to improve a drug&#8217;s properties. We designed our GalNAc LICA medicines to provide an increase in potency for targets in the liver. We have successfully obtained issued patent claims covering our LICA technology conjugated to any modified
    oligonucleotide, including gapmers, double-stranded siRNA compounds, and fully modified oligonucleotides. The following patents are some examples of our issued patents in this category:</div>

  <div><br />
  </div>

  <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; border-collapse: collapse; text-align: left; color: #000000;">


  <tr>

    <td style="width: 16.86%; vertical-align: bottom; border-bottom: #000000 2px solid;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Jurisdiction</div>
        </td>

    <td style="width: 1.67%; vertical-align: bottom;">&#160;</td>

    <td style="width: 11.11%; vertical-align: bottom; border-bottom: #000000 2px solid;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Patent</div>
        </td>

    <td style="width: 1.67%; vertical-align: bottom;">&#160;</td>

    <td style="width: 27.72%; vertical-align: bottom; border-bottom: 2px solid rgb(0, 0, 0);">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Title</div>
        </td>

    <td style="width: 1.67%; vertical-align: bottom;">&#160;</td>

    <td style="width: 12.82%; vertical-align: bottom; border-bottom: #000000 2px solid;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Expiration</div>
        </td>

    <td style="width: 1.67%; vertical-align: bottom;">&#160;</td>

    <td style="width: 24.82%; vertical-align: bottom; border-bottom: 2px solid rgb(0, 0, 0);">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Description of Claims</div>
        </td>

  </tr>

  <tr>

    <td style="width: 16.86%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">United States</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 11.11%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">9,127,276</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 27.72%; vertical-align: top; background-color: rgb(204, 238, 255);">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">CONJUGATED ANTISENSE COMPOUNDS AND THEIR USE</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 12.82%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">2034</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 24.82%; vertical-align: top; background-color: rgb(204, 238, 255);">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Preferred THA LICA conjugated to any group of nucleosides, including gapmers, double-stranded siRNA compounds, and fully modified
            oligonucleotides</div>
        </td>

  </tr>

  <tr>

    <td style="width: 16.86%; vertical-align: top; background-color: #FFFFFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">United States</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 11.11%; vertical-align: top; background-color: #FFFFFF;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">9,181,549</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 27.72%; vertical-align: top; background-color: rgb(255, 255, 255);">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">CONJUGATED ANTISENSE COMPOUNDS AND THEIR USE</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 12.82%; vertical-align: top; background-color: #FFFFFF;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">2034</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 24.82%; vertical-align: top; background-color: rgb(255, 255, 255);">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Preferred THA conjugate having our preferred linker and cleavable moiety conjugated to any oligomeric compound or any nucleoside having
            a 2&#8217;-MOE modification or a cEt modification</div>
        </td>

  </tr>

  <tr>

    <td style="width: 16.86%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Europe</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 11.11%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">2991661</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 27.72%; vertical-align: top; background-color: rgb(204, 238, 255);">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">CONJUGATED ANTISENSE COMPOUNDS AND THEIR USE</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 12.82%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">2034</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 24.82%; vertical-align: top; background-color: rgb(204, 238, 255);">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Preferred THA LICA conjugated to any group of nucleosides, including gapmers, double-stranded siRNA compounds, and fully modified
            oligonucleotides</div>
        </td>

  </tr>


</table>
  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"><span style="text-decoration: underline;">Therapeutic Methods of Treatment and Antisense Drug Sequences</span></div>

  <div style="text-align: justify; text-indent: 36pt;"><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">In addition to our broad core patents, we also own hundreds of patents, worldwide, with claims to antisense compounds
    having particular sequences and compounds directed to particular therapeutically important targets or methods of achieving cellular or clinical endpoints using these antisense compounds. These &#8220;Target&#8221; patents also include claims reciting the specific
    nucleic acid sequences utilized by our products, independent of chemical modifications and motifs. In addition, our product-specific patents typically include claims combining specific nucleic acid sequences with nucleoside modifications and motifs. In
    this way, we seek patent claims narrowly tailored to protect our products specifically, in addition to the broader core antisense patents described above.</div>

  <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" class="DSPFPageBreakArea">
    <div class="DSPFPageFooter">
      <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span class="DSPFPageNumber">35</span></div>

    </div>

    <div style="page-break-after:always;" class="DSPFPageBreak">
      <hr style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;" /></div>


  </div>

  <div><br />
  </div>

  <div style="text-align: left; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic; font-weight: bold;">SPINRAZA and Survival Motor Neuron</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We believe SPINRAZA is protected from generic competition in the U.S. until at least 2035 and in Europe until at least
    2030 by a suite of patents. These issued patents include: (i) patents licensed from the University of Massachusetts drawn to antisense compounds having the sequence of SPINRAZA, independent of chemical modification and uses of such compounds for
    treating SMA, and (ii) joint patents with Cold Spring Harbor Laboratory claiming fully modified 2&#8217;MOE compositions targeting SMN2, including the precise composition of matter of SPINRAZA and methods of using such compositions. We have filed for patent
    term extension, to potentially extend the term beyond 2030. With Biogen&#8217;s license of SPINRAZA, we assigned our interest in these patents to Biogen. The table below lists some key issued patents protecting SPINRAZA in the U.S. and Europe:</div>

  <div><br />
  </div>

  <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; border-collapse: collapse; text-align: left; color: #000000;">


  <tr>

    <td style="width: 16.86%; vertical-align: bottom; border-bottom: #000000 2px solid;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Jurisdiction</div>
        </td>

    <td style="width: 1.67%; vertical-align: bottom;">&#160;</td>

    <td style="width: 11.11%; vertical-align: bottom; border-bottom: 2px solid rgb(0, 0, 0);">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Patent No.</div>
        </td>

    <td style="width: 1.67%; vertical-align: bottom;">&#160;</td>

    <td style="width: 27.72%; vertical-align: bottom; border-bottom: 2px solid rgb(0, 0, 0);">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Title</div>
        </td>

    <td style="width: 1.67%; vertical-align: bottom;">&#160;</td>

    <td style="width: 12.82%; vertical-align: bottom; border-bottom: #000000 2px solid;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Expiration</div>
        </td>

    <td style="width: 1.67%; vertical-align: bottom;">&#160;</td>

    <td style="width: 24.82%; vertical-align: bottom; border-bottom: 2px solid rgb(0, 0, 0);">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Description of Claims</div>
        </td>

  </tr>

  <tr>

    <td style="width: 16.86%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">United States</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 11.11%; vertical-align: top; background-color: rgb(204, 238, 255);">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">10,266,822</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 27.72%; vertical-align: top; background-color: rgb(204, 238, 255);">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">SPINAL MUSCULAR ATROPHY (SMA) TREATMENT VIA TARGETING OF SMN2 SPLICE SITE INHIBITORY SEQUENCES</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 12.82%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">2025</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 24.82%; vertical-align: top; background-color: rgb(204, 238, 255);">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Methods of increasing exon-7 containing SMN2 mRNA in a cell using an oligonucleotide having the sequence of SPINRAZA</div>
        </td>

  </tr>

  <tr>

    <td style="width: 16.86%; vertical-align: top; background-color: #FFFFFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">United States</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 11.11%; vertical-align: top; background-color: rgb(255, 255, 255);">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">8,110,560</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 27.72%; vertical-align: top; background-color: rgb(255, 255, 255);">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">SPINAL MUSCULAR ATROPHY (SMA) TREATMENT VIA TARGETING OF SMN2 SPLICE SITE INHIBITORY SEQUENCES</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 12.82%; vertical-align: top; background-color: #FFFFFF;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">2025</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 24.82%; vertical-align: top; background-color: rgb(255, 255, 255);">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Methods of using antisense oligonucleotides having sequence of SPINRAZA to alter splicing of SMN2 and/or to treat SMA</div>
        </td>

  </tr>

  <tr>

    <td style="width: 16.86%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Europe</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 11.11%; vertical-align: top; background-color: rgb(204, 238, 255);">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">1910395</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 27.72%; vertical-align: top; background-color: rgb(204, 238, 255);">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">COMPOSITIONS AND METHODS FOR MODULATION OF SMN2 SPLICING</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 12.82%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">2026</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 24.82%; vertical-align: top; background-color: rgb(204, 238, 255);">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Sequence and chemistry (full 2&#8217;-MOE) of SPINRAZA</div>
        </td>

  </tr>

  <tr>

    <td style="width: 16.86%; vertical-align: top; background-color: #FFFFFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Europe</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 11.11%; vertical-align: top; background-color: rgb(255, 255, 255);">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">3308788</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 27.72%; vertical-align: top; background-color: rgb(255, 255, 255);">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">COMPOSITIONS AND METHODS FOR MODULATION OF SMN2 SPLICING</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 12.82%; vertical-align: top; background-color: #FFFFFF;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">2026</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 24.82%; vertical-align: top; background-color: rgb(255, 255, 255);">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Pharmaceutical compositions that include SPINRAZA</div>
        </td>

  </tr>

  <tr>

    <td style="width: 16.86%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">United States</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 11.11%; vertical-align: top; background-color: rgb(204, 238, 255);">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">7,838,657</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 27.72%; vertical-align: top; background-color: rgb(204, 238, 255);">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">SPINAL MUSCULAR ATROPHY (SMA) TREATMENT VIA TARGETING OF SMN2 SPLICE SITE INHIBITORY SEQUENCES</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 12.82%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">2027</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 24.82%; vertical-align: top; background-color: rgb(204, 238, 255);">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Oligonucleotides having sequence of SPINRAZA</div>
        </td>

  </tr>

  <tr>

    <td style="width: 16.86%; vertical-align: top; background-color: #FFFFFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">United States</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 11.11%; vertical-align: top; background-color: rgb(255, 255, 255);">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">8,361,977</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 27.72%; vertical-align: top; background-color: rgb(255, 255, 255);">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">COMPOSITIONS AND METHODS FOR MODULATION OF SMN2 SPLICING</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 12.82%; vertical-align: top; background-color: #FFFFFF;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">2030</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 24.82%; vertical-align: top; background-color: rgb(255, 255, 255);">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Sequence and chemistry (full 2&#8217;-MOE) of SPINRAZA</div>
        </td>

  </tr>

  <tr>

    <td style="width: 16.86%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">United States</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 11.11%; vertical-align: top; background-color: rgb(204, 238, 255);">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">8,980,853</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 27.72%; vertical-align: top; background-color: rgb(204, 238, 255);">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">COMPOSITIONS AND METHODS FOR MODULATION OF SMN2 SPLICING IN A SUBJECT</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 12.82%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">2030</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 24.82%; vertical-align: top; background-color: rgb(204, 238, 255);">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Methods of administering SPINRAZA</div>
        </td>

  </tr>

  <tr>

    <td style="width: 16.86%; vertical-align: top; background-color: #FFFFFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">United States</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 11.11%; vertical-align: top; background-color: rgb(255, 255, 255);">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">9,717,750</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 27.72%; vertical-align: top; background-color: rgb(255, 255, 255);">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">COMPOSITIONS AND METHODS FOR MODULATION OF SMN2 SPLICING IN A SUBJECT</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 12.82%; vertical-align: top; background-color: #FFFFFF;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">2030</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 24.82%; vertical-align: top; background-color: rgb(255, 255, 255);">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Methods of administering SPINRAZA to a patient</div>
        </td>

  </tr>

  <tr>

    <td style="width: 16.86%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Europe</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 11.11%; vertical-align: top; background-color: rgb(204, 238, 255);">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">3449926</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 27.72%; vertical-align: top; background-color: rgb(204, 238, 255);">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">COMPOSITIONS AND METHODS FOR MODULATION OF SMN2 SPLICING IN A SUBJECT</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 12.82%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">2030</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 24.82%; vertical-align: top; background-color: rgb(204, 238, 255);">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Pharmaceutical compositions that include SPINRAZA for treating SMA</div>
        </td>

  </tr>

  <tr>

    <td style="width: 16.86%; vertical-align: top; background-color: #FFFFFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Europe</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 11.11%; vertical-align: top; background-color: rgb(255, 255, 255);">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">3305302</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 27.72%; vertical-align: top; background-color: rgb(255, 255, 255);">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">COMPOSITIONS AND METHODS FOR MODULATION OF SMN2 SPLICING IN A SUBJECT</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 12.82%; vertical-align: top; background-color: #FFFFFF;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">2030</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 24.82%; vertical-align: top; background-color: rgb(255, 255, 255);">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Antisense compounds including SPINRAZA for treating SMA</div>
        </td>

  </tr>

  <tr>

    <td style="width: 16.86%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">United States</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 11.11%; vertical-align: top; background-color: rgb(204, 238, 255);">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">9,926,559</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 27.72%; vertical-align: top; background-color: rgb(204, 238, 255);">
          <div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">COMPOSITIONS AND METHODS FOR MODULATION OF SMN2 SPLICING IN A SUBJECT</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 12.82%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">2034</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 24.82%; vertical-align: top; background-color: rgb(204, 238, 255);">
          <div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">SPINRAZA doses for treating SMA</div>
        </td>

  </tr>

  <tr>

    <td style="width: 16.86%; vertical-align: top; background-color: #FFFFFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">United States</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 11.11%; vertical-align: top; background-color: rgb(255, 255, 255);">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">10,436,802</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 27.72%; vertical-align: top; background-color: rgb(255, 255, 255);">
          <div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">METHODS FOR TREATING SPINAL MUSCULAR ATROPHY</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 12.82%; vertical-align: top; background-color: #FFFFFF;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">2035</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 24.82%; vertical-align: top; background-color: rgb(255, 255, 255);">
          <div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">SPINRAZA dosing regimen for treating SMA</div>
        </td>

  </tr>


</table>
  <div style="text-align: left;"><br />
  </div>

  <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" class="DSPFPageBreakArea">
    <div class="DSPFPageFooter">
      <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span class="DSPFPageNumber">36</span></div>

    </div>

    <div style="page-break-after:always;" class="DSPFPageBreak">
      <hr style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;" /></div>


  </div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic; font-weight: bold;">TEGSEDI and Transthyretin</div>

  <div style="text-align: justify;"><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We believe TEGSEDI is protected from generic competition in the U.S. and Europe until at least 2031. Additional patent
    applications designed to protect TEGSEDI in other foreign jurisdictions are being pursued. The table below lists some key issued patents protecting TEGSEDI<sub>&#160;</sub>in the U.S. and Europe:</div>

  <div><br />
  </div>

  <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; border-collapse: collapse; text-align: left; color: #000000;">


  <tr>

    <td style="width: 16.86%; vertical-align: bottom; border-bottom: #000000 2px solid;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Jurisdiction</div>
        </td>

    <td style="width: 1.67%; vertical-align: bottom;">&#160;</td>

    <td style="width: 11.11%; vertical-align: bottom; border-bottom: #000000 2px solid;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Patent No.</div>
        </td>

    <td style="width: 1.67%; vertical-align: bottom;">&#160;</td>

    <td style="width: 27.72%; vertical-align: bottom; border-bottom: 2px solid rgb(0, 0, 0);">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Title</div>
        </td>

    <td style="width: 1.67%; vertical-align: bottom;">&#160;</td>

    <td style="width: 12.82%; vertical-align: bottom; border-bottom: #000000 2px solid;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Expiration</div>
        </td>

    <td style="width: 1.67%; vertical-align: bottom;">&#160;</td>

    <td style="width: 24.82%; vertical-align: bottom; border-bottom: 2px solid rgb(0, 0, 0);">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Description of Claims</div>
        </td>

  </tr>

  <tr>

    <td style="width: 16.86%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">United States</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 11.11%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">8,101,743</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 27.72%; vertical-align: top; background-color: rgb(204, 238, 255);">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">MODULATION OF TRANSTHYRETIN EXPRESSION</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 12.82%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">2025</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 24.82%; vertical-align: top; background-color: rgb(204, 238, 255);">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Antisense sequence and chemistry of TEGSEDI</div>
        </td>

  </tr>

  <tr>

    <td style="width: 16.86%; vertical-align: top; background-color: #FFFFFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">United States</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 11.11%; vertical-align: top; background-color: #FFFFFF;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">8,697,860</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 27.72%; vertical-align: top; background-color: rgb(255, 255, 255);">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">DIAGNOSIS AND TREATMENT OF DISEASE</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 12.82%; vertical-align: top; background-color: #FFFFFF;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">2031</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 24.82%; vertical-align: top; background-color: rgb(255, 255, 255);">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Composition of TEGSEDI</div>
        </td>

  </tr>

  <tr>

    <td style="width: 16.86%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">United States</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 11.11%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">9,061,044</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 27.72%; vertical-align: top; background-color: rgb(204, 238, 255);">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">MODULATION OF TRANSTHYRETIN EXPRESSION</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 12.82%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">2031</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 24.82%; vertical-align: top; background-color: rgb(204, 238, 255);">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Sodium salt composition of TEGSEDI</div>
        </td>

  </tr>

  <tr>

    <td style="width: 16.86%; vertical-align: top; background-color: #FFFFFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">United States</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 11.11%; vertical-align: top; background-color: #FFFFFF;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">9,399,774</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 27.72%; vertical-align: top; background-color: rgb(255, 255, 255);">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">MODULATION OF TRANSTHYRETIN EXPRESSION</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 12.82%; vertical-align: top; background-color: #FFFFFF;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">2031</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 24.82%; vertical-align: top; background-color: rgb(255, 255, 255);">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Methods of treating transthyretin amyloidosis by administering TEGSEDI</div>
        </td>

  </tr>

  <tr>

    <td style="width: 16.86%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Europe</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 11.11%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">2563920</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 27.72%; vertical-align: top; background-color: rgb(204, 238, 255);">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">MODULATION OF TRANSTHYRETIN EXPRESSION</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 12.82%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">2031</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 24.82%; vertical-align: top; background-color: rgb(204, 238, 255);">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Composition of TEGSEDI</div>
        </td>

  </tr>


</table>
  <div style="text-align: left; text-indent: 36pt;"><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic; font-weight: bold;">WAYLIVRA and Apolipoprotein C-III</div>

  <div style="text-align: justify; text-indent: 36pt;"><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We have obtained patent claims in the U.S. and Europe drawn to the use of antisense compounds complementary to a broad
    active region of human ApoC-III, including the site targeted by WAYLIVRA. We have also obtained issued patents claiming the specific sequence and chemical composition of WAYLIVRA in the U.S. and Europe. We believe the issued claims protect WAYLIVRA
    from generic competition in the U.S. and Europe until at least 2023 and 2024, respectively. We are pursuing additional patent applications designed to protect WAYLIVRA worldwide. The table below lists some key issued patents protecting WAYLIVRA in the
    U.S. and Europe:</div>

  <div><br />
  </div>

  <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; border-collapse: collapse; text-align: left; color: #000000;">


  <tr>

    <td style="width: 16.86%; vertical-align: bottom; border-bottom: #000000 2px solid;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Jurisdiction</div>
        </td>

    <td style="width: 1.67%; vertical-align: bottom;">&#160;</td>

    <td style="width: 11.11%; vertical-align: bottom; border-bottom: #000000 2px solid;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Patent No.</div>
        </td>

    <td style="width: 1.67%; vertical-align: bottom;">&#160;</td>

    <td style="width: 27.72%; vertical-align: bottom; border-bottom: 2px solid rgb(0, 0, 0);">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Title</div>
        </td>

    <td style="width: 1.67%; vertical-align: bottom;">&#160;</td>

    <td style="width: 12.82%; vertical-align: bottom; border-bottom: #000000 2px solid;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Expiration</div>
        </td>

    <td style="width: 1.67%; vertical-align: bottom;">&#160;</td>

    <td style="width: 24.82%; vertical-align: bottom; border-bottom: 2px solid rgb(0, 0, 0);">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Description of Claims</div>
        </td>

  </tr>

  <tr>

    <td style="width: 16.86%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">United States</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 11.11%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">9,624,496</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 27.72%; vertical-align: top; background-color: rgb(204, 238, 255);">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">MODULATION OF APOLIPOPROTEIN C-III EXPRESSION</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 12.82%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">2023</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 24.82%; vertical-align: top; background-color: rgb(204, 238, 255);">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Antisense compounds specifically hybridizable within the nucleotide region of ApoCIII targeted by WAYLIVRA</div>
        </td>

  </tr>

  <tr>

    <td style="width: 16.86%; vertical-align: top; background-color: #FFFFFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">United States</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 11.11%; vertical-align: top; background-color: #FFFFFF;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">7,598,227</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 27.72%; vertical-align: top; background-color: rgb(255, 255, 255);">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">MODULATION OF APOLIPOPROTEIN C-III EXPRESSION</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 12.82%; vertical-align: top; background-color: #FFFFFF;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">2023</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 24.82%; vertical-align: top; background-color: rgb(255, 255, 255);">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Methods of treating hyperlipidemia, lowering cholesterol levels or lowering triglyceride levels with WAYLIVRA</div>
        </td>

  </tr>

  <tr>

    <td style="width: 16.86%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">United States</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 11.11%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">7,750,141</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 27.72%; vertical-align: top; background-color: rgb(204, 238, 255);">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">MODULATION OF APOLIPOPROTEIN C-III EXPRESSION</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 12.82%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">2023</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 24.82%; vertical-align: top; background-color: rgb(204, 238, 255);">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Antisense sequence and chemistry of WAYLIVRA</div>
        </td>

  </tr>

  <tr>

    <td style="width: 16.86%; vertical-align: top; background-color: #FFFFFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Europe</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 11.11%; vertical-align: top; background-color: #FFFFFF;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">1622597</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 27.72%; vertical-align: top; background-color: rgb(255, 255, 255);">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">MODULATION OF APOLIPOPROTEIN C-III EXPRESSION</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 12.82%; vertical-align: top; background-color: #FFFFFF;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">2024</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 24.82%; vertical-align: top; background-color: rgb(255, 255, 255);">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Antisense sequence and chemistry of WAYLIVRA</div>
        </td>

  </tr>

  <tr>

    <td style="width: 16.86%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Europe</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 11.11%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">2441449</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 27.72%; vertical-align: top; background-color: rgb(204, 238, 255);">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">MODULATION OF APOLIPOPROTEIN C-III EXPRESSION</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 12.82%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">2024</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 24.82%; vertical-align: top; background-color: rgb(204, 238, 255);">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Antisense compounds specifically hybridizable within the nucleotide region of ApoCIII targeted by WAYLIVRA</div>
        </td>

  </tr>

  <tr>

    <td style="width: 16.86%; vertical-align: top; background-color: #FFFFFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Europe</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 11.11%; vertical-align: top; background-color: #FFFFFF;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">3002007</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 27.72%; vertical-align: top; background-color: rgb(255, 255, 255);">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">MODULATION OF APOLIPOPROTEIN C-III EXPRESSION</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 12.82%; vertical-align: top; background-color: #FFFFFF;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">2024</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 24.82%; vertical-align: top; background-color: rgb(255, 255, 255);">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Compounds complementary to an ApoCIII nucleic acid for use in therapy</div>
        </td>

  </tr>

  <tr>

    <td style="width: 16.86%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">United States</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 11.11%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">9,157,082</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 27.72%; vertical-align: top; background-color: rgb(204, 238, 255);">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">MODULATION OF APOLIPOPROTEIN C-III (APOCIII) EXPRESSION</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 12.82%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">2032</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 24.82%; vertical-align: top; background-color: rgb(204, 238, 255);">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Methods of using ApoCIII antisense oligonucleotides for reducing pancreatitis and chylomicronemia and increasing HDL</div>
        </td>

  </tr>

  <tr>

    <td style="width: 16.86%; vertical-align: top; background-color: #FFFFFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">United States</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 11.11%; vertical-align: top; background-color: #FFFFFF;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">9,593,333</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 27.72%; vertical-align: top; background-color: rgb(255, 255, 255);">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">MODULATION OF APOLIPOPROTEIN C-III (APOCIII) EXPRESSION IN LIPOPROTEIN LIPASE DEFICIENT (LPLD) POPULATIONS</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 12.82%; vertical-align: top; background-color: #FFFFFF;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">2034</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 24.82%; vertical-align: top; background-color: rgb(255, 255, 255);">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Methods of treating lipoprotein lipase deficiency with an ApoCIII specific inhibitor wherein triglyceride levels are reduced</div>
        </td>

  </tr>

  <tr>

    <td style="width: 16.86%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Europe</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 11.11%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">2956176</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 27.72%; vertical-align: top; background-color: rgb(204, 238, 255);">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">MODULATION OF APOLIPOPROTEIN C-III (APOCIII) EXPRESSION IN LIPOPROTEIN LIPASE DEFICIENT (LPLD) POPULATIONS</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 12.82%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">2034</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 24.82%; vertical-align: top; background-color: rgb(204, 238, 255);">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">ApoCIII specific inhibitors including WAYLIVRA for treating lipoprotein lipase deficiency or familial chylomicronemia syndrome</div>
        </td>

  </tr>


</table>
  <div><br />
  </div>

  <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" class="DSPFPageBreakArea">
    <div class="DSPFPageFooter">
      <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span class="DSPFPageNumber">37</span></div>

    </div>

    <div style="page-break-after:always;" class="DSPFPageBreak">
      <hr style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;" /></div>


  </div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic; font-weight: bold;">Eplontersen <span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">and Transthyretin</span></div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">We believe eplontersen is protected from
      generic competition in the U.S. and Europe until at least 2034. Additional patent applications to protect eplontersen in other foreign jurisdictions are being pursued. The table below lists some key issued patents protecting </span>eplontersen <span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">in the U.S. and Europe:</span></div>

  <div><br />
  </div>

  <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; border-collapse: collapse; text-align: left; color: #000000;">


  <tr>

    <td style="width: 16.86%; vertical-align: bottom; border-bottom: 2px solid rgb(0, 0, 0);">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Jurisdiction</div>
        </td>

    <td style="width: 1.67%; vertical-align: bottom;">&#160;</td>

    <td style="width: 11.11%; vertical-align: bottom; border-bottom: 2px solid rgb(0, 0, 0);">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Patent No.</div>
        </td>

    <td style="width: 1.67%; vertical-align: bottom;">&#160;</td>

    <td style="width: 27.72%; vertical-align: bottom; border-bottom: 2px solid rgb(0, 0, 0);">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Title</div>
        </td>

    <td style="width: 1.67%; vertical-align: bottom;">&#160;</td>

    <td style="width: 12.82%; vertical-align: bottom; border-bottom: #000000 2px solid;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Expiration</div>
        </td>

    <td style="width: 1.67%; vertical-align: bottom;">&#160;</td>

    <td style="width: 24.82%; vertical-align: bottom; border-bottom: 2px solid rgb(0, 0, 0);">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Description of Claims</div>
        </td>

  </tr>

  <tr>

    <td style="width: 16.86%; vertical-align: top; background-color: rgb(204, 238, 255);">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">United States</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 11.11%; vertical-align: top; background-color: rgb(204, 238, 255);">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">10,683,499</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 27.72%; vertical-align: top; background-color: rgb(204, 238, 255);">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">COMPOSITIONS AND METHODS FOR MODULATING TTR EXPRESSION</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 12.82%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">2034</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 24.82%; vertical-align: top; background-color: rgb(204, 238, 255);">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Composition of eplontersen</div>
        </td>

  </tr>

  <tr>

    <td style="width: 16.86%; vertical-align: top; background-color: rgb(255, 255, 255);">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Europe</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 11.11%; vertical-align: top; background-color: rgb(255, 255, 255);">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">3524680</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 27.72%; vertical-align: top; background-color: rgb(255, 255, 255);">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">COMPOSITIONS AND METHODS FOR MODULATING TTR EXPRESSION</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 12.82%; vertical-align: top; background-color: #FFFFFF;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">2034</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 24.82%; vertical-align: top; background-color: rgb(255, 255, 255);">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Composition of eplontersen</div>
        </td>

  </tr>


</table>
  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic; font-weight: bold;">Olezarsen and ApoC-III</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We believe olezarsen is protected from generic competition in the U.S. and Europe until at least 2034. Additional patent
    applications to protect olezarsen in other foreign jurisdictions are being pursued. The table below lists some key issued patents protecting olezarsen in the U.S. and Europe.</div>

  <div><br />
  </div>

  <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; border-collapse: collapse; text-align: left; color: #000000;">


  <tr>

    <td style="width: 16.86%; vertical-align: bottom; border-bottom: 2px solid rgb(0, 0, 0);">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Jurisdiction</div>
        </td>

    <td style="width: 1.67%; vertical-align: bottom;">&#160;</td>

    <td style="width: 11.11%; vertical-align: bottom; border-bottom: #000000 2px solid;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Patent No.</div>
        </td>

    <td style="width: 1.67%; vertical-align: bottom;">&#160;</td>

    <td style="width: 27.72%; vertical-align: bottom; border-bottom: 2px solid rgb(0, 0, 0);">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Title</div>
        </td>

    <td style="width: 1.67%; vertical-align: bottom;">&#160;</td>

    <td style="width: 12.82%; vertical-align: bottom; border-bottom: #000000 2px solid;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Expiration</div>
        </td>

    <td style="width: 1.67%; vertical-align: bottom;">&#160;</td>

    <td style="width: 24.82%; vertical-align: bottom; border-bottom: 2px solid rgb(0, 0, 0);">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Description of Claims</div>
        </td>

  </tr>

  <tr>

    <td style="width: 16.86%; vertical-align: top; background-color: rgb(204, 238, 255);">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">United States</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 11.11%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">9,163,239</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 27.72%; vertical-align: top; background-color: rgb(204, 238, 255);">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">COMPOSITIONS AND METHODS FOR MODULATING APOLIPOPROTEIN C-III EXPRESSION</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 12.82%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">2034</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 24.82%; vertical-align: top; background-color: rgb(204, 238, 255);">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Composition of olezarsen</div>
        </td>

  </tr>

  <tr>

    <td style="width: 16.86%; vertical-align: top; background-color: rgb(255, 255, 255);">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Europe</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 11.11%; vertical-align: top; background-color: #FFFFFF;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">2991656</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 27.72%; vertical-align: top; background-color: rgb(255, 255, 255);">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">COMPOSITIONS AND METHODS FOR MODULATING APOLIPOPROTEIN C-III EXPRESSION</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 12.82%; vertical-align: top; background-color: #FFFFFF;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">2034</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 24.82%; vertical-align: top; background-color: rgb(255, 255, 255);">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Composition of olezarsen</div>
        </td>

  </tr>


</table>
  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic; font-weight: bold;">Donidalorsen and PKK</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We believe donidalorsen is protected from generic competition in the U.S. and Europe until at least 2035. Additional
    patent applications to protect donidalorsen in other foreign jurisdictions are being pursued. The table below lists some key issued patents protecting donidalorsen in the U.S. and Europe.</div>

  <div><br />
  </div>

  <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; border-collapse: collapse; text-align: left; color: #000000;">


  <tr>

    <td style="width: 16.86%; vertical-align: bottom; border-bottom: 2px solid rgb(0, 0, 0);">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Jurisdiction</div>
        </td>

    <td style="width: 1.67%; vertical-align: bottom;">&#160;</td>

    <td style="width: 11.11%; vertical-align: bottom; border-bottom: 2px solid rgb(0, 0, 0);">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Patent No.</div>
        </td>

    <td style="width: 1.67%; vertical-align: bottom;">&#160;</td>

    <td style="width: 27.72%; vertical-align: bottom; border-bottom: 2px solid rgb(0, 0, 0);">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Title</div>
        </td>

    <td style="width: 1.67%; vertical-align: bottom;">&#160;</td>

    <td style="width: 12.82%; vertical-align: bottom; border-bottom: #000000 2px solid;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Expiration</div>
        </td>

    <td style="width: 1.67%; vertical-align: bottom;">&#160;</td>

    <td style="width: 24.82%; vertical-align: bottom; border-bottom: 2px solid rgb(0, 0, 0);">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Description of Claims</div>
        </td>

  </tr>

  <tr>

    <td style="width: 16.86%; vertical-align: top; background-color: rgb(204, 238, 255);">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">United States</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 11.11%; vertical-align: top; background-color: rgb(204, 238, 255);">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">9,315,811</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 27.72%; vertical-align: top; background-color: rgb(204, 238, 255);">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">METHODS FOR MODULATING KALLIKREIN (KLKB1) EXPRESSION</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 12.82%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">2032</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 24.82%; vertical-align: top; background-color: rgb(204, 238, 255);">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Methods of treating HAE</div>
        </td>

  </tr>

  <tr>

    <td style="width: 16.86%; vertical-align: top; background-color: rgb(255, 255, 255);">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Europe</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 11.11%; vertical-align: top; background-color: rgb(255, 255, 255);">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">2717923</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 27.72%; vertical-align: top; background-color: rgb(255, 255, 255);">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">METHODS FOR MODULATING KALLIKREIN (KLKB1) EXPRESSION</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 12.82%; vertical-align: top; background-color: #FFFFFF;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">2032</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 24.82%; vertical-align: top; background-color: rgb(255, 255, 255);">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Compounds for use in treating an inflammatory condition, including HAE</div>
        </td>

  </tr>

  <tr>

    <td style="width: 16.86%; vertical-align: top; background-color: rgb(204, 238, 255);">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">United States</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 11.11%; vertical-align: top; background-color: rgb(204, 238, 255);">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">10,294,477</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 27.72%; vertical-align: top; background-color: rgb(204, 238, 255);">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">COMPOSITIONS AND METHODS FOR MODULATING PKK EXPRESSION</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 12.82%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">2035</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 24.82%; vertical-align: top; background-color: rgb(204, 238, 255);">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Composition of donidalorsen</div>
        </td>

  </tr>

  <tr>

    <td style="width: 16.86%; vertical-align: top; background-color: rgb(255, 255, 255);">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Europe</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 11.11%; vertical-align: top; background-color: rgb(255, 255, 255);">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">3137091</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 27.72%; vertical-align: top; background-color: rgb(255, 255, 255);">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">COMPOSITIONS AND METHODS FOR MODULATING PKK EXPRESSION</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 12.82%; vertical-align: top; background-color: #FFFFFF;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">2035</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 24.82%; vertical-align: top; background-color: rgb(255, 255, 255);">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Composition of donidalorsen</div>
        </td>

  </tr>


</table>
  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic; font-weight: bold;">ION363 and FUS</div>

  <div style="text-align: justify; text-indent: 36pt;"><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Patent applications designed to protect ION363 from generic competition are being pursued in the U.S. and Europe; patents issuing from
    these applications would have term until at least 2040. <span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">The table below lists some key pending patent applications designed to protect ION363</span> in the
    U.S. and Europe:</div>

  <div style="text-align: justify; text-indent: 36pt;"><br />
  </div>

  <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; border-collapse: collapse; text-align: left; color: #000000;">


  <tr>

    <td style="width: 16.86%; vertical-align: bottom; border-bottom: #000000 2px solid;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Jurisdiction</div>
        </td>

    <td style="width: 1.67%; vertical-align: bottom;">&#160;</td>

    <td style="width: 11.11%; vertical-align: bottom; border-bottom: 2px solid rgb(0, 0, 0);">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Application No.</div>
        </td>

    <td style="width: 1.67%; vertical-align: bottom;">&#160;</td>

    <td style="width: 27.72%; vertical-align: bottom; border-bottom: 2px solid rgb(0, 0, 0);">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Title</div>
        </td>

    <td style="width: 1.67%; vertical-align: bottom;">&#160;</td>

    <td style="width: 12.82%; vertical-align: bottom; border-bottom: #000000 2px solid;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Expiration</div>
        </td>

    <td style="width: 1.67%; vertical-align: bottom;">&#160;</td>

    <td style="width: 24.82%; vertical-align: bottom; border-bottom: 2px solid rgb(0, 0, 0);">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Description of Claims</div>
        </td>

  </tr>

  <tr>

    <td style="width: 16.86%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">United States</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 11.11%; vertical-align: top; background-color: rgb(204, 238, 255);">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">17/613,183</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 27.72%; vertical-align: top; background-color: rgb(204, 238, 255);">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">COMPOUNDS AND METHODS FOR REDUCING FUS EXPRESSION</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 12.82%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">2040</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 24.82%; vertical-align: top; background-color: rgb(204, 238, 255);">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Composition of ION363</div>
        </td>

  </tr>

  <tr>

    <td style="width: 16.86%; vertical-align: top; background-color: #FFFFFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Europe</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 11.11%; vertical-align: top; background-color: rgb(255, 255, 255);">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">20815459.1</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 27.72%; vertical-align: top; background-color: rgb(255, 255, 255);">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">COMPOUNDS AND METHODS FOR REDUCING FUS EXPRESSION</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 12.82%; vertical-align: top; background-color: #FFFFFF;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">2040</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 24.82%; vertical-align: top; background-color: rgb(255, 255, 255);">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Composition of ION363</div>
        </td>

  </tr>


</table>
  <div><br />
  </div>

  <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" class="DSPFPageBreakArea">
    <div class="DSPFPageFooter">
      <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span class="DSPFPageNumber">38</span></div>

    </div>

    <div style="page-break-after:always;" class="DSPFPageBreak">
      <hr style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;" /></div>


  </div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic; font-weight: bold;">Pelacarsen and Apo(a)</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We believe pelacarsen<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> is protected from
      generic competition in the U.S. and Europe until at least 2034. Additional patent protection designed to protect pelacarsen in other foreign jurisdictions is being pursued. The table below lists some key issued patents protecting </span>pelacarsen<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> in the U.S. and Europe:</span></div>

  <div><br />
  </div>

  <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; border-collapse: collapse; text-align: left; color: #000000;">


  <tr>

    <td style="width: 16.86%; vertical-align: bottom; border-bottom: #000000 2px solid;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Jurisdiction</div>
        </td>

    <td style="width: 1.67%; vertical-align: bottom;">&#160;</td>

    <td style="width: 11.11%; vertical-align: bottom; border-bottom: 2px solid rgb(0, 0, 0);">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Patent No.</div>
        </td>

    <td style="width: 1.67%; vertical-align: bottom;">&#160;</td>

    <td style="width: 27.72%; vertical-align: bottom; border-bottom: 2px solid rgb(0, 0, 0);">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Title</div>
        </td>

    <td style="width: 1.67%; vertical-align: bottom;">&#160;</td>

    <td style="width: 12.82%; vertical-align: bottom; border-bottom: #000000 2px solid;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Expiration</div>
        </td>

    <td style="width: 1.67%; vertical-align: bottom;">&#160;</td>

    <td style="width: 24.82%; vertical-align: bottom; border-bottom: 2px solid rgb(0, 0, 0);">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Description of Claims</div>
        </td>

  </tr>

  <tr>

    <td style="width: 16.86%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">United States</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 11.11%; vertical-align: top; background-color: rgb(204, 238, 255);">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">9,574,193</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 27.72%; vertical-align: top; background-color: rgb(204, 238, 255);">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">METHODS AND COMPOSITIONS FOR MODULATING APOLIPOPROTEIN (A) EXPRESSION</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 12.82%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">2033</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 24.82%; vertical-align: top; background-color: rgb(204, 238, 255);">
          <div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">Methods of lowering Apo(a) and/or Lp(a) levels with an
              oligonucleotide complementary within the nucleotide region of Apo(a) targeted by p</span>elacarsen</div>
        </td>

  </tr>

  <tr>

    <td style="width: 16.86%; vertical-align: top; background-color: #FFFFFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">United States</div>
          <div>&#160;</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 11.11%; vertical-align: top; background-color: rgb(255, 255, 255);">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">10,478,448</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 27.72%; vertical-align: top; background-color: rgb(255, 255, 255);">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">METHODS AND COMPOSITIONS FOR MODULATING APOLIPOPROTEIN (A) EXPRESSION</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 12.82%; vertical-align: top; background-color: #FFFFFF;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">2033</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 24.82%; vertical-align: top; background-color: rgb(255, 255, 255);">
          <div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">Methods of treating hyperlipidemia with an oligonucleotide
              complementary within the nucleotide region of Apo(a) targeted by p</span>elacarsen</div>
        </td>

  </tr>

  <tr>

    <td style="width: 16.86%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">United States</div>
          <div>&#160;</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 11.11%; vertical-align: top; background-color: rgb(204, 238, 255);">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">9,884,072</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 27.72%; vertical-align: top; background-color: rgb(204, 238, 255);">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">METHODS AND COMPOSITIONS FOR MODULATING APOLIPOPROTEIN (A) EXPRESSION</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 12.82%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">2033</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 24.82%; vertical-align: top; background-color: rgb(204, 238, 255);">
          <div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Oligonucleotides complementary within the nucleotide region of Apo(a) targeted by pelacarsen</div>
        </td>

  </tr>

  <tr>

    <td style="width: 16.86%; vertical-align: top; background-color: #FFFFFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Europe</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 11.11%; vertical-align: top; background-color: rgb(255, 255, 255);">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">2855500</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 27.72%; vertical-align: top; background-color: rgb(255, 255, 255);">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">METHODS AND COMPOSITIONS FOR MODULATING APOLIPOPROTEIN (A) EXPRESSION</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 12.82%; vertical-align: top; background-color: #FFFFFF;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">2033</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 24.82%; vertical-align: top; background-color: rgb(255, 255, 255);">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Oligonucleotides complementary within the nucleotide region of Apo(a) targeted by pelacarsen for decreasing Apo(a) expression</div>
        </td>

  </tr>

  <tr>

    <td style="width: 16.86%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">United States</div>
          <div>&#160;</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 11.11%; vertical-align: top; background-color: rgb(204, 238, 255);">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">9,181,550</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 27.72%; vertical-align: top; background-color: rgb(204, 238, 255);">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">COMPOSITIONS AND METHODS FOR MODULATING APOLIPOPROTEIN (a) EXPRESSION</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 12.82%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">2034</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 24.82%; vertical-align: top; background-color: rgb(204, 238, 255);">
          <div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">Composition of p</span>elacarsen</div>
        </td>

  </tr>

  <tr>

    <td style="width: 16.86%; vertical-align: top; background-color: #FFFFFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Europe</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 11.11%; vertical-align: top; background-color: rgb(255, 255, 255);">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">2992009</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 27.72%; vertical-align: top; background-color: rgb(255, 255, 255);">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">COMPOSITIONS AND METHODS FOR MODULATING APOLIPOPROTEIN (a) EXPRESSION</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 12.82%; vertical-align: top; background-color: #FFFFFF;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">2034</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 24.82%; vertical-align: top; background-color: rgb(255, 255, 255);">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Composition of pelacarsen</div>
        </td>

  </tr>


</table>
  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic; font-weight: bold;">Tofersen and SOD-1</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We believe tofersen is protected from generic competition in the U.S. and Europe until at least 2035. Additional patent applications
    designed to protect tofersen in other foreign jurisdictions are being pursued. With Biogen&#8217;s license of tofersen, we assigned our interest in these patents to Biogen. <span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">The table below lists some key issued patents protecting t</span>ofersen in the U.S. and Europe:</div>

  <div><br />
  </div>

  <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; border-collapse: collapse; text-align: left; color: #000000;">


  <tr>

    <td style="width: 16.86%; vertical-align: bottom; border-bottom: #000000 2px solid;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Jurisdiction</div>
        </td>

    <td style="width: 1.67%; vertical-align: bottom;">&#160;</td>

    <td style="width: 11.11%; vertical-align: bottom; border-bottom: 2px solid rgb(0, 0, 0);">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Patent No.</div>
        </td>

    <td style="width: 1.67%; vertical-align: bottom;">&#160;</td>

    <td style="width: 27.72%; vertical-align: bottom; border-bottom: 2px solid rgb(0, 0, 0);">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Title</div>
        </td>

    <td style="width: 1.67%; vertical-align: bottom;">&#160;</td>

    <td style="width: 12.82%; vertical-align: bottom; border-bottom: #000000 2px solid;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Expiration</div>
        </td>

    <td style="width: 1.67%; vertical-align: bottom;">&#160;</td>

    <td style="width: 24.82%; vertical-align: bottom; border-bottom: 2px solid rgb(0, 0, 0);">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Description of Claims</div>
        </td>

  </tr>

  <tr>

    <td style="width: 16.86%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">United States</div>
          <div>&#160;</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 11.11%; vertical-align: top; background-color: rgb(204, 238, 255);">
          <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">10,385,341</div>
          <div>&#160;</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 27.72%; vertical-align: top; background-color: rgb(204, 238, 255);">
          <div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">COMPOSITIONS FOR MODULATING SOD-1 EXPRESSION</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 12.82%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">2035</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 24.82%; vertical-align: top; background-color: rgb(204, 238, 255);">
          <div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Composition of tofersen</div>
        </td>

  </tr>

  <tr>

    <td style="width: 16.86%; vertical-align: top; background-color: #FFFFFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">United States</div>
          <div>&#160;</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 11.11%; vertical-align: top; background-color: rgb(255, 255, 255);">
          <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">10,669,546</div>
          <div>&#160;</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 27.72%; vertical-align: top; background-color: rgb(255, 255, 255);">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">COMPOSITIONS FOR MODULATING SOD-1 EXPRESSION</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 12.82%; vertical-align: top; background-color: #FFFFFF;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">2035</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 24.82%; vertical-align: top; background-color: rgb(255, 255, 255);">
          <div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Methods of treating a SOD-1 associated neurodegenerative disorder by administering tofersen</div>
        </td>

  </tr>

  <tr>

    <td style="width: 16.86%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">United States</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 11.11%; vertical-align: top; background-color: rgb(204, 238, 255);">
          <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">10,968,453</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 27.72%; vertical-align: top; background-color: rgb(204, 238, 255);">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">COMPOSITIONS FOR MODULATING SOD-1 EXPRESSION</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 12.82%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">2035</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 24.82%; vertical-align: top; background-color: rgb(204, 238, 255);">
          <div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Methods of treating a SOD-1 associated neurodegenerative disorder by administering a pharmaceutical composition of tofersen</div>
        </td>

  </tr>

  <tr>

    <td style="width: 16.86%; vertical-align: top; background-color: #FFFFFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Europe</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 11.11%; vertical-align: top; background-color: rgb(255, 255, 255);">
          <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">3126499</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 27.72%; vertical-align: top; background-color: rgb(255, 255, 255);">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">COMPOSITIONS FOR MODULATING SOD-1 EXPRESSION</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 12.82%; vertical-align: top; background-color: #FFFFFF;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">2035</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 24.82%; vertical-align: top; background-color: rgb(255, 255, 255);">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Composition of tofersen</div>
        </td>

  </tr>


</table>
  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We seek patent protection in significant markets and/or countries for each medicine in development. We also seek to
    maximize patent term. In some cases, the patent term can be extended to recapture a portion of the term lost during FDA regulatory review. The patent exclusivity period for a medicine will prevent generic medicines from entering the market. Patent
    exclusivity depends on a number of factors including initial patent term and available patent term extensions based upon delays caused by the regulatory approval process.</div>

  <div><br />
  </div>

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  <div style="text-align: left; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"><span style="text-decoration: underline;">Manufacturing Patents</span></div>

  <div style="text-align: justify; text-indent: 36pt;"><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We also own patents claiming methods of manufacturing and purifying oligonucleotides. These patents claim methods for
    improving oligonucleotide drug manufacturing, including processes for large-scale oligonucleotide synthesis and purification. These methods allow us to manufacture oligonucleotides at lower cost by, for example, eliminating expensive manufacturing
    steps.</div>

  <div style="text-align: justify; text-indent: 36pt;"><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We also rely on trade secrets, proprietary know-how and continuing technological innovation to develop and maintain a
    competitive position in antisense therapeutics.</div>

  <div><br />
  </div>

  <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Government Regulation</div>

  <div style="text-align: justify;"><br />
  </div>

  <div style="text-align: justify; text-indent: 35pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Regulation by government authorities in the U.S. and other countries is a significant component in the development,
    manufacture and commercialization of pharmaceutical products and services. In addition to regulations enforced by the FDA and relevant foreign regulatory authorities, we are also subject to regulation under the Occupational Safety and Health Act, the
    Environmental Protection Act, the Toxic Substances Control Act, the Resource Conservation and Recovery Act and other present and potential future federal, state and local regulations.</div>

  <div style="text-align: justify; text-indent: 35pt;"><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Extensive regulation by the U.S. and foreign governmental authorities governs the development, manufacture and sale of our
    medicines. In particular, our medicines are subject to a number of approval requirements by the FDA in the U.S. under the Federal Food, Drug and Cosmetic Act, or FDCA, and other laws and by comparable agencies in those foreign countries in which we
    conduct business. The FDCA and other various federal, state and foreign statutes govern or influence the research, testing, manufacture, safety, labeling, storage, recordkeeping, approval, promotion, marketing, distribution, post-approval monitoring
    and reporting, sampling, quality, and import and export of our medicines. State, local, and other authorities also regulate pharmaceutical manufacturing facilities and procedures.</div>

  <div style="text-align: justify; text-indent: 36pt;"><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Our manufacturing facility and our CMOs are subject to periodic inspection by the FDA and other foreign equivalents to
    ensure that they are operating in compliance with cGMP requirements. In addition, marketing authorization for each new medicine may require a rigorous manufacturing pre-approval inspection by regulatory authorities. Post approval, there are strict
    regulations regarding changes to the manufacturing process, and, depending on the significance of the change, changes may require prior FDA approval. FDA regulations also require investigation and correction of any deviations from cGMP and impose
    reporting and documentation requirements upon us and any third-party manufacturers that we may decide to use.</div>

  <div style="text-align: justify; text-indent: 36pt;"><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">The FDA must approve any new medicine before a manufacturer can market it in the U.S. In order to obtain approval, we and
    our partners must complete clinical studies and prepare and submit an NDA to the FDA. If the FDA approves a medicine, it will issue an approval letter authorizing commercial marketing of the medicine and may require a risk evaluation and mitigation
    strategy, or REMS, to help ensure the benefits of the medicine outweigh the potential risks. For example, TEGSEDI has a REMS program. The requirements for REMS can materially affect the potential market and profitability of our medicines. In foreign
    jurisdictions, the drug approval process is similarly demanding.</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">For any approved medicine, domestic and foreign sales of the medicine depend, in part, on the availability and amount of
    coverage and adequate reimbursement by third-party payers, including governments and private health plans. The process for determining whether a payer will provide coverage for a product may be separate from the process for setting the reimbursement
    rate that the payer will pay for the product, or procedures which utilize such product. Private health plans may seek to manage cost and use of our medicines by implementing coverage and reimbursement limitations. For example, third-party payers may
    limit coverage to specific products on an approved list, or formulary, which might not include all of U.S. FDA-approved products for a particular indication. In certain jurisdictions, governments may also regulate or influence coverage, reimbursement
    and/or pricing of our medicines to control cost or affect use. Within the EU a variety of payers pay for medicines, with governments being the primary source of payment. Negotiating pricing with governmental authorities can delay commercialization.
    Such pricing and reimbursement factors could impact our ability and that of our commercial partners to successfully commercialize approved medicines. Further, it is possible that additional governmental action is taken in response to the COVID-19
    pandemic.</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">In the U.S. and foreign jurisdictions, the legislative landscape continues to evolve. There have been a number of
    legislative and regulatory changes to the healthcare system that could affect our future results of operations. In particular, there have been and continue to be a number of initiatives at the U.S. federal and state levels and by foreign governments
    that seek to reduce healthcare costs. There has also been heightened governmental scrutiny over the manner in which manufacturers set prices for their marketed products, which has resulted in efforts to bring more transparency to drug pricing, review
    the relationship between pricing and manufacturer patient programs, and reform government program reimbursement methodologies for medicines. Further, it is possible that additional governmental action is taken in response to the COVID-19 pandemic.</div>

  <div><br />
  </div>

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  <div><br />
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  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">In addition, the distribution of prescription pharmaceutical products is subject to the Drug Supply Chain Security Act, or
    DSCA, which regulates the distribution and tracing of prescription drugs and prescription drug samples at the federal level, and set minimum standards for the regulation of drug distributors by the states. The DSCA imposes requirements to ensure
    accountability in distribution and to identify and remove counterfeit and other illegitimate products from the market.</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Other healthcare laws that may affect our ability to operate include, for example, the following:</div>

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    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">The federal Health Insurance Portability and Accountability Act of 1996, or HIPAA, as amended by the Health Information Technology for Economic and
            Clinical Health Act, which governs the conduct of certain electronic healthcare transactions and protects the security and privacy of protected health information;</div>
        </td>

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    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Foreign and state laws governing the privacy and security of health information, such as the General Data Protection Regulation, or GDPR, in the EU; and
            the California Consumer Privacy Act, or CCPA, in California, some of which are more stringent than HIPAA and many of which differ from each other in significant ways and may not have the same effect; and</div>
        </td>

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    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">The Physician Payments Sunshine Act, which requires manufacturers of medicines, devices, biologics, and medical supplies to report annually to the U.S.
            Department of Health and Human Services information related to payments and other transfers of value to physicians (defined to include doctors, dentists, optometrists, podiatrists, and chiropractors), other healthcare providers (such as
            physician assistants and nurse practitioners), and teaching hospitals, and ownership and investment interests held by physicians and their immediate family members.</div>
        </td>

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  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;">Sales and Marketing</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 40.8pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Numerous regulatory authorities in addition to the FDA, including, in the U.S., the Centers for Medicare and Medicaid
    Services, other divisions of the U.S. Department of Health and Human Services, the U.S. Department of Justice, and similar foreign, state and local government authorities, regulate sales, promotion and other activities following drug approval. As
    described above, the FDA regulates all advertising and promotion activities for drugs under its jurisdiction both prior to and after approval. Only those claims relating to safety and efficacy that the FDA has approved may be used in labeling.
    Physicians may prescribe legally available drugs for uses that are not described in the drug&#8217;s labeling and that differ from those we tested and the FDA approved. Such off-label uses are common across medical specialties and often reflect a physician&#8217;s
    belief that the off-label use is the best treatment for the patients. The FDA does not regulate the behavior of physicians in their choice of treatments, but FDA regulations do impose stringent restrictions on manufacturers&#8217; communications regarding
    off-label uses. If we do not comply with applicable FDA requirements, we may face adverse publicity, enforcement action by the FDA, corrective advertising, consent decrees and the full range of civil and criminal penalties available to the FDA.
    Promotion of off-label uses of drugs can also implicate the false claims laws described below.</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 40.8pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">In the U.S. sales, marketing and scientific/educational programs must also comply with various federal and state laws
    pertaining to healthcare &#8220;fraud and abuse,&#8221; including anti-kickback laws and false claims laws. Anti-kickback laws make it illegal for a prescription drug manufacturer to solicit, offer, receive, or pay any remuneration in exchange for, or to induce,
    the referral of business, including the purchase or prescription of a particular drug. Due to the breadth of the statutory provisions, limited statutory exceptions and regulatory safe harbors, and the absence of guidance in the form of regulations and
    very few court decisions addressing industry practices, it is possible that our practices might be challenged under anti-kickback or similar laws. Moreover, recent healthcare reform legislation has strengthened these laws. For example, the Patient
    Protection and Affordable Act, as amended by the Health Care and Education Reconciliation Act of 2010, or Affordable Care Act, among other things, amends the intent requirement of the federal anti-kickback and criminal healthcare fraud statutes to
    clarify that a person or entity does not need to have actual knowledge of this statute or specific intent to violate it. In addition, the Affordable Care Act clarifies that the government may assert that a claim that includes items or services
    resulting from a violation of the federal anti-kickback statute constitutes a false or fraudulent claim for purposes of the false claims statutes. False claims laws prohibit anyone from knowingly and willingly presenting, or causing to be presented for
    payment, to third-party payers (including Medicare and Medicaid) claims for reimbursed drugs or services that are false or fraudulent, claims for items or services not provided as claimed, or claims for medically unnecessary items or services. Our
    activities relating to the sale and marketing of our drugs may be subject to scrutiny under these laws. Violations of fraud and abuse laws may be punishable by criminal and civil sanctions, including fines and civil monetary penalties, the possibility
    of exclusion from federal healthcare programs (including Medicare and Medicaid) and corporate integrity agreements, which impose, among other things, rigorous operational and monitoring requirements on companies. Similar sanctions and penalties also
    can be imposed upon executive officers and employees, including criminal sanctions against executive officers under the so-called &#8220;responsible corporate officer&#8221; doctrine, even in situations where the executive officer did not intend to violate the law
    and was unaware of any wrongdoing.</div>

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  <div style="text-align: justify; text-indent: 40.8pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Given the significant penalties and fines that can be imposed on companies and individuals if convicted, allegations of
    such violations often result in settlements even if the company or individual being investigated admits no wrongdoing. Settlements often include significant civil sanctions, including fines and civil monetary penalties, and corporate integrity
    agreements. If the government were to allege or convict us or our executive officers of violating these laws, our business could be harmed. In addition, private individuals can bring similar actions. Our activities could be subject to challenge for the
    reasons discussed above and due to the broad scope of these laws and the increasing attention being given to them by law enforcement authorities. Other healthcare laws that may affect our ability to operate include HIPAA, which prohibits, among other
    things, executing or attempting to execute a scheme to defraud any healthcare benefit program or making false statements relating to healthcare matters. HIPAA, as amended by the Health Information Technology for Economic and Clinical Health Act, also
    governs the conduct of certain electronic healthcare transactions and protects the security and privacy of protected health information; analogous state laws governing the privacy and security of health information, some of which are more stringent
    than HIPAA and many of which differ from each other in significant ways and may not have the same effect, and the Physician Payments Sunshine Act, which requires manufacturers of drugs, devices, biologics, and medical supplies to report annually to the
    U.S. Department of Health and Human Services information related to payments and other transfers of value to physicians, other healthcare providers and teaching hospitals, and ownership and investment interests held by physicians and their immediate
    family members. Further, there are an increasing number of state laws that require manufacturers to make reports to states on pricing and marketing information. Many of these laws contain ambiguities as to what is required to comply with the laws.
    Given the lack of clarity in laws and their implementation, our reporting actions could be subject to the penalty provisions of the pertinent state authorities.</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 40.8pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Similar rigid restrictions are imposed on the promotion and marketing of drugs in the E.U. and other countries. Even in
    those countries where we may not be directly responsible for the promotion and marketing of our medicines, if our potential international distribution partners engage in inappropriate activity, it can have adverse implications for us.</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">The U.S. Foreign Corrupt Practices Act, or FCPA, prohibits certain individuals and entities, including us, from promising,
    paying, offering to pay, or authorizing the payment of anything of value to any foreign government official, directly or indirectly, to obtain or retain business or an improper advantage. If we violate the FCPA, it could result in large civil and
    criminal penalties as well as an adverse effect on our reputation, operations, and financial condition. We could also face collateral consequences such as debarment and the loss of export privileges.</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Both the federal and state governments in the U.S. and foreign governments continue to propose and pass new legislation and regulations
    designed to contain or reduce the cost of healthcare. For example, in July 2021, the Biden administration released an executive order, &#8220;Promoting Competition in the American Economy,&#8221; with multiple provisions aimed at prescription drugs. In response to
    Biden&#8217;s executive order, on September 9, 2021, the U.S. Department of Health and Human Services, or HHS, released a Comprehensive Plan for Addressing High Drug Prices that outlines principles for drug pricing reform and sets out a variety of potential
    legislative policies that Congress could pursue as well as potential administrative actions HHS can take to advance these principles. No legislation or administrative actions have been finalized to implement these principles. Congress is also
    considering additional health reform measures. Such legislation and regulations may result in decreased reimbursement, which may further exacerbate industry-wide pressure to reduce the prices charged for medical products.</div>

  <div><br />
  </div>

  <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Competition</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 39.6pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;">Our Business in General</div>

  <div style="text-align: justify; text-indent: 39.6pt;"><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Some of our medicines may compete with existing therapies for market share and some of our medicines in development may
    compete for patients in clinical trials. In addition, there are a number of companies pursuing the development of oligonucleotide-based technologies and the development of pharmaceuticals utilizing these technologies. These companies include
    biopharmaceutical companies and large pharmaceutical companies acting either independently or together. Our medicines are differentiated from traditional small molecule medicines by their chemistry, how they move in the body, how they act in the body,
    delivery technology, and formulations.</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Our approved medicines and our medicines under development address numerous markets. The diseases our medicines target for which we have
    or may receive marketing authorization will determine our competition. For some of our medicines, an important factor may be the timing of market introduction of competitive products. Accordingly, the relative speed with which we can develop medicines,
    complete the clinical trials and marketing authorization processes and supply commercial quantities of the medicines to the market are important competitive factors. We expect to compete with products approved for sale based on a variety of factors,
    including, among other things, product efficacy, safety, mechanism of action, dosing convenience, marketing and sales strategy and tactics, availability, price, and reimbursement.</div>

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  <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Below we have included what we believe to be the competitive landscape for our marketed medicines and for the medicines we currently have
    in Phase 3 trials. We have included medicines that we believe compete or may compete directly with our medicines. We included competitors, potential competitors that are past Phase 1 development or potential competitors that plan to start a pivotal
    study this year.<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> We do not believe that any medicines meet these criteria to compete with ION363.</span></div>

  <div><br />
  </div>

  <div style="text-align: justify; margin-left: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;">SPINRAZA</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We consider the following medicines as competitors to SPINRAZA for the indication of SMA:</div>

  <div><br />
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          <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Medicine</div>
        </td>

    <td style="width: 1.67%; vertical-align: bottom;">&#160;</td>

    <td style="width: 12.15%; vertical-align: bottom; border-bottom: #000000 2px solid;">
          <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Company</div>
        </td>

    <td style="width: 2.42%; vertical-align: bottom;">&#160;</td>

    <td style="width: 22.53%; vertical-align: bottom; border-bottom: #000000 2px solid;">
          <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Medicine Description</span><sup> (1)</sup></div>
        </td>

    <td style="width: 2.42%; vertical-align: bottom;">&#160;</td>

    <td style="width: 20.85%; vertical-align: bottom; border-bottom: #000000 2px solid;">
          <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Phase</span><sup> (1)</sup></div>
        </td>

    <td style="width: 1.67%; vertical-align: bottom;">&#160;</td>

    <td style="width: 18.24%; vertical-align: bottom; border-bottom: #000000 2px solid;">
          <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Route of Administration</span><sup> (1)</sup></div>
        </td>

  </tr>

  <tr>

    <td style="width: 18.07%; vertical-align: middle; background-color: #CCEEFF;">
          <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Zolgensma</div>
          <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(Onasemnogene abeparvovec)</div>
        </td>

    <td style="width: 1.67%; vertical-align: middle; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 12.15%; vertical-align: middle; background-color: #CCEEFF;">
          <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Novartis</div>
        </td>

    <td style="width: 2.42%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 22.53%; vertical-align: middle; background-color: #CCEEFF;">
          <div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Gene therapy targeting the genetic root cause of SMA by replacing the missing or nonworking SMN1 gene</div>
        </td>

    <td style="width: 2.42%; vertical-align: middle; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 20.85%; vertical-align: middle; background-color: #CCEEFF;">
          <div style="text-align: center; font-family: 'Times New Roman',Times,serif; font-size: 10pt;">Approved for pediatric SMA patients less than 2 years of age</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 18.24%; vertical-align: middle; background-color: #CCEEFF;">
          <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Intravenous infusion</div>
        </td>

  </tr>

  <tr>

    <td style="width: 18.07%; vertical-align: middle; background-color: #FFFFFF;">
          <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Evrysdi</div>
          <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(Risdiplam)</div>
        </td>

    <td style="width: 1.67%; vertical-align: middle; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 12.15%; vertical-align: middle; background-color: #FFFFFF;">
          <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Roche</div>
        </td>

    <td style="width: 2.42%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 22.53%; vertical-align: middle; background-color: #FFFFFF;">
          <div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">A small molecule medicine that modulates splicing of the SMN2 gene</div>
        </td>

    <td style="width: 2.42%; vertical-align: middle; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 20.85%; vertical-align: middle; background-color: #FFFFFF;">
          <div style="text-align: center; font-family: 'Times New Roman',Times,serif; font-size: 10pt;">Approved for SMA patients of 2 months or older</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 18.24%; vertical-align: middle; background-color: #FFFFFF;">
          <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Oral</div>
        </td>

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    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 8pt;">(1)</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 8pt;">Taken from public documents including respective company press releases, company presentations, and scientific presentations.</div>
        </td>

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  <div><br />
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  <div style="text-align: left; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;">TEGSEDI and Eplontersen</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We consider the following medicines as competitors and potential future competitors to TEGSEDI and eplontersen for the
    indication of hATTR amyloidosis and/or ATTR cardiomyopathy:</div>

  <div><br />
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          <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Medicine</div>
        </td>

    <td style="width: 1.67%; vertical-align: bottom;">&#160;</td>

    <td style="width: 12.15%; vertical-align: bottom; border-bottom: 2px solid rgb(0, 0, 0);">
          <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Company</div>
        </td>

    <td style="width: 2.42%; vertical-align: bottom;">&#160;</td>

    <td style="width: 22.53%; vertical-align: bottom; border-bottom: 2px solid rgb(0, 0, 0);">
          <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Medicine Description</span><sup> (1)</sup></div>
        </td>

    <td style="width: 2.42%; vertical-align: bottom;">&#160;</td>

    <td style="width: 20.85%; vertical-align: bottom; border-bottom: 2px solid rgb(0, 0, 0);">
          <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Phase</span><sup> (1)</sup></div>
        </td>

    <td style="width: 1.67%; vertical-align: bottom;">&#160;</td>

    <td style="width: 18.24%; vertical-align: bottom; border-bottom: #000000 2px solid;">
          <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Route of Administration</span><sup> (1)</sup></div>
        </td>

  </tr>

  <tr>

    <td style="width: 18.07%; vertical-align: middle; background-color: rgb(204, 238, 255);">
          <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Onpattro</div>
          <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(Patisiran)</div>
        </td>

    <td style="width: 1.67%; vertical-align: middle; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 12.15%; vertical-align: middle; background-color: rgb(204, 238, 255);">
          <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Alnylam</div>
        </td>

    <td style="width: 2.42%; vertical-align: middle; background-color: rgb(204, 238, 255);">&#160;</td>

    <td style="width: 22.53%; vertical-align: middle; background-color: rgb(204, 238, 255);">
          <div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">An RNAi medicine formulated with lipid nanoparticles to inhibit TTR mRNA</div>
        </td>

    <td style="width: 2.42%; vertical-align: middle; background-color: rgb(204, 238, 255);">&#160;</td>

    <td style="width: 20.85%; vertical-align: middle; background-color: rgb(204, 238, 255);">
          <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Approved hATTR/</div>
          <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Phase 3 ATTR-CM</div>
        </td>

    <td style="width: 1.67%; vertical-align: middle; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 18.24%; vertical-align: middle; background-color: #CCEEFF;">
          <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Intravenous infusion</div>
        </td>

  </tr>

  <tr>

    <td style="width: 18.07%; vertical-align: middle; background-color: rgb(255, 255, 255);">
          <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Vyndaqel/Vyndamax</div>
          <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(Tafamidis and tafamidis meglumine)</div>
        </td>

    <td style="width: 1.67%; vertical-align: middle; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 12.15%; vertical-align: middle; background-color: rgb(255, 255, 255);">
          <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Pfizer</div>
        </td>

    <td style="width: 2.42%; vertical-align: middle; background-color: rgb(255, 255, 255);">&#160;</td>

    <td style="width: 22.53%; vertical-align: middle; background-color: rgb(255, 255, 255);">
          <div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">A small molecule medicine to stabilize TTR protein</div>
        </td>

    <td style="width: 2.42%; vertical-align: middle; background-color: rgb(255, 255, 255);">&#160;</td>

    <td style="width: 20.85%; vertical-align: middle; background-color: rgb(255, 255, 255);">
          <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Approved in U.S., EU, Japan and select other markets for hATTR-PN and/or ATTR-CM; indications vary by region</div>
        </td>

    <td style="width: 1.67%; vertical-align: middle; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 18.24%; vertical-align: middle; background-color: #FFFFFF;">
          <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Oral</div>
        </td>

  </tr>

  <tr>

    <td style="width: 18.07%; vertical-align: middle; background-color: rgb(204, 238, 255);">
          <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Vutrisiran</div>
        </td>

    <td style="width: 1.67%; vertical-align: middle; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 12.15%; vertical-align: middle; background-color: rgb(204, 238, 255);">
          <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Alnylam</div>
        </td>

    <td style="width: 2.42%; vertical-align: middle; background-color: rgb(204, 238, 255);">&#160;</td>

    <td style="width: 22.53%; vertical-align: middle; background-color: rgb(204, 238, 255);">
          <div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">An RNAi medicine conjugated with GalNAC to inhibit TTR mRNA</div>
        </td>

    <td style="width: 2.42%; vertical-align: middle; background-color: rgb(204, 238, 255);">&#160;</td>

    <td style="width: 20.85%; vertical-align: middle; background-color: rgb(204, 238, 255);">
          <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Submitted US/EU for ATTR-PN, Phase 3 for ATTR-CM</div>
        </td>

    <td style="width: 1.67%; vertical-align: middle; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 18.24%; vertical-align: middle; background-color: #CCEEFF;">
          <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Subcutaneous Injection</div>
        </td>

  </tr>

  <tr>

    <td style="width: 18.07%; vertical-align: middle; background-color: rgb(255, 255, 255);">
          <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Acoramidis</div>
        </td>

    <td style="width: 1.67%; vertical-align: middle; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 12.15%; vertical-align: middle; background-color: rgb(255, 255, 255);">
          <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Bridgebio</div>
        </td>

    <td style="width: 2.42%; vertical-align: middle; background-color: rgb(255, 255, 255);">&#160;</td>

    <td style="width: 22.53%; vertical-align: middle; background-color: rgb(255, 255, 255);">
          <div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Small molecule that binds and stabilizes TTR in the blood</div>
        </td>

    <td style="width: 2.42%; vertical-align: middle; background-color: rgb(255, 255, 255);">&#160;</td>

    <td style="width: 20.85%; vertical-align: middle; background-color: rgb(255, 255, 255);">
          <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Phase 3 ATTR-CM</div>
        </td>

    <td style="width: 1.67%; vertical-align: middle; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 18.24%; vertical-align: middle; background-color: #FFFFFF;">
          <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Oral</div>
        </td>

  </tr>


</table>
  <div><br />
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  <tr>

    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 8pt;">(1)</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 8pt;">Taken from public documents including respective company press releases, company presentations, and scientific presentations.</div>
        </td>

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  <div><br />
  </div>

  <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" class="DSPFPageBreakArea">
    <div class="DSPFPageFooter">
      <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span class="DSPFPageNumber">43</span></div>

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  <div><br />
  </div>

  <div style="text-align: left; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;">WAYLIVRA and Olezarsen</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We believe that the following medicines could compete with WAYLIVRA and olezarsen in FCS and SHTG:</div>

  <div><br />
  </div>

  <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; border-collapse: collapse; text-align: left; color: #000000;">


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    <td style="width: 18.07%; vertical-align: bottom; border-bottom: 2px solid rgb(0, 0, 0);">
          <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Medicine</div>
        </td>

    <td style="width: 1.67%; vertical-align: bottom;">&#160;</td>

    <td style="width: 12.15%; vertical-align: bottom; border-bottom: 2px solid rgb(0, 0, 0);">
          <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Company</div>
        </td>

    <td style="width: 2.42%; vertical-align: bottom;">&#160;</td>

    <td style="width: 22.53%; vertical-align: bottom; border-bottom: 2px solid rgb(0, 0, 0);">
          <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Medicine Description</span><sup> (1)</sup></div>
        </td>

    <td style="width: 2.42%; vertical-align: bottom;">&#160;</td>

    <td style="width: 20.85%; vertical-align: bottom; border-bottom: 2px solid rgb(0, 0, 0);">
          <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Phase</span><sup> (1)</sup></div>
        </td>

    <td style="width: 1.67%; vertical-align: bottom;">&#160;</td>

    <td style="width: 18.24%; vertical-align: bottom; border-bottom: #000000 2px solid;">
          <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Route of Administration</span><sup> (1)</sup></div>
        </td>

  </tr>

  <tr>

    <td style="width: 18.07%; vertical-align: middle; background-color: rgb(204, 238, 255);">
          <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">ARO-APOC3</div>
        </td>

    <td style="width: 1.67%; vertical-align: middle; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 12.15%; vertical-align: middle; background-color: rgb(204, 238, 255);">
          <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Arrowhead Pharmaceuticals</div>
        </td>

    <td style="width: 2.42%; vertical-align: top; background-color: rgb(204, 238, 255);">&#160;</td>

    <td style="width: 22.53%; vertical-align: middle; background-color: rgb(204, 238, 255);">
          <div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Targets APOCIII by utilizing Targeted RNAi Molecule Platform</div>
          <div>&#160;</div>
        </td>

    <td style="width: 2.42%; vertical-align: top; background-color: rgb(204, 238, 255);">&#160;</td>

    <td style="width: 20.85%; vertical-align: middle; background-color: rgb(204, 238, 255);">
          <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">3 (FCS), 2 (SHTG)</div>
        </td>

    <td style="width: 1.67%; vertical-align: middle; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 18.24%; vertical-align: middle; background-color: #CCEEFF;">
          <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Subcutaneous Injection</div>
        </td>

  </tr>

  <tr>

    <td style="width: 18.07%; vertical-align: middle; background-color: rgb(255, 255, 255);">
          <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Lomitapide</div>
        </td>

    <td style="width: 1.67%; vertical-align: middle; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 12.15%; vertical-align: middle; background-color: rgb(255, 255, 255);">
          <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Amryt Pharma</div>
        </td>

    <td style="width: 2.42%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>

    <td style="width: 22.53%; vertical-align: middle; background-color: rgb(255, 255, 255);">
          <div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Microsomal triglyceride transfer protein (MTP) inhibitor</div>
        </td>

    <td style="width: 2.42%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>

    <td style="width: 20.85%; vertical-align: middle; background-color: rgb(255, 255, 255);">
          <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">2 (FCS) (investigator led)</div>
          <div>&#160;</div>
        </td>

    <td style="width: 1.67%; vertical-align: middle; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 18.24%; vertical-align: middle; background-color: #FFFFFF;">
          <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Oral</div>
        </td>

  </tr>

  <tr>

    <td style="width: 18.07%; vertical-align: middle; background-color: rgb(204, 238, 255);">
          <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Evinacumab</div>
        </td>

    <td style="width: 1.67%; vertical-align: middle; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 12.15%; vertical-align: middle; background-color: rgb(204, 238, 255);">
          <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Regenerion</div>
        </td>

    <td style="width: 2.42%; vertical-align: top; background-color: rgb(204, 238, 255);">&#160;</td>

    <td style="width: 22.53%; vertical-align: middle; background-color: rgb(204, 238, 255);">
          <div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">ANGPTL3 mAb</div>
        </td>

    <td style="width: 2.42%; vertical-align: top; background-color: rgb(204, 238, 255);">&#160;</td>

    <td style="width: 20.85%; vertical-align: middle; background-color: rgb(204, 238, 255);">
          <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">2 (SHTG)</div>
        </td>

    <td style="width: 1.67%; vertical-align: middle; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 18.24%; vertical-align: middle; background-color: #CCEEFF;">
          <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Intravenous Infusion</div>
        </td>

  </tr>

  <tr>

    <td style="width: 18.07%; vertical-align: middle; background-color: rgb(255, 255, 255);">
          <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">BIO89-100</div>
        </td>

    <td style="width: 1.67%; vertical-align: middle; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 12.15%; vertical-align: middle; background-color: rgb(255, 255, 255);">
          <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Bio 89</div>
        </td>

    <td style="width: 2.42%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>

    <td style="width: 22.53%; vertical-align: middle; background-color: rgb(255, 255, 255);">
          <div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">FGF21 analog</div>
        </td>

    <td style="width: 2.42%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>

    <td style="width: 20.85%; vertical-align: middle; background-color: rgb(255, 255, 255);">
          <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">2 (SHTG)</div>
        </td>

    <td style="width: 1.67%; vertical-align: middle; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 18.24%; vertical-align: middle; background-color: #FFFFFF;">
          <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Subcutaneous Injection</div>
        </td>

  </tr>


</table>
  <div><br />
  </div>

  <table cellspacing="0" cellpadding="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">


  <tr>

    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 8pt;">(1)</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 8pt;">Taken from public documents including respective company press releases, company presentations, and scientific presentations.</div>
        </td>

  </tr>


</table>
  <div><br />
  </div>

  <div style="text-align: left; margin-left: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;">Donidalorsen</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We believe that the following medicines could compete with donidalorsen as a prophylactic treatment for patients with HAE:</div>

  <div><br />
  </div>

  <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; border-collapse: collapse; text-align: left; color: #000000;">


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    <td style="width: 18.07%; vertical-align: bottom; border-bottom: 2px solid rgb(0, 0, 0);">
          <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Medicine</div>
        </td>

    <td style="width: 1.67%; vertical-align: bottom;">&#160;</td>

    <td style="width: 12.15%; vertical-align: bottom; border-bottom: 2px solid rgb(0, 0, 0);">
          <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Company</div>
        </td>

    <td style="width: 2.42%; vertical-align: bottom;">&#160;</td>

    <td style="width: 22.53%; vertical-align: bottom; border-bottom: 2px solid rgb(0, 0, 0);">
          <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Medicine Description</span><sup> (1)</sup></div>
        </td>

    <td style="width: 2.42%; vertical-align: bottom;">&#160;</td>

    <td style="width: 20.85%; vertical-align: bottom; border-bottom: 2px solid rgb(0, 0, 0);">
          <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Phase</span><sup> (1)</sup></div>
        </td>

    <td style="width: 1.67%; vertical-align: bottom;">&#160;</td>

    <td style="width: 18.24%; vertical-align: bottom; border-bottom: 2px solid rgb(0, 0, 0);">
          <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Route of Administration</span><sup> (1)</sup></div>
        </td>

  </tr>

  <tr>

    <td style="width: 18.07%; vertical-align: middle; background-color: rgb(204, 238, 255);">
          <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Takhzyro</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(lanadelumab-flyo)</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 12.15%; vertical-align: middle; background-color: rgb(204, 238, 255);">
          <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Takeda</div>
        </td>

    <td style="width: 2.42%; vertical-align: top; background-color: rgb(204, 238, 255);">&#160;</td>

    <td style="width: 22.53%; vertical-align: middle; background-color: rgb(204, 238, 255);">
          <div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">A monoclonal antibody that inhibits plasma kallikrein activity</div>
        </td>

    <td style="width: 2.42%; vertical-align: top; background-color: rgb(204, 238, 255);">&#160;</td>

    <td style="width: 20.85%; vertical-align: middle; background-color: rgb(204, 238, 255);">
          <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Approved for HAE patients 12 years and older</div>
        </td>

    <td style="width: 1.67%; vertical-align: middle; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 18.24%; vertical-align: middle; background-color: rgb(204, 238, 255);">
          <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Subcutaneous</div>
          <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Infusion</div>
        </td>

  </tr>

  <tr>

    <td style="width: 18.07%; vertical-align: middle; background-color: rgb(255, 255, 255);">
          <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Cinryze</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(C1-esterase inhibitor)</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 12.15%; vertical-align: middle; background-color: rgb(255, 255, 255);">
          <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Takeda</div>
        </td>

    <td style="width: 2.42%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>

    <td style="width: 22.53%; vertical-align: middle; background-color: rgb(255, 255, 255);">
          <div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">A human plasma protein that mediates inflammation and coagulation</div>
        </td>

    <td style="width: 2.42%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>

    <td style="width: 20.85%; vertical-align: middle; background-color: rgb(255, 255, 255);">
          <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Approved for HAE patients 6 years and older</div>
        </td>

    <td style="width: 1.67%; vertical-align: middle; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 18.24%; vertical-align: middle; background-color: rgb(255, 255, 255);">
          <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Intravenous</div>
          <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Infusion</div>
        </td>

  </tr>

  <tr>

    <td style="width: 18.07%; vertical-align: middle; background-color: rgb(204, 238, 255);">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Orladeyo</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(berotralstat)</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 12.15%; vertical-align: middle; background-color: rgb(204, 238, 255);">
          <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">BioCryst</div>
        </td>

    <td style="width: 2.42%; vertical-align: top; background-color: rgb(204, 238, 255);">&#160;</td>

    <td style="width: 22.53%; vertical-align: middle; background-color: rgb(204, 238, 255);">
          <div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Oral plasma kallikrein inhibitor</div>
        </td>

    <td style="width: 2.42%; vertical-align: top; background-color: rgb(204, 238, 255);">&#160;</td>

    <td style="width: 20.85%; vertical-align: middle; background-color: rgb(204, 238, 255);">
          <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Approved for HAE patients 12 years and older</div>
        </td>

    <td style="width: 1.67%; vertical-align: middle; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 18.24%; vertical-align: middle; background-color: rgb(204, 238, 255);">
          <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Oral</div>
        </td>

  </tr>

  <tr>

    <td style="width: 18.07%; vertical-align: middle; background-color: rgb(255, 255, 255);">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Haegarda</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(C1 esterase inhibitor)</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 12.15%; vertical-align: middle; background-color: rgb(255, 255, 255);">
          <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">CSL Behring</div>
        </td>

    <td style="width: 2.42%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>

    <td style="width: 22.53%; vertical-align: middle; background-color: rgb(255, 255, 255);">
          <div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">C1 esterase inhibitor</div>
        </td>

    <td style="width: 2.42%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>

    <td style="width: 20.85%; vertical-align: middle; background-color: rgb(255, 255, 255);">
          <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Approved for HAE patients 6 years and older</div>
        </td>

    <td style="width: 1.67%; vertical-align: middle; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 18.24%; vertical-align: middle; background-color: rgb(255, 255, 255);">
          <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Subcutaneous</div>
          <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Infusion</div>
        </td>

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  <tr>

    <td style="width: 18.07%; vertical-align: middle; background-color: rgb(204, 238, 255);">
          <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">garadacimab</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 12.15%; vertical-align: middle; background-color: rgb(204, 238, 255);">
          <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">CSL Behring</div>
        </td>

    <td style="width: 2.42%; vertical-align: top; background-color: rgb(204, 238, 255);">&#160;</td>

    <td style="width: 22.53%; vertical-align: middle; background-color: rgb(204, 238, 255);">
          <div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">An anti-factor XIIa monoclonal antibody</div>
        </td>

    <td style="width: 2.42%; vertical-align: top; background-color: rgb(204, 238, 255);">&#160;</td>

    <td style="width: 20.85%; vertical-align: middle; background-color: rgb(204, 238, 255);">
          <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">3</div>
        </td>

    <td style="width: 1.67%; vertical-align: middle; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 18.24%; vertical-align: middle; background-color: rgb(204, 238, 255);">
          <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Subcutaneous</div>
          <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Infusion</div>
        </td>

  </tr>

  <tr>

    <td style="width: 18.07%; vertical-align: middle; background-color: rgb(255, 255, 255);">
          <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">KVD824</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 12.15%; vertical-align: middle; background-color: rgb(255, 255, 255);">
          <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">KalVista</div>
        </td>

    <td style="width: 2.42%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>

    <td style="width: 22.53%; vertical-align: middle; background-color: rgb(255, 255, 255);">
          <div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Oral plasma kallikrein inhibitor</div>
        </td>

    <td style="width: 2.42%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>

    <td style="width: 20.85%; vertical-align: middle; background-color: rgb(255, 255, 255);">
          <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">2</div>
        </td>

    <td style="width: 1.67%; vertical-align: middle; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 18.24%; vertical-align: middle; background-color: rgb(255, 255, 255);">
          <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Oral</div>
        </td>

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    <td style="width: 18.07%; vertical-align: middle; background-color: rgb(204, 238, 255);">
          <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">NTLA-2002</div>
        </td>

    <td style="width: 1.67%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 12.15%; vertical-align: middle; background-color: rgb(204, 238, 255);">
          <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Intellia</div>
        </td>

    <td style="width: 2.42%; vertical-align: top; background-color: rgb(204, 238, 255);">&#160;</td>

    <td style="width: 22.53%; vertical-align: middle; background-color: rgb(204, 238, 255);">
          <div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">CRISPR therapeutic candidate designed to inactivate the kallikrein B1 gene</div>
        </td>

    <td style="width: 2.42%; vertical-align: top; background-color: rgb(204, 238, 255);">&#160;</td>

    <td style="width: 20.85%; vertical-align: middle; background-color: rgb(204, 238, 255);">
          <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">1/2</div>
        </td>

    <td style="width: 1.67%; vertical-align: middle; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 18.24%; vertical-align: middle; background-color: rgb(204, 238, 255);">
          <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Intravenous</div>
          <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Infusion</div>
        </td>

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    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 8pt;">(1)</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 8pt;">Taken from public documents including respective company press releases, company presentations, and scientific presentations.</div>
        </td>

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  <div><br />
  </div>

  <div style="text-align: left; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;">Pelacarsen</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We believe that the following medicine could compete with pelacarsen in CVD in patients with elevated LP(a):</div>

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          <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Medicine</div>
        </td>

    <td style="width: 1.67%; vertical-align: bottom;">&#160;</td>

    <td style="width: 12.15%; vertical-align: bottom; border-bottom: 2px solid rgb(0, 0, 0);">
          <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Company</div>
        </td>

    <td style="width: 2.42%; vertical-align: bottom;">&#160;</td>

    <td style="width: 22.53%; vertical-align: bottom; border-bottom: 2px solid rgb(0, 0, 0);">
          <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Medicine Description</span><sup> (1)</sup></div>
        </td>

    <td style="width: 2.42%; vertical-align: bottom;">&#160;</td>

    <td style="width: 20.85%; vertical-align: bottom; border-bottom: 2px solid rgb(0, 0, 0);">
          <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Phase</span><sup> (1)</sup></div>
        </td>

    <td style="width: 1.67%; vertical-align: bottom;">&#160;</td>

    <td style="width: 18.24%; vertical-align: bottom; border-bottom: #000000 2px solid;">
          <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Route of Administration</span><sup> (1)</sup></div>
        </td>

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  <tr>

    <td style="width: 18.07%; vertical-align: middle; background-color: rgb(204, 238, 255);">
          <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">AMG 890</div>
        </td>

    <td style="width: 1.67%; vertical-align: middle; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 12.15%; vertical-align: middle; background-color: rgb(204, 238, 255);">
          <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Amgen/ Arrowhead Pharmaceuticals</div>
        </td>

    <td style="width: 2.42%; vertical-align: top; background-color: rgb(204, 238, 255);">&#160;</td>

    <td style="width: 22.53%; vertical-align: middle; background-color: rgb(204, 238, 255);">
          <div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">RNAi therapeutic designed to lower Lp(a)</div>
        </td>

    <td style="width: 2.42%; vertical-align: top; background-color: rgb(204, 238, 255);">&#160;</td>

    <td style="width: 20.85%; vertical-align: middle; background-color: rgb(204, 238, 255);">
          <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">2</div>
        </td>

    <td style="width: 1.67%; vertical-align: middle; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 18.24%; vertical-align: middle; background-color: #CCEEFF;">
          <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Subcutaneous Injection</div>
        </td>

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</table>
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    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 8pt;">(1)</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 8pt;">Taken from public documents including respective company press releases, company presentations, and scientific presentations.</div>
        </td>

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  <div style="text-align: left; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;">Tofersen</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We believe that the following medicines could compete with tofersen in SOD1-ALS:</div>

  <div><br />
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    <td style="width: 18.07%; vertical-align: bottom; border-bottom: 2px solid rgb(0, 0, 0);">
          <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Medicine</div>
        </td>

    <td style="width: 1.67%; vertical-align: bottom;">&#160;</td>

    <td style="width: 12.15%; vertical-align: bottom; border-bottom: 2px solid rgb(0, 0, 0);">
          <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Company</div>
        </td>

    <td style="width: 2.42%; vertical-align: bottom;">&#160;</td>

    <td style="width: 22.53%; vertical-align: bottom; border-bottom: 2px solid rgb(0, 0, 0);">
          <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Medicine Description</span><sup> (1)</sup></div>
        </td>

    <td style="width: 2.42%; vertical-align: bottom;">&#160;</td>

    <td style="width: 20.85%; vertical-align: bottom; border-bottom: 2px solid rgb(0, 0, 0);">
          <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Phase</span><sup> (1)</sup></div>
        </td>

    <td style="width: 1.67%; vertical-align: bottom;">&#160;</td>

    <td style="width: 18.24%; vertical-align: bottom; border-bottom: #000000 2px solid;">
          <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Route of Administration</span><sup> (1)</sup></div>
        </td>

  </tr>

  <tr>

    <td style="width: 18.07%; vertical-align: middle; background-color: rgb(204, 238, 255);">
          <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Arimoclomol</div>
        </td>

    <td style="width: 1.67%; vertical-align: middle; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 12.15%; vertical-align: middle; background-color: rgb(204, 238, 255);">
          <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Orphazyme</div>
        </td>

    <td style="width: 2.42%; vertical-align: top; background-color: rgb(204, 238, 255);">&#160;</td>

    <td style="width: 22.53%; vertical-align: middle; background-color: rgb(204, 238, 255);">
          <div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Provides cellular protection from abnormal proteins by activating molecular &#8220;chaperone&#8221; proteins that can repair or degrade the damaged proteins</div>
        </td>

    <td style="width: 2.42%; vertical-align: top; background-color: rgb(204, 238, 255);">&#160;</td>

    <td style="width: 20.85%; vertical-align: middle; background-color: rgb(204, 238, 255);">
          <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">3</div>
        </td>

    <td style="width: 1.67%; vertical-align: middle; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 18.24%; vertical-align: middle; background-color: #CCEEFF;">
          <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Oral</div>
        </td>

  </tr>

  <tr>

    <td style="width: 18.07%; vertical-align: middle; background-color: rgb(255, 255, 255);">
          <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">NI-204</div>
        </td>

    <td style="width: 1.67%; vertical-align: middle; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 12.15%; vertical-align: middle; background-color: rgb(255, 255, 255);">
          <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Neurimmune</div>
        </td>

    <td style="width: 2.42%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>

    <td style="width: 22.53%; vertical-align: middle; background-color: rgb(255, 255, 255);">
          <div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">A human derived antibody targeting misfolded SOD1</div>
        </td>

    <td style="width: 2.42%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>

    <td style="width: 20.85%; vertical-align: middle; background-color: rgb(255, 255, 255);">
          <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">2</div>
        </td>

    <td style="width: 1.67%; vertical-align: middle; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 18.24%; vertical-align: middle; background-color: #FFFFFF;">
          <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Intravenous</div>
          <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Infusion</div>
        </td>

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    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 8pt;">(1)</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 8pt;">Taken from public documents including respective company press releases, company presentations, and scientific presentations.</div>
        </td>

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  <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"><a id="_Hlk92660799"><!--Anchor--></a>Environmental, Social and Governance Initiatives</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We recognize the importance of Environmental, Social and Governance, or ESG, initiatives as it relates to our business
    strategy and risk assessment. During 2020 and 2021, we took steps to formalize our corporate responsibility program. In December 2021, we issued our inaugural corporate responsibility report. As part of our ongoing work, we identified the following
    corporate responsibility initiatives that we believe are most important to our business:</div>

  <div><br />
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    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: left;">
          <div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Safety of patients in clinical trials;</div>
        </td>

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    <td style="width: 36pt;"></td>

    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: left;">
          <div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Drug safety and supply chain management;</div>
        </td>

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  <tr>

    <td style="width: 36pt;"></td>

    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: left;">
          <div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Access to medicines and tackling devastating diseases;</div>
        </td>

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    <td style="width: 36pt;"></td>

    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: left;">
          <div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Human resources management;</div>
        </td>

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    <td style="width: 36pt;"></td>

    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: left;">
          <div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Diversity, equity and inclusion;</div>
        </td>

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    <td style="width: 36pt;"></td>

    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: left;">
          <div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Employee health and safety; and</div>
        </td>

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    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: left;">
          <div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Governance and business ethics</div>
        </td>

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</table>
  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We have a relatively small environmental footprint, so our stewardship programs focus on improving eco-awareness,
    identifying efficiencies and integrating more sustainable practices into our daily operations. Our priority assessment considered investor and other stakeholder interests and is aligned with the requirements of ESG ratings agencies and with leading ESG
    frameworks, including the Sustainability Accounting Standards Board, or SASB.</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We encourage you to view our <span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">2021 Corporate Responsibility Report</span> published on our website for more detailed information regarding our ESG initiatives. Nothing in the report or on our website shall be deemed incorporated by reference into this Annual Report on
    Form 10-K.</div>

  <div><br />
  </div>

  <div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Employees &amp; Human Capital</div>

  <div style="text-align: justify; text-indent: 36pt;"><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">As of February 16, 2022,
    we employed 660 people, the vast majority of whom reside in the U.S. A significant number of our management and professional employees have had prior experience with pharmaceutical, biotechnology or medical product companies. Our average employee
    turnover rate in 2021 was 16 percent, while the turnover for life sciences/ medical device companies over this period was 19 percent according to a survey published by Radford &#8211; an Aon Hewitt Company. Given the uniqueness and complexity of our
    technology, it is critical to retain the knowledge and experience of outstanding long service employees. The experience and seniority of our employees is as critical to our future success as it has been to the success we have enjoyed to date.</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><a id="_Hlk63342169"><!--Anchor--></a>Collective bargaining agreements do not cover any of our employees, and management
    considers relations with our employees to be good. We believe that the future will be defined by outstanding people and we are committed to recruiting, developing, motivating, and rewarding them.</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We encourage you to visit our website for more detailed information regarding our Human Capital programs and initiatives.
    Nothing on our website shall be deemed incorporated by reference into this Annual Report on Form 10-K.</div>

  <div><br />
  </div>

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  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic; font-weight: bold;">Benefits</div>

  <div><br />
  </div>

  <div style="text-align: left; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Employees are rewarded individually on the basis of their responsibilities and accomplishments. We offer competitive compensation and
    benefits to our employees. In addition to salary and bonus programs, we also offer:</div>

  <div><br />
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    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: left;">
          <div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Comprehensive medical, dental and vision insurance;</div>
        </td>

  </tr>


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    <td style="width: 36pt;"></td>

    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: left;">
          <div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;">401(k) matching;</div>
        </td>

  </tr>


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    <td style="width: 36pt;"></td>

    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: left;">
          <div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Stock options, RSUs and Employee Stock Purchase Plan, or ESPP;</div>
        </td>

  </tr>


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    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: left;">
          <div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Vacation, holiday, sick time and paid time off for volunteering;</div>
        </td>

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    <td style="width: 36pt;"></td>

    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: left;">
          <div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Wellness programs;</div>
        </td>

  </tr>


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    <td style="width: 36pt;"></td>

    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: left;">
          <div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Flexible spending accounts for health and dependent day care needs;</div>
        </td>

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  <tr>

    <td style="width: 36pt;"></td>

    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: left;">
          <div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Life, AD&amp;D insurance and long-term disability insurance coverage options; and</div>
        </td>

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    <td style="width: 36pt;"></td>

    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: left;">
          <div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Employee Assistance Program, or EAP.</div>
        </td>

  </tr>


</table>
  <div><br />
  </div>

  <div style="text-align: left; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We recognize achievements with salary increases, stock awards, promotions, and bonus opportunities.</div>

  <div><br />
  </div>

  <div style="text-align: left; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic; font-weight: bold;">Pay Equity</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We are committed to paying our employees fairly, regardless of their gender, race, or other personal characteristics. To
    ensure we are achieving our commitment, we benchmark and evaluate pay based on market data and consider factors such as an employee&#8217;s role and experience, an employee&#8217;s performance and internal equity. We also regularly review our compensation
    practices, both in terms of our overall workforce and individual employees, to ensure our pay is fair and equitable.</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">In 2021, we engaged an independent third-party expert to perform a pay equity analysis that reviewed pay equity by gender,
    race and age. We plan to continue to engage a third-party expert to review pay equity every two to three years, as we determine necessary.</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic; font-weight: bold;">Diversity, Equity and Inclusion</div>

  <div><br />
  </div>

  <div>
    <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">At Ionis, we encourage diversity in our workforce. Prejudicial barriers to human potential and productivity are foreign
      to our values. We recognize that for the full potential of our workforce to be realized, we must cultivate an inclusive culture where all employees feel empowered to contribute fully in an environment that values different perspectives, leading to
      better &#8203;&#8203;&#8203;&#8203;&#8203;&#8203;&#8203;ideas and increased innovation. We have several employee-led resource groups dedicated to different aspects of diversity and a diverse management team and board of directors.</div>

  </div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic; font-weight: bold;">Training and Development</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We designed our training and development programs to help employees gain important Ionis knowledge and develop the skills
    to be successful. All of our trainings from new hire through senior leader, are focused on the Ionis culture and core principles and learning what we mean when we say: &#8220;Working the Ionis Way.&#8221;</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We empower our employees to build rewarding careers at Ionis, driven by a culture of yes that encourages personal and
    professional employee growth. Ionis offers robust training opportunities with course offerings and events available to every employee regardless of level or function. In addition, employees also have access to Ionis&#8217; learning and development library
    that houses important information on career growth and planning. By supporting our employees, we know that each professional development milestone enables our continued success.</div>

  <div><br />
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  <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Information about our Executive Officers</div>

  <div style="text-align: justify; text-indent: 36pt;"><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">The following sets forth certain information regarding our executive officers as of February 16, 2022:</div>

  <div style="text-align: left;"><br />
  </div>

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    <td style="width: 25.83%; vertical-align: bottom; border-bottom: #000000 2px solid;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Name</div>
        </td>

    <td style="width: 1.67%; vertical-align: bottom;">&#160;</td>

    <td style="width: 8.33%; vertical-align: bottom; border-bottom: #000000 2px solid;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Age</div>
        </td>

    <td style="width: 1.67%; vertical-align: bottom;">&#160;</td>

    <td style="width: 62.5%; vertical-align: bottom; border-bottom: #000000 2px solid;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Position</div>
        </td>

  </tr>

  <tr>

    <td style="width: 25.83%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Brett P. Monia, Ph.D.</div>
        </td>

    <td style="width: 1.67%; vertical-align: bottom; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 8.33%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">60</div>
        </td>

    <td style="width: 1.67%; vertical-align: bottom; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 62.5%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Chief Executive Officer</div>
        </td>

  </tr>

  <tr>

    <td style="width: 25.83%; vertical-align: top; background-color: #FFFFFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Joseph T. Baroldi</div>
        </td>

    <td style="width: 1.67%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 8.33%; vertical-align: top; background-color: #FFFFFF;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">44</div>
        </td>

    <td style="width: 1.67%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 62.5%; vertical-align: top; background-color: #FFFFFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Executive Vice President, Chief Business Officer</div>
        </td>

  </tr>

  <tr>

    <td style="width: 25.83%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">C. Frank Bennett, Ph.D.</div>
        </td>

    <td style="width: 1.67%; vertical-align: bottom; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 8.33%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">65</div>
        </td>

    <td style="width: 1.67%; vertical-align: bottom; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 62.5%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Executive Vice President, Chief Scientific Officer</div>
        </td>

  </tr>

  <tr>

    <td style="width: 25.83%; vertical-align: top; background-color: #FFFFFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Onaiza Cadoret-Manier</div>
        </td>

    <td style="width: 1.67%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 8.33%; vertical-align: top; background-color: #FFFFFF;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">57</div>
        </td>

    <td style="width: 1.67%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 62.5%; vertical-align: top; background-color: #FFFFFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Executive Vice President, Chief Product Strategy and Operations Officer</div>
        </td>

  </tr>

  <tr>

    <td style="width: 25.83%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Richard S. Geary, Ph.D.</div>
        </td>

    <td style="width: 1.67%; vertical-align: bottom; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 8.33%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">64</div>
        </td>

    <td style="width: 1.67%; vertical-align: bottom; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 62.5%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Executive Vice President, Chief Development Officer</div>
        </td>

  </tr>

  <tr>

    <td style="width: 25.83%; vertical-align: top; background-color: #FFFFFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Elizabeth L. Hougen</div>
        </td>

    <td style="width: 1.67%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 8.33%; vertical-align: top; background-color: #FFFFFF;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">60</div>
        </td>

    <td style="width: 1.67%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 62.5%; vertical-align: top; background-color: #FFFFFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Executive Vice President, Finance and Chief Financial Officer</div>
        </td>

  </tr>

  <tr>

    <td style="width: 25.83%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Patrick R. O&#8217;Neil, Esq.</div>
        </td>

    <td style="width: 1.67%; vertical-align: bottom; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 8.33%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">48</div>
        </td>

    <td style="width: 1.67%; vertical-align: bottom; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 62.5%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Chief Legal Officer, General Counsel and Corporate Secretary</div>
        </td>

  </tr>

  <tr>

    <td style="width: 25.83%; vertical-align: top; background-color: #FFFFFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Eugene Schneider, M.D.</div>
        </td>

    <td style="width: 1.67%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 8.33%; vertical-align: top; background-color: #FFFFFF;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">49</div>
        </td>

    <td style="width: 1.67%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 62.5%; vertical-align: top; background-color: #FFFFFF;">
          <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Executive Vice President, Chief Clinical Development Officer</div>
        </td>

  </tr>

  <tr>

    <td style="width: 25.83%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Eric E. Swayze, Ph.D.</div>
        </td>

    <td style="width: 1.67%; vertical-align: bottom; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 8.33%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">56</div>
        </td>

    <td style="width: 1.67%; vertical-align: bottom; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 62.5%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Executive Vice President, Research</div>
        </td>

  </tr>


</table>
  <div><br />
  </div>

  <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">BRETT P. MONIA, Ph.D.</div>

  <div style="text-align: justify;"><br />
  </div>

  <div style="text-align: justify; text-indent: -18pt; margin-left: 54pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;">Chief Executive Officer</div>

  <div style="text-align: justify; text-indent: -18pt; margin-left: 54pt;"><br />
  </div>

  <div style="text-align: justify; text-indent: 38.15pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Dr. Monia was promoted to Chief Executive Officer in January 2020. From January 2018 to December 2019, Dr. Monia served
    as Chief Operating Officer. From January 2012 to January 2018, Dr. Monia served as Senior Vice President. From February 2009 to January 2012, Dr. Monia served as our Vice President, Drug Discovery and Corporate Development and from October 2000 to
    February 2009, he served as our Vice President, Preclinical Drug Discovery. From October 1989 to October 2000 he held various positions within our Molecular Pharmacology department.</div>

  <div><br />
  </div>

  <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">JOSEPH T. BAROLDI</div>

  <div style="text-align: justify;"><br />
  </div>

  <div style="text-align: justify; text-indent: -18pt; margin-left: 54pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;">Executive Vice President, Chief Business Officer</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Mr. Baroldi has served as Ionis&#8217; Executive Vice President, Chief Business Officer since January 2022. Prior to Ionis, Mr.
    Baroldi was the chief operating officer at Avidity Biosciences, a biotechnology company focused on oligonucleotide-based therapies. Prior to Avidity, Mr. Baroldi was vice president of Business Development and Alliance Management at Ionis from 2009 to
    2020. Mr. Baroldi has also held positions in strategic planning and scientific research for Gen-Probe Inc. and Ionis.</div>

  <div style="text-align: justify; text-indent: 36pt;"><br />
  </div>

  <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">C. FRANK BENNETT, Ph.D.</div>

  <div style="text-align: justify;"><br />
  </div>

  <div style="text-align: justify; text-indent: -18pt; margin-left: 54pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;">Executive Vice President, Chief Scientific Officer</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Dr. Bennett has served as Ionis&#8217; Executive Vice President, Chief Scientific Officer since April 2020. In January 2020, Dr.
    Bennett was promoted to Chief Scientific Officer. From January 2006 to December 2019, Dr. Bennett served as Senior Vice President, Antisense Research. From June 1995 to January 2006, Dr. Bennett served as our Vice President, Research. From March 1993
    to June 1995, he was Director, Molecular Pharmacology, and from May 1992 to March 1993, he was an Associate Director in our Molecular and Cellular Biology department. Prior to joining Ionis in 1989, Dr. Bennett was employed by SmithKline and French
    Laboratories in various research positions. He is a member of the Board of Directors for Flamingo Therapeutics and an external member of the Hereditary Disease Foundation.</div>

  <div><br />
  </div>

  <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">ONAIZA CADORET-MANIER</div>

  <div><br />
  </div>

  <div style="text-align: left; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;">Executive Vice President, Chief Product Strategy and Operations Officer</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">Ms. Cadoret-Manier has served as Ionis&#8217;
      Executive Vice President, Chief Product Strategy and Operations Officer since February 2022. From April 2020 to February 2022, Ms. Cadoret-Manier served as our Executive Vice President, </span>Chief Corporate Development and Commercial Officer<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">. Ms. Cadoret-Manier joined Ionis as Chief Corporate Development and Commercial Officer in January 2020. Prior to joining Ionis, from 2018 to 2019 Ms.
      Cadoret-Manier was the chief commercial officer for Grail Biosciences, an early detection genomics company. Prior to Grail, Ms. Cadoret-Manier was vice president of the Respiratory Franchise at Genentech where she worked from 2011 to 2018. Ms.
      Cadoret-Manier also has held multiple senior management positions overseeing corporate strategy, alliances, and marketing and sales for numerous disease areas for Genentech, Pfizer and Amylin Pharmaceuticals.</span></div>

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  <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">RICHARD S. GEARY, Ph.D.</div>

  <div style="text-align: justify;"><br />
  </div>

  <div style="text-align: justify; text-indent: -18pt; margin-left: 54pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;">Executive Vice President, Chief Development Officer</div>

  <div style="text-align: justify; text-indent: -18pt; margin-left: 54pt;"><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Dr. Geary has served as Ionis&#8217; Executive Vice President, Chief Development Officer since January 2021. From April 2020 to
    December 2020, Dr. Geary served as our Executive Vice President, Development and from August 2008 to March 2020, was our Senior Vice President, Development. From August 2003 to August 2008, Dr. Geary served as our Vice President, Preclinical
    Development. From November 1995 to August 2003, he held various positions within the Preclinical Development department. Prior to joining Ionis in 1995, Dr. Geary was Senior Research Scientist and Group Leader for the bioanalytical and preclinical
    pharmacokinetics group in the Applied Chemistry Department at Southwest Research Institute.</div>

  <div><br />
  </div>

  <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">ELIZABETH L. HOUGEN</div>

  <div style="text-align: justify;"><br />
  </div>

  <div style="text-align: justify; text-indent: -18pt; margin-left: 54pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;">Executive Vice President, Finance and Chief Financial Officer</div>

  <div style="text-align: justify; text-indent: -18pt; margin-left: 54pt;"><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Ms. Hougen has served as Ionis&#8217; Executive Vice President and Chief Financial Officer since April 2020. From January 2013
    to March 2020, Ms. Hougen served as our Senior Vice President, Finance and Chief Financial Officer. From January 2007 to December 2012, Ms. Hougen served as our Vice President, Finance and Chief Accounting Officer and from May 2000 to January 2007, she
    served as our Vice President, Finance. Prior to joining Ionis in 2000, Ms. Hougen was Executive Director, Finance and Chief Financial Officer for Molecular Biosystems, Inc., a public biotechnology company.</div>

  <div style="text-align: justify; text-indent: 36pt;"><br />
  </div>

  <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">PATRICK R. O&#8217;NEIL, Esq.</div>

  <div style="text-align: justify;"><br />
  </div>

  <div style="text-align: justify; text-indent: -18pt; margin-left: 54pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;">Chief Legal Officer, General Counsel and Corporate Secretary</div>

  <div style="text-align: justify; text-indent: -18pt; margin-left: 54pt;"><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Mr. O&#8217;Neil has served as Ionis&#8217; Chief Legal Officer and General Counsel since September 2021. Mr. O&#8217;Neil also serves as
    our Corporate Secretary. From March 2020 to September 2021, Mr. O&#8217;Neil served as our Executive Vice President, Legal &amp; General Counsel and Chief Compliance Officer. From January 2013 to March 2020, Mr. O&#8217;Neil served as our Senior Vice President,
    Legal and General Counsel. From September 2010 to January 2013, Mr. O&#8217;Neil served as our Vice President, Legal and General Counsel and from January 2009 to September 2010, he served as our Vice President, Legal and Senior Transactions Counsel. From
    October 2001 to January 2009 he held various positions within our Legal department. Prior to joining Ionis, Mr. O&#8217;Neil was an associate at Cooley LLP.</div>

  <div><br />
  </div>

  <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">EUGENE SCHNEIDER, M.D.</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;">Executive Vice President, Chief Clinical Development Officer</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Dr. Schneider was promoted to Executive Vice President and Chief Clinical Development Officer of Ionis in January 2021.
    From August 2018 to December 2020, Dr. Schneider served as our Senior Vice President, Head of Clinical Development. From April 2015 to July 2018, Dr. Schneider was our Vice President, Clinical Development, Severe and Rare Diseases. Dr. Schneider joined
    Ionis in December 2013 as Executive Director, Clinical Development. Dr. Schneider has two decades of experience in clinical development primarily in the rare diseases space. Prior to joining Ionis, Dr. Schneider was senior medical director at both
    Synageva BioPharma and Biovail Technologies Ltd.</div>

  <div><br />
  </div>

  <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">ERIC E. SWAYZE, Ph.D.</div>

  <div style="text-align: justify;"><br />
  </div>

  <div style="text-align: justify; text-indent: -18pt; margin-left: 54pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;">Executive Vice President, Research</div>

  <div><br />
  </div>

  <div>
    <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Dr. Swayze has served as Ionis&#8217; Executive Vice President, Research since April 2020 and is responsible for leading
      preclinical antisense drug discovery and antisense technology research. In January 2020, Dr. Swayze was promoted to Senior Vice President of Research. Previously, Dr. Swayze was Vice President of Chemistry and Neuroscience Drug Discovery at Ionis,
      overseeing the advancement of multiple programs to clinical development. He joined Ionis in 1994 and has contributed to key technology advancements, including Ionis&#8217; Generation 2.5 chemistry and LICA technology.</div>

  </div>

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  <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Item 1A. RISK FACTORS</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;">Investing in our securities involves a high degree of risk. You should carefully consider the
    following information about the risks described below, together with the other information contained in this report and in our other public filings in evaluating our business. If any of the following risks actually occur, our business could be
    materially harmed, and our financial condition and results of operations could be materially and adversely affected. As a result, the trading price of our securities could decline, and you might lose all or part of your investment.</div>

  <div><br />
  </div>

  <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Risks Related to the COVID-19 Pandemic</div>

  <div><br />
  </div>

  <div style="text-align: justify; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Our business could be materially adversely affected by the effects of health epidemics. To date, we believe the impacts of the recent
    COVID-19 pandemic on our business are limited and manageable.</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 40.5pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Our business could be materially adversely affected by health epidemics in regions where we or our partners are commercializing our
    medicines, have concentrations of clinical trial sites or other business operations, and could cause significant disruption in the operations of third-party manufacturers and contract research organizations upon whom we rely. For example, since
    December 2019, a novel strain of coronavirus, SARS-CoV-2, causing a disease referred to as COVID-19, has spread worldwide. In March 2020, the World Health Organization declared the COVID-19 outbreak a pandemic, or the COVID-19 Pandemic, and the U.S.
    government imposed restrictions on travel between the U.S., Europe and certain other countries. In addition, the Governor of the State of California and the Governor of the Commonwealth of Massachusetts, the states in which our offices are located,
    each declared a state of emergency related to the spread of COVID-19 and issued executive orders that directed residents to stay at home.</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 40.5pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">In response to these public health directives and orders, in March 2020, we implemented work-from-home policies for most of our
    employees globally and generally suspended business-related travel.&#160; In the U.S., as vaccinations have become more widely available, states have lifted restrictions implemented as part of the pandemic response and reopened their economies. In June
    2021, the Governor of California terminated the vast majority of executive actions that were put in place beginning in March 2020, leaving only a subset of provisions that facilitate the ongoing recovery. In May 2021, the Commonwealth of Massachusetts
    also lifted most of its pandemic restrictions. We continue to modify our policies for our employees in California, Massachusetts, and internationally to align with current local guidance.&#160; We believe the effects of these work-from-home and travel
    policies have had a limited impact on our business.</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">These public health directives and orders have impacted our and our partners&#8217; sales efforts. For example, some physician and hospital
    policies that have been put in place as a result of the COVID-19 Pandemic restrict in-person access by third parties, which has in some cases impacted our commercialization efforts for TEGSEDI and WAYLIVRA. Additionally, Biogen has reported that it is
    monitoring the demand for SPINRAZA, including the duration and degree to which it might see delays in starting new patients on SPINRAZA due to hospitals diverting resources necessary to administer SPINRAZA to care for COVID-19 patients. These and
    similar, and perhaps more severe, disruptions in our or our partner&#8217;s commercial operations could materially impact our business, operating results and financial condition in the future.</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 40.5pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Quarantines, shelter-in-place, executive and similar government orders, or the perception that such orders, shutdowns or other
    restrictions on the conduct of business operations could occur, could impact personnel at third-party manufacturing facilities in the U.S. and other countries, or the availability or cost of materials, which would disrupt our supply chain.&#160; Recently
    there have been major disruptions to the global supply chain due to the COVID-19 Pandemic. To date, we have not experienced any significant consequences to our business as a result of the current supply chain disruptions, but could in the future if
    such disruptions persist or worsen.</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We have experienced impacts to our clinical trial operations due to the COVID-19 Pandemic; however, we believe such impacts are limited
    and manageable. Some examples of these impacts include:</div>

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    <td style="width: 36pt;"></td>

    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;">delays in clinical site initiation, site monitoring and patient enrollment due to restrictions imposed as a result of the COVID-19 Pandemic;</div>
        </td>

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    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">o</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;">For example, in March 2020, we instituted a temporary suspension of enrollment for new subjects in our Phase 3 studies of eplontersen based on advice from our trial
            advisory committee; however, enrollment has resumed.</div>
        </td>

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    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;">some patients have not been able to meet protocol requirements, as quarantines have impeded patient movement and interrupted healthcare services;</div>
        </td>

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    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;">delays in site initiations due to principle investigators and site staff focusing on and prioritizing COVID-19 patient care; and</div>
        </td>

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    <td style="width: 36pt;"></td>

    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;">delays in necessary interactions with regulators, ethics committees and other important agencies and contractors due to limitations in employee resources or forced
            furlough of government or contractor personnel.</div>
        </td>

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  <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">In addition, some of our partners have experienced impacts to their clinical trial operations as a result of the COVID-19 Pandemic. For
    example, in December 2021, Novartis announced that enrollment for the Phase 3 HORIZON study had been delayed due to the COVID-19 Pandemic.</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">The spread of COVID-19 has caused a broad impact globally. While the potential economic impact brought by, and the duration of, the
    COVID-19 Pandemic may be difficult to assess or predict, it could result in significant disruption of global financial markets, reducing our ability to access capital, which could in the future negatively affect our liquidity. In addition, a recession
    or market correction resulting from the spread of COVID-19 could materially affect our business and has and could continue to affect the value of our securities.</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">The global COVID-19 Pandemic continues to rapidly evolve. While we have not yet experienced material adverse effects to our business as a
    result of the COVID-19 Pandemic, the ultimate impact of the COVID-19 Pandemic or a similar health epidemic is highly uncertain and subject to change. As such, we do not yet know the full extent of delays or impacts on our business, our clinical trials,
    healthcare systems or the global economy as a whole. However, these effects could have a material impact on our operations, and we will continue to monitor the COVID-19 Pandemic closely.</div>

  <div><br />
  </div>

  <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Risks Related to the Commercialization of our Medicines</div>

  <div>
    <div><br />
    </div>

  </div>

  <div style="text-align: justify; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">We have limited experience as a company in commercializing medicines and we will have to invest significant resources to develop these
    capabilities. If we are unable to establish effective marketing, sales, market access, distribution, and related functions, or enter into agreements with third parties to commercialize our medicines, we may not be able to generate revenue from our
    medicines.</div>

  <div><br />
  </div>

  <div>
    <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We have limited experience as a company in commercializing medicines and we will have to invest significant financial
      and management resources to develop the infrastructure required to successfully commercialize our medicines. There are significant risks involved in building and managing a sales organization, including our ability to hire, retain and incentivize
      qualified individuals, generate sufficient sales leads, provide adequate training to sales and marketing personnel, and effectively manage a geographically dispersed sales and marketing team. We will also need to scale-up existing internal support
      functions to aid our commercialization efforts, in particular, regulatory affairs and medical affairs. Any failure to effectively build or maintain the infrastructure required to successfully commercialize our medicines, including our sales,
      marketing, market access, distribution, and related capabilities, or scale-up our existing support functions, could adversely impact the revenue we generate from our medicines. In addition, if we choose to rely on third parties to assist us in
      commercializing our medicines, we may not be able to enter into collaborations or hire consultants or external service providers on acceptable financial terms, or at all.&#160; If we do engage third parties to assist us in the commercialization of our
      medicines, our product revenues and profitability may be lower than if we commercialized such medicines ourselves.</div>

  </div>

  <div><br />
  </div>

  <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">If the market does not accept our medicines, including SPINRAZA, TEGSEDI and WAYLIVRA, and our medicines in development,
    we are not likely to generate substantial revenues or become consistently profitable.</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Even if our medicines are authorized for marketing, our success will depend upon the medical community, patients and
    third-party payers accepting our medicines as medically useful, cost-effective, safe and convenient. Even when the FDA or foreign regulatory authorities authorize our or our partners&#8217; medicines for commercialization, doctors may not prescribe our
    medicines to treat patients. Furthermore, we and our partners may not successfully commercialize additional medicines.</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">Additionally, in many of the markets where we
      or our partners may sell our medicines in the future, if we or our partners cannot agree with the government or other third-party payers regarding the price we can charge for our medicines, then we may not be able to sell our medicines in that
      market. Similarly, cost control initiatives by governments or third-party payers could decrease the price received for our medicines or increase patient coinsurance to a level that makes our medicines, including SPINRAZA, TEGSEDI and WAYLIVRA, and
      our medicines in development, economically unviable. </span>If the pricing of any of our medicines decreases for any reason, it will reduce our revenue for such medicine. For example, Biogen has disclosed that SPINRAZA revenue has decreased in part
    due to lower pricing in the U.S. and certain rest of world markets.</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">The degree of market acceptance for our medicines, including SPINRAZA, TEGSEDI and WAYLIVRA, and our medicines in
    development, depends upon a number of factors, including the:</div>

  <div><br />
  </div>

  <table cellspacing="0" cellpadding="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">


  <tr>

    <td style="width: 36pt;"></td>

    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">receipt and scope of marketing authorizations;</div>
        </td>

  </tr>


</table>
  <table cellspacing="0" cellpadding="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">


  <tr>

    <td style="width: 36pt;"></td>

    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">establishment and demonstration in the medical and patient community of the efficacy and safety of our medicines and their potential advantages over
            competing products;</div>
        </td>

  </tr>


</table>
  <table cellspacing="0" cellpadding="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">


  <tr>

    <td style="width: 36pt;"></td>

    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">cost and effectiveness of our medicines compared to other available therapies;</div>
        </td>

  </tr>


</table>
  <table cellspacing="0" cellpadding="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">


  <tr>

    <td style="width: 36pt;"></td>

    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">patient convenience of the dosing regimen for our medicines; and</div>
        </td>

  </tr>


</table>
  <table cellspacing="0" cellpadding="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">


  <tr>

    <td style="width: 36pt;"></td>

    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">reimbursement policies of government and third-party payers.</div>
        </td>

  </tr>


</table>
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    <div class="DSPFPageFooter">
      <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span class="DSPFPageNumber">50</span></div>

    </div>

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  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Based on the profile of our medicines, physicians, patients, patient advocates, payers or the medical community in general
    may not accept or use any medicines that we may develop.</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">For example, TEGSEDI requires periodic blood and urine monitoring, is available in the U.S. only through a REMS program,
    and the product label in the U.S. has a boxed warning for thrombocytopenia and glomerulonephritis. Our main competition in the U.S. market for TEGSEDI is patisiran, marketed by Alnylam Pharmaceuticals, Inc. Although patisiran requires intravenous
    administration and pre-treatment with steroids, it does not have a boxed warning nor is it available only through a REMS program. Additionally, the product label for WAYLIVRA in the EU requires regular blood monitoring. In each case, these label
    requirements have negatively affected our ability to attract and retain patients for these medicines. If we or our partner cannot effectively maintain patients on TEGSEDI or WAYLIVRA, including due to limitations or restrictions on the ability to
    conduct periodic blood and urine monitoring of our patients as a result of the current COVID-19 Pandemic, we may not be able to generate substantial revenue from TEGSEDI or WAYLIVRA sales.</div>

  <div><br />
  </div>

  <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">If we or our partners fail to compete effectively, our medicines, including SPINRAZA, TEGSEDI and WAYLIVRA, and our
    medicines in development, will not generate significant revenues.</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Our competitors engage in drug discovery throughout the world, are numerous, and include, among others, major
    pharmaceutical companies and specialized biopharmaceutical firms. Other companies are engaged in developing antisense technology. Our competitors may succeed in developing medicines that are:</div>

  <div><br />
  </div>

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    <td style="width: 36pt;"></td>

    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">priced lower than our medicines;</div>
        </td>

  </tr>


</table>
  <table cellspacing="0" cellpadding="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">


  <tr>

    <td style="width: 36pt;"></td>

    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">reimbursed more favorably by government and other third-party payers than our medicines;</div>
        </td>

  </tr>


</table>
  <table cellspacing="0" cellpadding="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">


  <tr>

    <td style="width: 36pt;"></td>

    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">safer than our medicines;</div>
        </td>

  </tr>


</table>
  <table cellspacing="0" cellpadding="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">


  <tr>

    <td style="width: 36pt;"></td>

    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">more effective than our medicines; or</div>
        </td>

  </tr>


</table>
  <table cellspacing="0" cellpadding="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">


  <tr>

    <td style="width: 36pt;"></td>

    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">more convenient to use than our medicines.</div>
        </td>

  </tr>


</table>
  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">These competitive developments could make our medicines, including SPINRAZA, TEGSEDI and WAYLIVRA, and our medicines in
    development, obsolete or non-competitive.</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Certain of our partners are pursuing other technologies or developing other medicines either on their own or in
    collaboration with others, including our competitors, to treat the same diseases our own collaborative programs target. Competition may negatively impact a partner&#8217;s focus on and commitment to our medicines and, as a result, could delay or otherwise
    negatively affect the commercialization of our medicines, including SPINRAZA, TEGSEDI and WAYLIVRA.</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Many of our competitors have substantially greater financial, technical and human resources than we do. In addition, many
    of these competitors have significantly greater experience than we do in conducting preclinical testing and human clinical studies of new pharmaceutical products, in obtaining FDA and other regulatory authorizations of such products and in
    commercializing such products. Accordingly, our competitors may succeed in obtaining regulatory authorization for products earlier than we do.</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">There are several pharmaceutical and biotechnology companies engaged in the development or commercialization in certain
    geographic markets of products against targets that are also targets of products in our development pipeline. For example:</div>

  <div><br />
  </div>

  <table cellspacing="0" cellpadding="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">


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    <td style="width: 36pt;"></td>

    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Onasemnogene abeparvovec and risdiplam compete with SPINRAZA;</div>
        </td>

  </tr>


</table>
  <table cellspacing="0" cellpadding="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">


  <tr>

    <td style="width: 36pt;"></td>

    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Patisiran, tafamidis, and tafamidis meglumine compete with TEGSEDI and could compete with eplontersen;</div>
        </td>

  </tr>


</table>
  <table cellspacing="0" cellpadding="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">


  <tr>

    <td style="width: 36pt;"></td>

    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">Vutrisiran and acoramidis could compete with TEGSEDI and </span>eplontersen<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">;</span></div>
        </td>

  </tr>


</table>
  <table cellspacing="0" cellpadding="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">


  <tr>

    <td style="width: 36pt;"></td>

    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">ARO-APOC3, lomitapide, evinacumab, BIO89-100, and gemcabene could compete with WAYLIVRA and olezarsen;</div>
        </td>

  </tr>


</table>
  <table cellspacing="0" cellpadding="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">


  <tr>

    <td style="width: 36pt;"></td>

    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">AMG890 could compete with pelacarsen;</div>
        </td>

  </tr>


</table>
  <table cellspacing="0" cellpadding="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">


  <tr>

    <td style="width: 36pt;"></td>

    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Arimoclomol, ultomiris, mastinib and trehalose could compete with tofersen; and</div>
        </td>

  </tr>


</table>
  <table cellspacing="0" cellpadding="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">


  <tr>

    <td style="width: 36pt;"></td>

    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">Lanadelumab-flyo, C1 esterase inhibitor, berotralstat, C1 esterase inhibitor
              subcutaneous, garadacimab, KVD824, and </span>NTLA-2002<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> could compete with donidalorsen.</span></div>
        </td>

  </tr>


</table>
  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">SPINRAZA injection for intrathecal use is an antisense medicine indicated for the treatment of SMA patients of all ages approved in over
    50 countries. Specifically, SPINRAZA faces competition from onasemnogene abeparvovec, a gene therapy product that was approved in the U.S. in May 2019 and in the EU in May 2020 for the treatment of SMA, as well as risdiplam, an oral product for the
    treatment of SMA that was approved in the U.S. in August 2020 and in the EU in March 2021. Biogen has disclosed that SPINRAZA revenue has decreased primarily due to a reduction in demand as a result of increased competition and that future sales of
    SPINRAZA may be adversely affected by competing products.</div>

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      <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span class="DSPFPageNumber">51</span></div>

    </div>

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  </div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Additionally, companies that are developing medicines that target the same patient populations as our medicines in development may compete
    with us to enroll participants in the clinical trials for such medicines, which could make it more difficult for us to complete enrollment for these clinical trials.</div>

  <div><br />
  </div>

  <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Our medicines could be subject to regulatory limitations following approval.</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Following approval of a medicine, we and our partners must comply with comprehensive government regulations regarding the
    manufacture, marketing and distribution of medicines. Promotional communications regarding prescription medicines must be consistent with the information in the product&#8217;s approved labeling. We or our partners may not obtain the labeling claims
    necessary or desirable to successfully commercialize our medicines, including SPINRAZA, TEGSEDI and WAYLIVRA, and our medicines in development.</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">The FDA and foreign regulatory bodies have the authority to impose significant restrictions on an approved medicine
    through the product label and on advertising, promotional and distribution activities. For example:</div>

  <div><br />
  </div>

  <table cellspacing="0" cellpadding="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">


  <tr>

    <td style="width: 36pt;"></td>

    <td style="width: 18pt; vertical-align: top; align: right; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;">in the U.S., TEGSEDI&#8217;s label contains a boxed warning for thrombocytopenia and glomerulonephritis;</div>
        </td>

  </tr>


</table>
  <table cellspacing="0" cellpadding="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">


  <tr>

    <td style="width: 36pt;"></td>

    <td style="width: 18pt; vertical-align: top; align: right; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;">TEGSEDI requires periodic blood and urine monitoring; and</div>
        </td>

  </tr>


</table>
  <table cellspacing="0" cellpadding="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">


  <tr>

    <td style="width: 36pt;"></td>

    <td style="width: 18pt; vertical-align: top; align: right; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;">in the U.S., TEGSEDI is available only through a REMS program.</div>
        </td>

  </tr>


</table>
  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 39.6pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Prescription medicines may be promoted only for the approved indications in accordance with the approved label. The FDA
    and other agencies actively enforce the laws and regulations prohibiting the promotion of off-label uses, and a company that is found to have improperly promoted off-label uses may be subject to significant liability.</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 39.6pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">In addition, when approved, the FDA or a foreign regulatory authority may condition approval on the performance of
    post-approval clinical studies or patient monitoring, which could be time consuming and expensive. For example, in connection with the conditional marketing approval for WAYLIVRA in the EU, we are required to conduct a post-authorization safety study
    to evaluate the safety of WAYLIVRA on thrombocytopenia and bleeding in FCS patients taking WAYLIVRA. If the results of such post-marketing studies are not satisfactory, the FDA, EC or other foreign regulatory authority may withdraw marketing
    authorization or may condition continued marketing on commitments from us or our partners that may be expensive and time consuming to fulfill.</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 39.6pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">If we or others identify side effects after any of our medicines are on the market, or if manufacturing problems occur
    subsequent to regulatory approval, or if we, our manufacturers or our partners fail to comply with regulatory requirements, we or our partners may, among other things, lose regulatory approval and be forced to withdraw products from the market, need to
    conduct additional clinical studies, incur restrictions on the marketing, distribution or manufacturing of the product, and/or change the labeling of our medicines, including SPINRAZA, TEGSEDI and WAYLIVRA.</div>

  <div><br />
  </div>

  <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">We depend on our collaboration with Biogen for the development and commercialization of SPINRAZA.</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We have entered into a collaborative arrangement with Biogen to develop and commercialize SPINRAZA. We entered into this
    collaboration primarily to:</div>

  <div><br />
  </div>

  <table cellspacing="0" cellpadding="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">


  <tr>

    <td style="width: 36pt;"></td>

    <td style="width: 18pt; vertical-align: top; align: right; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;">fund our development activities for SPINRAZA;</div>
        </td>

  </tr>


</table>
  <table cellspacing="0" cellpadding="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">


  <tr>

    <td style="width: 36pt;"></td>

    <td style="width: 18pt; vertical-align: top; align: right; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;">seek and obtain regulatory approvals for SPINRAZA; and</div>
        </td>

  </tr>


</table>
  <table cellspacing="0" cellpadding="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">


  <tr>

    <td style="width: 36pt;"></td>

    <td style="width: 18pt; vertical-align: top; align: right; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;">successfully commercialize SPINRAZA.</div>
        </td>

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  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We are relying on Biogen to obtain additional regulatory approvals for SPINRAZA, generate additional clinical data for
    SPINRAZA, manufacture and successfully commercialize SPINRAZA. In general, we cannot control the amount and timing of resources that Biogen devotes to our collaboration. If Biogen fails to further develop SPINRAZA, obtain additional regulatory
    approvals for SPINRAZA, manufacture or commercialize SPINRAZA, or if Biogen&#8217;s efforts are not effective, our business may be negatively affected.</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Our collaboration with Biogen may not continue for various reasons. Biogen can terminate our collaboration at any time. If
    Biogen stops developing or commercializing SPINRAZA, we would have to seek or spend additional funding, and SPINRAZA&#8217;s commercialization may be harmed or delayed.</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Our collaboration with Biogen may not result in the continued successful commercialization of SPINRAZA. If Biogen does not
    continue to successfully commercialize SPINRAZA, we will receive limited revenues for SPINRAZA.</div>

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  <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">We depend on our collaboration with AstraZeneca for the joint development and commercialization of eplontersen.</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We have entered into a collaborative arrangement with AstraZeneca to develop and commercialize eplontersen. Under the
    terms of the collaboration agreement, Ionis and AstraZeneca will co-develop and co-commercialize eplontersen in the U.S. and AstraZeneca will have the sole right to commercialize eplontersen in all other countries. Prior to co-commercializing
    eplontersen in the U.S., we will need to negotiate a co-commercialization agreement with AstraZeneca to govern the parties&#8217; performance of co-commercialization, which agreement will include a commercial plan and budget. As a company we do not have
    experience with co-commercialization arrangements. We also do not have control over the amount and timing of resources that AstraZeneca devotes to our collaboration, particularly outside of the U.S. If the co-commercialization arrangement for
    eplontersen is not successful for any reason, eplontersen may not meet our commercial objectives and our revenues for eplontersen may be limited.</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">In addition, a Joint Steering Committee, or JSC, having equal membership from us and AstraZeneca, and various
    subcommittees oversee and coordinate the development, manufacturing, commercialization and other exploitation activities for eplontersen in the U.S. by mutual agreement. If any subcommittee cannot reach unanimous agreement on any matter within its
    respective scope of authority, such matter may be referred to the JSC for resolution. If the JSC cannot come to a mutual agreement on any particular matter, this could delay our ability to develop or commercialize eplontersen.</div>

  <div><br />
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  <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">We are relying on third parties to market, sell and distribute TEGSEDI and WAYLIVRA.</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We have entered into agreements with third parties to commercialize TEGSEDI and WAYLIVRA as follows:</div>

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          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">In April 2021, we entered into a distribution agreement with Sobi to commercialize TEGSEDI in the U.S. and Canada;</div>
        </td>

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    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">In December 2020, we entered into a distribution agreement with Sobi to commercialize TEGSEDI and WAYLIVRA in Europe; and</div>
        </td>

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    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">In August 2018, we granted PTC the exclusive right to commercialize TEGSEDI and WAYLIVRA in Latin America and
            certain Caribbean countries.</div>
        </td>

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</table>
  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We are relying on Sobi and PTC to effectively market, sell and distribute TEGSEDI and WAYLIVRA and have less control over sales efforts
    and may receive less revenue than if we commercialized TEGSEDI or WAYLIVRA by ourselves. If Sobi or PTC does not successfully commercialize TEGSEDI or WAYLIVRA, including as a result of delays or disruption caused by the current COVID-19 Pandemic, we
    may receive limited revenue for TEGSEDI or WAYLIVRA in the U.S., Canada, Europe, Latin America or certain Caribbean countries, which could have a material adverse effect on our business, prospects, financial condition and results of operations.</div>

  <div><br />
  </div>

  <div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Our operations are subject to additional healthcare laws.</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Our operations are subject to additional healthcare laws, including federal and state anti-kickback laws, false claims laws, transparency
    laws, such as the federal Sunshine Act, and health information privacy and security laws, which are subject to change at any time.&#160; For example, <span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">in November
      2020, the U.S. Department of Health and Human Services issued a final rule modifying the anti-kickback law safe harbors for Medicare Part D plans, pharmacies, and pharmaceutical benefit managers.</span> Efforts to ensure that our operations comply
    with current applicable healthcare laws and regulations involve substantial costs. It is possible that governmental authorities will conclude that our business practices may not comply with current or future statutes, regulations or case law involving
    applicable fraud and abuse or other healthcare laws and regulations. Penalties for violations of applicable healthcare laws and regulations may include significant civil, criminal and administrative penalties, damages, disgorgement, fines,
    imprisonment, exclusion of products from government funded healthcare programs, such as Medicare and Medicaid, and additional reporting requirements and oversight if we enter into a corporate integrity agreement or similar agreement to resolve
    allegations of non-compliance with these laws. In addition, violations may also result in reputational harm, diminished profits and future earnings.</div>

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  <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">If government or other third-party payers fail to provide adequate coverage and payment rates for our medicines, including
    SPINRAZA, TEGSEDI and WAYLIVRA, and our medicines in development, our revenue will be limited.</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">In both domestic and foreign markets, sales of our current and future products will depend in part upon the availability of coverage and
    reimbursement from third-party payers. The majority of patients in the U.S. who would fit within our target patient populations for our medicines have their healthcare supported by a combination of Medicare coverage, other government health programs
    such as Medicaid, managed care providers, private health insurers and other organizations. Coverage decisions may depend upon clinical and economic standards that disfavor new medicines when more established or lower cost therapeutic alternatives are
    already available or subsequently become available. Assuming coverage is approved, the resulting reimbursement payment rates might not be enough to make our medicines affordable. Even if favorable coverage status and adequate reimbursement rates are
    attained, less favorable coverage policies and reimbursement rates may be implemented in the future. Accordingly, SPINRAZA, TEGSEDI and WAYLIVRA, and our medicines in development, will face competition from other therapies and medicines for limited
    financial resources. We or our partners may need to conduct post-marketing studies to demonstrate the cost-effectiveness of any future products to satisfy third-party payers. These studies might require us to commit a significant amount of management
    time and financial and other resources. Third-party payers may never consider our future products as cost-effective. Adequate third-party coverage and reimbursement might not be available to enable us to maintain price levels sufficient to realize an
    appropriate return on investment in product development.</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Third-party payers, whether foreign or domestic, or governmental or commercial, are developing increasingly sophisticated
    methods of controlling healthcare costs. In addition, in the U.S., no uniform policy of coverage and reimbursement for medicines exists among third-party payers. Therefore, coverage and reimbursement for medicines can differ significantly from payer to
    payer. For example, the Affordable Care Act was passed in March 2010, and substantially changed the way healthcare is financed by both governmental and private insurers, and continues to significantly impact the U.S. pharmaceutical industry. There have
    been judicial and Congressional challenges to certain aspects of the Affordable Care Act, as well as efforts to repeal or replace certain aspects of the Affordable Care Act. It is unclear how future litigation and healthcare reform measures will impact
    the Affordable Care Act and our business.</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">Further, we believe that future coverage,
      reimbursement and pricing will likely be subject to increased restrictions both in the U.S. and in international markets. In the U.S., recent health reform measures have resulted in reductions in Medicare and other healthcare funding, and there have
      been several recent U.S. Congressional inquiries, legislation and executive orders designed to, among other things, reduce drug prices (e.g., by supporting drug price negotiation in Medicare Parts B and D, with those negotiated prices also available
      to commercial plans, and progressing legislation to slow price increases over time on existing drugs), increase competition (e.g., by supporting legislation to speed the entry of biosimilar and generic drugs, including shortening the period of
      exclusivity, policies in Medicare Part B to increase the prescribing of biosimilars by physicians, and a prohibition on &#8220;pay-for-delay&#8221; agreements and anti-competitive practices by drug manufacturers), lower out-of-pocket drug costs for patients
      (e.g., by capping Medicare Part D beneficiary out-of-pocket pharmacy expenses), and foster scientific innovation to promote better health care and improved health (e.g., by</span>&#160;<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">investing in public and private research and incentivizing the market to promote discovery of valuable and accessible new treatments). At the state level, legislatures have increasingly passed legislation and implemented
      regulations designed to control pharmaceutical and biological product pricing, including price or patient reimbursement constraints, discounts, restrictions on certain product access and marketing cost disclosure and transparency measures, and, in
      some cases, designed to encourage importation from other countries and bulk purchasing. Third-party coverage and reimbursement for medicines may not be available or adequate in either the U.S. or international markets, and third-party payers, whether
      foreign or domestic, or governmental or commercial, may allocate their resources to address the current COVID-19 Pandemic or experience delays or disruptions in their ability to devote resources to coverage and reimbursement matters related to our
      products or medicines as a result of the COVID-19 Pandemic, which would negatively affect the potential commercial success of our products, our revenue and our profits</span>.</div>

  <div><br />
  </div>

  <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">If we cannot manufacture our medicines or contract with a third party to manufacture our medicines at costs that allow us
    to charge competitive prices to buyers, we cannot market our products profitably.</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">To successfully commercialize any of our medicines, we would need to optimize and manage large-scale commercial
    manufacturing capabilities either on a standalone basis or through a third-party manufacturer. We rely on third-party manufacturers to supply the drug substance and drug product for TEGSEDI and drug product for WAYLIVRA. Any delays or disruption to our
    own or third-party commercial manufacturing capabilities, including any interruption to our supply chain as a result of the current COVID-19 Pandemic, could limit the commercial success of our medicines. In addition, as our drug development and
    commercial pipeline increases and matures, we will have a greater need for clinical trial and commercial manufacturing capacity. For example, we have plans to expand our manufacturing infrastructure to support our wholly owned pipeline. If we are not
    successful in executing this expansion, it could limit our ability to meet our manufacturing requirements and commercial objectives in the future.</div>

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  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Additionally, we have limited experience manufacturing pharmaceutical products of the chemical class represented by our
    medicines, called oligonucleotides, on a commercial scale for the systemic administration of a medicine. There are a small number of suppliers for certain capital equipment and raw materials that we use to manufacture our medicines, and some of these
    suppliers will need to increase their scale of production to meet our projected needs for commercial manufacturing. Further, we must continue to improve our manufacturing processes to allow us to reduce our drug costs. We or our partners may not be
    able to manufacture our medicines at a cost or in quantities necessary to make commercially successful products.</div>

  <div><br />
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  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Also, manufacturers, including us, must adhere to the FDA&#8217;s cGMP regulations and similar regulations in foreign countries,
    which the applicable regulatory authorities enforce through facilities inspection programs. We, our partners and our contract manufacturers may not comply or maintain compliance with cGMP, or similar foreign regulations. Non-compliance could
    significantly delay or prevent receipt of marketing authorizations for our medicines, including authorizations for SPINRAZA, TEGSEDI and WAYLIVRA, and our medicines in development, or result in enforcement action after authorization that could limit
    the commercial success of our medicines, including SPINRAZA, TEGSEDI and WAYLIVRA, and our medicines in development.</div>

  <div><br />
  </div>

  <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Risks Related to the Development and Regulatory Approval of our Medicines</div>

  <div><br />
  </div>

  <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">If we or our partners fail to obtain regulatory approval for our medicines and additional approvals for SPINRAZA, TEGSEDI
    and WAYLIVRA, we or our partners cannot sell them in the applicable markets.</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We cannot guarantee that any of our medicines will be considered safe and effective or will be approved for
    commercialization. In addition, it is possible that SPINRAZA, TEGSEDI and WAYLIVRA may not be approved in additional markets or for additional indications. We and our partners must conduct time-consuming, extensive and costly clinical studies to
    demonstrate the safety and efficacy of each of our medicines before they can be approved or receive additional approvals for sale. We and our partners must conduct these studies in compliance with FDA regulations and with comparable regulations in
    other countries.</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We and our partners may not obtain necessary regulatory approvals on a timely basis, if at all, for our medicines. It is
    possible that regulatory agencies will not approve our medicines for marketing or SPINRAZA, TEGSEDI or WAYLIVRA in additional markets or for additional indications. If the FDA or another regulatory agency believes that we or our partners have not
    sufficiently demonstrated the safety or efficacy of any of our medicines, including SPINRAZA, TEGSEDI and WAYLIVRA, or our medicines in development, the agency will not approve the specific medicine or will require additional studies, which can be time
    consuming and expensive and will delay or harm commercialization of the medicine. For example, in August 2018 we received a complete response letter from the FDA regarding the new drug application for WAYLIVRA in which the FDA determined that the
    safety concerns identified with WAYLIVRA in our clinical development program outweighed the expected benefits of triglyceride lowering in patients with FCS. We also received a Non-W from Health Canada for WAYLIVRA in November 2018.</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">The FDA or other comparable foreign regulatory authorities can delay, limit or deny approval of a medicine for many
    reasons, including:</div>

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    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">such authorities may disagree with the design or implementation of our clinical studies;</div>
        </td>

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    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">we or our partners may be unable to demonstrate to the satisfaction of the FDA or other regulatory authorities that a medicine is safe and effective for
            any indication;</div>
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    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">such authorities may not accept clinical data from studies conducted at clinical facilities that have deficient clinical practices or that are in
            countries where the standard of care is potentially different from that in the U.S.;</div>
        </td>

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    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">we or our partners may be unable to demonstrate that our medicine&#8217;s clinical and other benefits outweigh its safety risks to support approval;</div>
        </td>

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    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">such authorities may disagree with the interpretation of data from preclinical or clinical studies;</div>
        </td>

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    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">such authorities may find deficiencies in the manufacturing processes or facilities of third-party manufacturers who manufacture clinical and commercial
            supplies for our medicines, or may delay the inspection of such facilities due to restrictions related to the COVID-19 Pandemic; and</div>
        </td>

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    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">the approval policies or regulations of such authorities or their prior guidance to us or our partners during clinical development may significantly
            change in a manner rendering our clinical data insufficient for approval.</div>
        </td>

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  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Failure to receive marketing authorization for our medicines, or failure to receive additional marketing authorizations
    for SPINRAZA, TEGSEDI or WAYLIVRA, or delays in these authorizations, could prevent or delay commercial introduction of the medicine, and, as a result, could negatively impact our ability to generate revenue from product sales.</div>

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  <div>&#160;</div>

  <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">We may not be able to benefit from orphan drug designation for our medicines.</div>

  <div>&#160;</div>

  <div style="text-align: justify; text-indent: 40.8pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">In the U.S., under the Orphan Drug Act, the FDA may designate a medicine as an orphan drug if it is intended to treat a
    rare disease or condition affecting fewer than 200,000 individuals in the U.S. Orphan drug designation does not convey any advantage in, or shorten the duration of, the regulatory review and approval process, but it can provide financial incentives,
    such as tax advantages and user-fee waivers, as well as longer regulatory exclusivity periods. The FDA has granted orphan drug designation to eplontersen for the treatment of patients with transthyretin-mediated amyloidosis. The FDA and EMA have
    granted orphan drug designation to TEGSEDI for the treatment of patients with polyneuropathy due to hATTR amyloidosis, to WAYLIVRA for the treatment of patients with FCS, and to tominersen for the treatment of patients with HD. In addition, the EMA has
    granted orphan drug designation to WAYLIVRA for the treatment of patients with FPL. Even if approval is obtained on a medicine that has been designated as an orphan drug, we may lose orphan drug exclusivity if the FDA or EMA determines that the request
    for designation was materially defective or if we cannot assure sufficient quantity of the applicable medicine to meet the needs of patients with the rare disease or condition, or if a competitor is able to gain approval for the same medicine in a
    safer or more effective form or that makes a major contribution to patient care.<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> If we lose orphan drug exclusivity on any of our medicines, </span>we may face increased
    competition and lose market share for such medicine.</div>

  <div><br />
  </div>

  <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">If the results of clinical testing indicate that any of our medicines are not suitable for commercial use, we may need to
    abandon one or more of our drug development programs.</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Drug discovery and development has inherent risks and the historical failure rate for drugs is high. Antisense medicines
    are a relatively new approach to therapeutics. If we cannot demonstrate that our medicines are safe and effective for human use in the intended indication, we may need to abandon one or more of our drug development programs.</div>

  <div><br />
  </div>

  <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Even if our medicines are successful in preclinical and human clinical studies, the medicines may not be successful in
    late-stage clinical studies.</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">Successful results in preclinical or initial
      human clinical studies, including the Phase 2 results for some of our medicines in development, may not predict the results of subsequent clinical studies. If any of our medicines in Phase 3 clinical studies, including the studies of </span>eplontersen<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">, olezarsen, donidalorsen, ION363, pelacarsen and tofersen, do not show sufficient efficacy in patients with the targeted indication, or if such studies are
      discontinued for any other reason, it could negatively impact our development and commercialization goals for these medicines and our stock price could decline.</span></div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">In the past, we have invested in clinical
      studies of medicines that have not met the primary clinical endpoints in their Phase 3 studies or have been discontinued for other reasons. For example, </span><a id="_Hlk85441436"><!--Anchor--></a><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">in October 2021, Biogen reported that tofersen did not meet the primary clinical endpoint in the Phase 3 VALOR study; however, trends favoring tofersen were seen across multiple secondary and exploratory
      measures of disease activity and clinical function. In addition, in March 2021, Roche decided to discontinue dosing in the Phase 3 GENERATION HD1 study of tominersen in patients with manifest Huntington&#8217;s disease based on the results of a pre-planned
      review of data from the Phase 3 study conducted by an unblinded Independent Data Monitoring Committee. Similar results could occur in clinical studies for our other medicines, including the studies of </span>eplontersen<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">, olezarsen, donidalorsen, ION363 and pelacarsen.</span></div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">There are a number of factors that could cause a clinical study to fail or be delayed, including:</div>

  <div><br />
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    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">the clinical study may produce negative or inconclusive results;</div>
        </td>

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    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">regulators may require that we hold, suspend or terminate clinical research for noncompliance with regulatory requirements;</div>
        </td>

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    <td style="width: 36pt;"></td>

    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">we, our partners, the FDA or foreign regulatory authorities could suspend or terminate a clinical study due to adverse side effects of a medicine on
            subjects or lack of efficacy in the trial;</div>
        </td>

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    <td style="width: 36pt;"></td>

    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">we, or our partners, may decide, or regulators may require us, to conduct additional preclinical testing or clinical studies;</div>
        </td>

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    <td style="width: 36pt;"></td>

    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">enrollment in our clinical studies may be slower than we anticipate;</div>
        </td>

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    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">we or our partners, including our independent clinical investigators, contract research organizations and other third-party service providers on which we
            rely, may not identify, recruit and train suitable clinical investigators at a sufficient number of study sites or timely enroll a sufficient number of study subjects in the clinical study;</div>
        </td>

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    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">the institutional review board for a prospective site might withhold or delay its approval for the study;</div>
        </td>

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    <td style="width: 18pt; vertical-align: top; align: right; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;">people who enroll in the clinical study may later drop out due to adverse events, a perception they are not benefiting from participating in the study, fatigue with the
            clinical study process or personal issues;</div>
        </td>

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    <td style="width: 18pt; vertical-align: top; align: right; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;">a clinical study site may deviate from the protocol for the study;</div>
        </td>

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    <td style="width: 36pt;"></td>

    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">the cost of our clinical studies may be greater than we anticipate;</div>
        </td>

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    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">our partners may decide not to exercise any existing options to license and conduct additional clinical studies for our medicines; and</div>
        </td>

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    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">the supply or quality of our medicines or other materials necessary to conduct our clinical studies may be insufficient, inadequate or delayed.</div>
        </td>

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  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">The current COVID-19 Pandemic could make some of these factors more likely to occur.</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">In addition, our current medicines, including SPINRAZA, TEGSEDI and WAYLIVRA, are chemically similar to each other. As a
    result, a safety observation we encounter with one of our medicines could have, or be perceived by a regulatory authority to have, an impact on a different medicine we are developing. This could cause the FDA or other regulators to ask questions or
    take actions that could harm or delay our ability to develop and commercialize our medicines or increase our costs. For example, the FDA or other regulatory agencies could request, among other things, any of the following regarding one of our
    medicines: additional information or commitments before we can start or continue a clinical study, protocol amendments, increased safety monitoring, additional product labeling information, and post-approval commitments. This happened in connection
    with the conditional marketing approval for WAYLIVRA in the EU, as the EC is requiring us to conduct a post-authorization safety study to evaluate the safety of WAYLIVRA on thrombocytopenia and bleeding in FCS patients taking WAYLIVRA. We have ongoing
    post-marketing studies for WAYLIVRA and TEGSEDI and an EAP for WAYLIVRA. Adverse events or results from these studies or the EAPs could negatively impact our pending or future marketing approval applications for WAYLIVRA and TEGSEDI in patients with
    FCS or hATTR amyloidosis or the commercial opportunity for WAYLIVRA or TEGSEDI.</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">Any failure or delay in our clinical studies,
      including the studies of tofersen, pelacarsen, </span>eplontersen<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">, olezarsen, donidalorsen, and ION363, could reduce the commercial potential or viability
      of our medicines.</span></div>

  <div><br />
  </div>

  <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">We depend on third parties to conduct our clinical studies for our medicines and any failure of those parties to fulfill
    their obligations could adversely affect our development and commercialization plans.</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">We depend on independent clinical
      investigators, contract research organizations and other third-party service providers to conduct our clinical studies for our medicines and expect to continue to do so in the future. For example, we use clinical research organizations, such as Icon
      Clinical Research Limited, Syneos Health, Inc., PPD and Medpace for the clinical studies for our medicines, including </span>eplontersen<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">, olezarsen,
      donidalorsen, ION363, pelacarsen and tofersen. We rely heavily on these parties for successful execution of our clinical studies, but do not control many aspects of their activities. For example, the investigators are not our employees. However, we
      are responsible for ensuring that these third parties conduct each of our clinical studies in accordance with the general investigational plan and approved protocols for the study. Third parties may not complete activities on schedule or may not
      conduct our clinical studies in accordance with regulatory requirements or our stated protocols. The failure of these third parties to carry out their obligations, including as a result of delays or disruption caused by the current COVID-19 Pandemic
      that may affect the third party&#8217;s ability to conduct the clinical studies for our medicines, or a termination of our relationship with these third parties, could delay or prevent the development, marketing authorization and commercialization of our
      medicines or additional marketing authorizations for TEGSEDI and WAYLIVRA.</span></div>

  <div><br />
  </div>

  <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Since corporate partnering is a significant part of our strategy to fund the advancement and commercialization of our
    development programs, if any of our collaborative partners fail to fund our collaborative programs, or if we cannot obtain additional partners, we may have to delay or stop progress on our drug development programs.</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">To date, corporate partnering has played a significant role in our strategy to fund our development programs and to add
    key development resources. We plan to continue to rely on additional collaborative arrangements to develop and commercialize many of our unpartnered medicines. However, we may not be able to negotiate favorable collaborative arrangements for these drug
    programs. If we cannot continue to secure additional collaborative partners, our revenues could decrease and the development of our medicines could suffer.</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Our corporate partners are developing and/or funding many of the medicines in our development pipeline. For example, we
    are relying on:</div>

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    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">AstraZeneca for the joint development and funding of eplontersen;</div>
        </td>

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    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Novartis for development and funding of pelacarsen;</div>
        </td>

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    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Biogen for development and funding of tofersen; and</div>
        </td>

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    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Roche for development and funding of tominersen.</div>
        </td>

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  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">If any of these pharmaceutical companies stops developing and/or funding these medicines, our business could suffer and we
    may not have, or be willing to dedicate, the resources available to develop these medicines on our own. Our collaborators can terminate their relationships with us under certain circumstances, many of which are outside of our control. For example,
    after a review of data from the global Phase 2b study of vupanorsen, Pfizer decided to discontinue the clinical development program for vupanorsen.</div>

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  <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Even with funding from corporate partners, if our partners do not effectively perform their obligations under our
    agreements with them, it would delay or stop the progress of our drug development and commercial programs.</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">In addition to receiving funding, we enter into collaborative arrangements with third parties to:</div>

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    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">conduct clinical studies;</div>
        </td>

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    <td style="width: 36pt;"></td>

    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">seek and obtain marketing authorizations; and</div>
        </td>

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    <td style="width: 36pt;"></td>

    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">manufacture, market and sell our medicines.</div>
        </td>

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  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Once we have secured a collaborative arrangement to further develop and commercialize one of our drug development
    programs, such as our collaborations with AstraZeneca, Bayer, Biogen, GSK, Janssen, Novartis, and Roche, these collaborations may not continue or result in commercialized medicines, or may not progress as quickly as we first anticipated.</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">For example, a collaborator such as AstraZeneca, Bayer, Biogen, GSK, Janssen, Novartis, or Roche, could determine that it
    is in its financial interest to:</div>

  <div><br />
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    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">pursue alternative technologies or develop alternative products that may be competitive with the medicine that is part of the collaboration with us;</div>
        </td>

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    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">pursue higher-priority programs or change the focus of its own development programs; or</div>
        </td>

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    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">choose to devote fewer resources to our medicines than it does for its own medicines.</div>
        </td>

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</table>
  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">If any of these occur, it could affect our partner&#8217;s commitment to the collaboration with us and could delay or otherwise
    negatively affect the commercialization of our medicines, including SPINRAZA, pelacarsen, tofersen, and eplontersen.</div>

  <div><br />
  </div>

  <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">If we do not progress in our programs as anticipated, the price of our securities could decrease.</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">For planning purposes, we estimate and may
      disclose the timing of a variety of clinical, regulatory and other milestones, such as when we anticipate a certain medicine will enter clinical trials, when we anticipate completing a clinical study, or when we anticipate filing an application for,
      or obtaining, marketing authorization, or when we or our partners plan to commercially launch a medicine. We base our estimates on present facts and a variety of assumptions, many of which are outside of our control, including the current COVID-19
      Pandemic. If we do not achieve milestones in accordance with our or our investors&#8217; or securities analysts&#8217; expectations, including milestones related to SPINRAZA, TEGSEDI, WAYLIVRA, </span>eplontersen<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">, olezarsen, donidalorsen, ION363, pelacarsen and tofersen, the price of our securities could decrease.</span></div>

  <div><br />
  </div>

  <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Risks Associated with our Businesses as a Whole</div>

  <div><br />
  </div>

  <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic; font-weight: bold;">Risks related to our financial condition</div>

  <div><br />
  </div>

  <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">We have incurred losses, and our business will suffer if we fail to consistently achieve profitability in the future.</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Because drug discovery and development requires substantial lead-time and money prior to commercialization, our expenses
    have generally exceeded our revenue since we were founded in January 1989. As of December 31, 2021, we had an accumulated deficit of
    approximately $1.2 billion and stockholders&#8217; equity of approximately $0.8 billion. Most of our historical losses resulted from costs incurred in connection with our research and development programs and from selling, general and administrative costs associated
    with our operations. Most of our income has come from collaborative arrangements, including commercial revenue from royalties and R&amp;D revenue, with additional income from research grants and the sale or licensing of our patents, as well as interest
    income. If we do not continue to earn substantial revenue, we may incur additional operating losses in the future. We may not successfully develop any additional medicines or achieve or sustain future profitability.</div>

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  <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">If we fail to obtain timely funding, we may need to curtail or abandon some of our programs.</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Many of our medicines are undergoing clinical studies or are in the early stages of research and development. Most of our
    drug programs will require significant additional research, development, manufacturing, preclinical and clinical testing, marketing authorizations, preclinical activities and commitment of significant additional resources prior to their successful
    commercialization. These activities will require significant cash. As of December 31, 2021, we had cash, cash equivalents and short-term
    investments equal to $2.1 billion. If we or our partners do not meet our goals to successfully commercialize our medicines, including SPINRAZA,
    TEGSEDI and WAYLIVRA, or to license certain medicines and proprietary technologies, we will need additional funding in the future. Our future capital requirements will depend on many factors, such as the following:</div>

  <div><br />
  </div>

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    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">successful commercialization of SPINRAZA, TEGSEDI and WAYLIVRA;</div>
        </td>

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    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">additional marketing approvals for WAYLIVRA and TEGSEDI;</div>
        </td>

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    <td style="width: 36pt;"></td>

    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">the profile and launch timing of our medicines, including eplontersen, olezarsen, donidalorsen, ION363, pelacarsen and tofersen;</div>
        </td>

  </tr>


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    <td style="width: 36pt;"></td>

    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">changes in existing collaborative relationships and our ability to establish and maintain additional collaborative arrangements;</div>
        </td>

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    <td style="width: 36pt;"></td>

    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">continued scientific progress in our research, drug discovery and development programs;</div>
        </td>

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</table>
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    <td style="width: 36pt;"></td>

    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">the size of our programs and progress with preclinical and clinical studies;</div>
        </td>

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</table>
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    <td style="width: 36pt;"></td>

    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">the time and costs involved in obtaining marketing authorizations;</div>
        </td>

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    <td style="width: 36pt;"></td>

    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">competing technological and market developments, including the introduction by others of new therapies that address our markets; and</div>
        </td>

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    <td style="width: 36pt;"></td>

    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">our manufacturing requirements and capacity to fulfill such requirements.</div>
        </td>

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</table>
  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">If we need additional funds, we may need to raise them through public or private financing. Additional financing may not
    be available at all or on acceptable terms. If we raise additional funds by issuing equity securities, the shares of existing stockholders will be diluted and the price, as well as the price of our other securities, may decline. If adequate funds are
    not available or not available on acceptable terms, we may have to cut back on one or more of our research, drug discovery or development programs. Alternatively, we may obtain funds through arrangements with collaborative partners or others, which
    could require us to give up rights to certain of our technologies or medicines.</div>

  <div><br />
  </div>

  <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic; font-weight: bold;">Risks related to our intellectual property</div>

  <div><br />
  </div>

  <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">If we cannot protect our patent rights or our other proprietary rights, others may compete more effectively against us.</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Our success depends to a significant degree upon whether we can continue to develop, secure and maintain intellectual
    property rights to proprietary products and services. However, we may not receive issued patents on any of our pending patent applications in the U.S. or in other countries and we may not be able to obtain, maintain or enforce our patents and other
    intellectual property rights which could impact our ability to compete effectively. In addition, the scope of any of our issued patents may not be sufficiently broad to provide us with a competitive advantage. Furthermore, other parties may
    successfully challenge, invalidate or circumvent our issued patents or patents licensed to us so that our patent rights do not create an effective competitive barrier or revenue source.</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We cannot be certain that the U.S. Patent and Trademark Office, or U.S. PTO, and courts in the U.S. or the patent offices and courts in
    foreign countries will consider the claims in our patents and applications covering SPINRAZA, TEGSEDI, WAYLIVRA, or any of our medicines in development as patentable. Method-of-use patents protect the use of a product for the specified method. This
    type of patent does not prevent a competitor from making and marketing a product that is identical to our product for an indication that is outside the scope of the patented method. Moreover, even if competitors do not actively promote their product
    for our targeted indications, physicians may prescribe these products off-label. Although off-label prescriptions may infringe or contribute to the infringement of method-of-use patents, the practice is common and such infringement is difficult to
    prevent, even through legal action.</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">If we or any licensor partner loses or cannot obtain patent protection for SPINRAZA, TEGSEDI, WAYLIVRA, or any of our other medicines in
    development, it could have a material adverse impact on our business.</div>

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  </div>

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  <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Intellectual property litigation could be expensive and prevent us from pursuing our programs.</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">From time to time we have to defend our intellectual property rights. If we are involved in an intellectual property
    dispute, we may need to litigate to defend our rights or assert them against others. Disputes can involve arbitration, litigation or proceedings declared by the U.S. PTO or the International Trade Commission or foreign patent authorities. Even if
    resolved in our favor, litigation or other legal proceedings relating to intellectual property claims may cause us to incur significant expenses and could distract our technical and management personnel from their normal responsibilities. In addition,
    there could be public announcements of the results of hearings, motions or other interim proceedings or developments and if securities analysts or investors perceive these results to be negative, it could have a substantial adverse effect on the price
    of our common stock.</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">If a third party claims that our medicines or technology infringe its patents or other intellectual property rights, we
    may have to discontinue an important product or product line, alter our products and processes, pay license fees or cease certain activities. We may not be able to obtain a license to needed intellectual property on favorable terms, if at all. There
    are many patents issued or applied for in the biotechnology industry, and we may not be aware of patents or patent applications held by others that relate to our business. This is especially true since patent applications in the U.S. are filed
    confidentially for the first 18 months. Moreover, the validity and breadth of biotechnology patents involve complex legal and factual questions for which important legal issues remain.</div>

  <div><br />
  </div>

  <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic; font-weight: bold;">Risks related to our personnel</div>

  <div><br />
  </div>

  <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">If our management transition is not successful our business could suffer.</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">In January 2020, Dr. Crooke, our founder and Chief Executive Officer, transitioned from Chief Executive Officer to Executive Chairman of
    our Board of Directors, and Dr. Monia, who was our Chief Operating Officer and a member of our team since our founding over 30 years ago, began serving as our Chief Executive Officer. Following the 2021 Annual Meeting of Stockholders, Dr. Crooke
    stepped down from the Board and now serves as a Strategic Advisor to the Company, providing strategic advice and continuing to participate in the Company&#8217;s scientific activities. In June 2021, Dr. Loscalzo, a member of our Board <span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">since February 2014,</span> was appointed Chairman of the Board. If this transition is not successful, our business could suffer.</div>

  <div><br />
  </div>

  <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">The loss of key personnel, or the inability to attract and retain highly skilled personnel, could make it more difficult
    to run our business and reduce our likelihood of success.</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">We are dependent on the principal members of
      our management and scientific staff. We do not have employment agreements with any of our executive officers that would prevent them from leaving us. The loss of our management and key scientific employees might slow the achievement of important
      research and development goals. It is also critical to our success that we recruit and retain qualified scientific personnel to perform research and development work. We may not be able to attract and retain skilled and experienced scientific
      personnel on acceptable terms because of intense competition for experienced scientists among many pharmaceutical and health care companies, universities and non-profit research institutions. In addition, failure to succeed in clinical studies may
      make it more challenging to recruit and retain qualified scientific personnel</span>.</div>

  <div><br />
  </div>

  <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic; font-weight: bold;">Risks related to taxes</div>

  <div><br />
  </div>

  <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Our ability to use our net operating loss carryovers and certain other tax attributes may be limited.</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Under the Internal Revenue Code of 1986, as amended, or the Code, a corporation is generally allowed a deduction for net operating losses,
    or NOLs, carried over from a prior taxable year. Under the Code, we can carryforward our NOLs to offset our future taxable income, if any, until such NOLs are used or expire. The same is true of other unused tax attributes, such as tax credits.</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Under the current U.S. federal income tax law, U.S. federal NOLs generated in taxable years beginning after December 31, 2017 may be
    carried forward indefinitely, but the deductibility of such U.S. federal NOLs in taxable years beginning after December 31, 2020 is limited to 80 percent of taxable income. It is uncertain if and to what extent various states will conform to current
    U.S. federal income tax law, and there may be periods during which states suspend or otherwise limit the use of NOLs for state income tax purposes.</div>

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  </div>

  <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">In addition, under Sections 382 and 383 of the Code, and corresponding provisions of state law, if a corporation undergoes an &#8220;ownership
    change,&#8221; which is generally defined as a greater than 50 percentage-point cumulative change, by value, in its equity ownership over a three-year period, the corporation&#8217;s ability to use its pre-change NOL carryforwards and other pre-change tax
    attributes to offset its post-change income or taxes may be limited. We may experience ownership changes in the future as a result of subsequent shifts in our stock ownership, some of which may be outside of our control. If an ownership change occurs
    and our ability to use our NOL carryforwards or other tax attributes is materially limited, it would harm our future operating results by effectively increasing our future tax obligations. As a result of the Akcea Merger, we are subject to the separate
    return limitation year, or SRLY, rules. Under the SRLY rules, our utilization of Akcea&#8217;s pre-merger NOL and tax credit carryforwards is limited to the amount of income that Akcea contributes to our consolidated taxable income. The Akcea pre-merger tax
    attributes cannot be used to offset any of the income that Ionis contributes to our consolidated taxable income. In addition, at the state level, there may be periods during which the use of net operating losses is suspended or otherwise limited, which
    could accelerate or permanently increase state taxes owed.</div>

  <div><br />
  </div>

  <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Our future taxable income could be impacted by changes in tax laws, regulations and treaties.</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">A change in tax laws, treaties or regulations, or their interpretation, of any country in which we operate could
    materially affect us.</div>

  <div><br />
  </div>

  <div style="text-align: justify; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">We could be subject to additional tax liabilities.</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We are subject to U.S. federal, state, local and foreign income taxes, sales taxes in the U.S., withholding taxes and transaction taxes in
    foreign jurisdictions. Significant judgment is required in evaluating our tax positions and our worldwide provision for taxes. During the ordinary course of business, there are many activities and transactions for which the ultimate tax determination
    is uncertain. In addition, our tax obligations and effective tax rates could be adversely affected by changes in the relevant tax, accounting and other laws, regulations, principles and interpretations, including those relating to income tax nexus, by
    recognizing tax losses or lower than anticipated earnings in jurisdictions where we have lower statutory rates and higher than anticipated earnings in jurisdictions where we have higher statutory rates, by changes in foreign currency exchange rates, or
    by changes in the valuation of our deferred tax assets and liabilities. We may be audited in various jurisdictions, and such jurisdictions may assess additional taxes, sales taxes and value-added taxes against us. Although we believe our tax estimates
    are reasonable, the final determination of any tax audits or litigation could be materially different from our historical tax provisions and accruals, which could have a material adverse effect on our operating results or cash flows in the period for
    which a determination is made.</div>

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  </div>

  <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic; font-weight: bold;">General risk factors</div>

  <div><br />
  </div>

  <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">If the price of our securities continues to be highly volatile, this could make it harder to liquidate your investment and
    could increase your risk of suffering a loss.</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">The market price of our common stock, like that of the securities of many other biopharmaceutical companies, has been and
    is likely to continue to be highly volatile. These fluctuations in our common stock price may significantly affect the trading price of our securities. During the 12 months preceding December 31, 2021, the market price of our common stock ranged from $64.37 to $25.04 per share. Many factors can affect the market price of our securities, including, for example, fluctuations in our operating results, announcements
    of collaborations, clinical study results, technological innovations or new products being developed by us or our competitors, the commercial success of our approved medicines, governmental regulation, marketing authorizations, changes in payers&#8217;
    reimbursement policies, developments in patent or other proprietary rights and public concern regarding the safety of our medicines.</div>

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  </div>

  <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">The current COVID-19 Pandemic has caused a </span>significant
    disruption of global financial markets and has resulted in increased volatility in the trading price of our common stock. Additionally, <span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">broad market and
      industry factors may materially harm the market price of our common stock irrespective of our operating performance. The stock market in general, and NASDAQ and the market for biotechnology companies in particular, have experienced extreme price and
      volume fluctuations that have often been unrelated or disproportionate to the operating performance of the particular companies affected. The trading prices and valuations of these stocks, and of ours, may not be predictable. A loss of investor
      confidence in the market for biotechnology or pharmaceutical stocks or the stocks of other companies which investors perceive to be similar to us, the opportunities in the biotechnology and pharmaceutical market or the stock market in general, could
      depress our stock price regardless of our business, prospects, financial conditions or results of operations.</span></div>

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  <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Provisions in our certificate of incorporation, convertible notes documents, call spread hedge transaction documents and
    Delaware law may prevent stockholders from receiving a premium for their shares.</div>

  <div><br />
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  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Our certificate of incorporation provides for classified terms for the members of our board of directors. Our certificate
    also includes a provision that requires at least 66 2/3 percent of our voting stockholders to approve a merger or certain other business transactions with, or proposed by, any holder of 15 percent or more of our voting stock, except in cases where
    certain directors approve the transaction or certain minimum price criteria and other procedural requirements are met.</div>

  <div><br />
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  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Our certificate of incorporation also requires that any action required or permitted to be taken by our stockholders must
    be taken at a duly called annual or special meeting of stockholders and may not be taken by written consent. In addition, only our board of directors, chairman of the board or chief executive officer can call special meetings of our stockholders. We
    have in the past, and may in the future, implement a stockholders&#8217; rights plan, also called a poison pill, which could make it uneconomical for a third party to acquire our company on a hostile basis. In addition, our board of directors has the
    authority to fix the rights and preferences of, and issue shares of preferred stock, which may have the effect of delaying or preventing a change in control of our company without action by our stockholders.</div>

  <div><br />
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  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">The provisions of our convertible senior notes could make it more difficult or more expensive for a third party to acquire
    us. Upon the occurrence of certain transactions constituting a fundamental change, holders of the notes will have the right, at their option, to require us to repurchase all of their notes or a portion of their notes, which may discourage certain types
    of transactions in which our stockholders might otherwise receive a premium for their shares over the then current market prices.</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">In April 2021, we completed a $632.5 million
      offering of 0% Notes and used a portion of the net proceeds from the issuance of the 0% Notes to repurchase $247.9 million of our 1% Notes for $257.0 million. </span><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">In
      December 2019, we entered into privately negotiated exchange and/or subscription agreements with certain new investors and certain holders of our existing 1% Notes to exchange $375.6 million of our 1% Notes for $439.3 million of our 0.125% Notes, and
      to issue $109.5 million of our 0.125% Notes. Additionally, in connection with the pricing of our 0% Notes and 0.125% Notes, we entered into call spread transactions in which we purchased note hedges and sold warrants. </span><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">Terminating or unwinding the call spread transactions could require us to make substantial payments to the counterparties under those agreements or may increase our stock price. The
      costs or any increase in stock price that may arise from terminating or unwinding such agreements could make an acquisition of our company significantly more expensive to the purchaser.</span></div>

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  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">These provisions, as well as Delaware law, including Section 203 of the Delaware General Corporation Law, and other of our
    agreements, may discourage certain types of transactions in which our stockholders might otherwise receive a premium for their shares over then current market prices, and may limit the ability of our stockholders to approve transactions that they think
    may be in their best interests.</div>

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  <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Future sales of our common stock in the public market could adversely affect the trading price of our securities.</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Future sales of substantial amounts of our common stock in the public market, or the perception that such sales could
    occur, could adversely affect trading prices of our securities. For example, we may issue approximately 17.5 million shares of our common stock upon conversion of our 0% Notes and 0.125% Notes, up to 10.9 million shares in connection with the warrant
    transactions we entered into in connection with the issuance of our 0% Notes, and up to 6.6 million shares in connection with the warrant transactions we entered into in connection with the issuance of our 0.125% Notes, in each case subject to
    customary anti-dilution adjustments. The addition of any of these shares into the public market may have an adverse effect on the price of our securities.</div>

  <div><br />
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  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">In addition, pursuant to the call spread transactions we entered into in connection with the pricing of our 0% Notes and
    0.125% Notes, the counterparties are likely to modify their hedge positions from time to time at or prior to the conversion or maturity of the notes by purchasing and selling shares of our common stock, other of our securities, or other instruments,
    including over-the-counter derivative instruments, that they may wish to use in connection with such hedging, which may have a negative effect on the conversion value of those notes and an adverse impact on the trading price of our common stock. The
    call spread transactions are expected generally to reduce potential dilution to holders of our common stock upon any conversion of our 0% Notes or 0.125% Notes or offset any cash payments we are required to make in excess of the principal amount of the
    converted 0% Notes or 0.125% Notes, as the case may be. However, the warrant transactions could separately have a dilutive effect to the extent that the market value per share of our common stock exceeds the applicable strike price of the warrants.</div>

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  <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">We are exposed to potential product liability claims, and insurance against these claims may not be available to us at a
    reasonable rate in the future or at all.</div>

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  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Our business exposes us to potential product liability risks that are inherent in the testing, manufacturing, marketing
    and sale of therapeutic products, including potential product liability claims related to SPINRAZA, TEGSEDI and WAYLIVRA, and our medicines in development. We have clinical study insurance coverage and commercial product liability insurance coverage.
    However, this insurance coverage may not be adequate to cover claims against us, or be available to us at an acceptable cost, if at all. Regardless of their merit or eventual outcome, product liability claims may result in decreased demand for our
    medicines, injury to our reputation, withdrawal of clinical study volunteers and loss of revenues. Thus, whether or not we are insured, a product liability claim or product recall may result in losses that could be material.</div>

  <div><br />
  </div>

  <div style="text-align: justify; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">We are dependent on information technology systems, infrastructure and data, which exposes us to data security risks.</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We are dependent upon our own and third-party information technology systems, infrastructure and data, including mobile technologies, to
    operate our business. The multitude and complexity of our computer systems may make them vulnerable to service interruption or destruction, disruption of data integrity, malicious intrusion, or random attacks. Likewise, data privacy or security
    incidents or breaches by employees or others may pose a risk that sensitive data, including our intellectual property, trade secrets or personal information of our employees, patients, customers or other business partners may be exposed to unauthorized
    persons or to the public. Cyber-attacks are increasing in their frequency, sophistication and intensity, with third-party phishing and social engineering attacks in particular increasing during the COVID-19 Pandemic. Cyber-attacks could include the
    deployment of harmful malware, denial-of-service, social engineering and other means to affect service reliability and threaten data confidentiality, integrity and availability. Our business partners face similar risks and any security breach of their
    systems could adversely affect our security posture. A security breach or privacy violation that leads to disclosure or modification of or prevents access to patient information, including personally identifiable information or protected health
    information, could harm our reputation, compel us to comply with federal and state breach notification laws and foreign law equivalents, subject us to financial penalties and mandatory and costly corrective action, require us to verify the correctness
    of database contents and otherwise subject us to litigation or other liability under laws and regulations that protect personal data, any of which could disrupt our business and result in increased costs or loss of revenue. Moreover, the prevalent use
    of mobile devices that access confidential information increases the risk of data security breaches, which could lead to the loss of confidential information, trade secrets or other intellectual property. While we have invested, and continue to invest,
    in the protection of our data and information technology infrastructure, our efforts may not prevent service interruptions or identify breaches in our systems that could adversely affect our business and operations and result in the loss of critical or
    sensitive information, which could result in financial, legal, business or reputational harm to us. In addition, our liability insurance may not be sufficient in type or amount to cover us against claims related to security breaches, cyber-attacks and
    other related breaches.</div>

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  <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Because we use biological materials, hazardous materials, chemicals and radioactive compounds, if we do not comply with
    laws regulating the protection of the environment and health and human safety, our business could be adversely affected.</div>

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  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Our research, development and manufacturing activities involve the use of potentially harmful biological materials as well
    as materials, chemicals and various radioactive compounds that could be hazardous to human health and safety or the environment. We store most of these materials and various wastes resulting from their use at our facilities in Carlsbad, California
    pending ultimate use and disposal. We cannot completely eliminate the risk of contamination, which could cause:</div>

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    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">interruption of our research, development and manufacturing efforts;</div>
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    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">injury to our employees and others;</div>
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    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">environmental damage resulting in costly clean up; and</div>
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    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">liabilities under federal, state and local laws and regulations governing health and human safety, as well as the use, storage, handling and disposal of
            these materials and resultant waste products.</div>
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  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">In such an event, we may be held liable for any resulting damages, and any liability could exceed our resources. Although
    we carry insurance in amounts and types that we consider commercially reasonable, we do not have insurance coverage for losses relating to an interruption of our research, development or manufacturing efforts caused by contamination, and the coverage
    or coverage limits of our insurance policies may not be adequate. If our losses exceed our insurance coverage, our financial condition would be adversely affected.</div>

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  <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Our business may be adversely affected by climate change, extreme weather events, earthquakes, pandemics, civil or
    political unrest, terrorism or other catastrophic events.</div>

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  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">In recent years, extreme weather events and changing weather patterns have become more common. As a result, we are
    potentially exposed to varying natural disaster or extreme weather risks such as hurricanes, tornadoes, fires, droughts, floods, or other events that may result from the impact of climate change on the environment. The potential impacts of climate
    change may also include increased operating costs associated with additional regulatory requirements and investments in reducing energy, water use and greenhouse gas emissions. In addition, we manufacture most of our research and clinical supplies in a
    manufacturing facility located in Carlsbad, California. We manufacture the finished drug product for TEGSEDI and WAYLIVRA at third-party contract manufacturers. Biogen manufactures the finished drug product for SPINRAZA. The facilities and the
    equipment we, our partners and our contract manufacturers use to research, develop and manufacture our medicines would be costly to replace and could require substantial lead time to repair or replace. Our facilities or those of our partners or
    contract manufacturers may be harmed by natural disasters or other events outside our control, such as earthquakes, pandemics, war, civil or political unrest, deliberate acts of sabotage, terrorism or industrial accidents such as fire and explosion,
    whether due to human or equipment error, and if such facilities are affected by a disaster or other event, our development and commercialization efforts would be delayed. Although we possess property damage and business interruption insurance coverage,
    this insurance may not be sufficient to cover all of our potential losses and may not continue to be available to us on acceptable terms, or at all. In addition, our development and commercialization activities could be harmed or delayed by a shutdown
    of the U.S. government, including the FDA.</div>

  <div><br />
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  <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Our business is subject to changing regulations for corporate governance and public disclosure that has increased both our
    costs and the risk of noncompliance.</div>

  <div><br />
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  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Each year we are required to evaluate our internal control systems in order to allow management to report on and our
    Independent Registered Public Accounting Firm to attest to, our internal controls as required by Section 404 of the Sarbanes-Oxley Act. As a result, we continue to incur additional expenses and divert our management&#8217;s time to comply with these
    regulations. In addition, if we cannot continue to comply with the requirements of Section 404 in a timely manner, we might be subject to sanctions or investigation by regulatory authorities, such as the SEC, the Public Company Accounting Oversight
    Board, or PCAOB, or The Nasdaq Global Select Market. Any such action could adversely affect our financial results and the market price of our common stock.</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">The SEC and other regulators have continued to adopt new rules and regulations and make additional changes to existing
    regulations that require our compliance. On July 21, 2010, the Dodd-Frank Wall Street Reform and Protection Act, or the Dodd-Frank Act, was enacted. There are significant corporate governance and executive compensation-related provisions in the
    Dodd-Frank Act that require the SEC to adopt, or where the SEC has adopted, additional rules and regulations in these areas such as &#8220;say on pay&#8221; and proxy access. Stockholder activism, the current political environment and the current high level of
    government intervention and regulatory reform may lead to substantial new regulations and disclosure obligations, which may lead to additional compliance costs and impact the manner in which we operate our business.</div>

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  <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Negative conditions in the global credit markets and financial services and other industries may adversely affect our
    business.</div>

  <div><br />
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  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">The global credit markets, the financial services industry, the U.S. capital markets, and the U.S. economy as a whole are
    currently experiencing substantial turmoil and uncertainty characterized by unprecedented intervention by the U.S. federal government in response to the COVID-19 Pandemic. In the past, the failure, bankruptcy, or sale of various financial and other
    institutions created similar turmoil and uncertainty in such markets and industries. It is possible that a crisis in the global credit markets, the U.S. capital markets, the financial services industry or the U.S. economy may adversely affect our
    business, vendors and prospects, as well as our liquidity and financial condition. More specifically, our insurance carriers and insurance policies covering all aspects of our business may become financially unstable or may not be sufficient to cover
    any or all of our losses and may not continue to be available to us on acceptable terms, or at all. In addition, due to the rapidly rising inflation rate, we may experience increased costs of goods and services for our business.</div>

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  <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">A variety of risks associated with operating our business and marketing our medicines internationally could adversely affect our business.
    In addition to our U.S. operations, we are commercializing TEGSEDI in the EU, Canada, Latin America and certain Caribbean countries, and WAYLIVRA in the EU, Latin America and certain Caribbean countries. We face risks associated with our international
    operations, including possible unfavorable regulatory, pricing and reimbursement, political, tax and labor conditions, which could harm our business. Because we have international operations, we are subject to numerous risks associated with
    international business activities, including:</div>

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          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">compliance with differing or unexpected regulatory requirements for our medicines and foreign employees;</div>
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    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">complexities associated with managing multiple payer reimbursement regimes, government payers or patient self-pay systems;</div>
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    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">difficulties in staffing and managing foreign operations;</div>
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  </tr>


</table>
  <table cellspacing="0" cellpadding="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">


  <tr>

    <td style="width: 36pt;"></td>

    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">in certain circumstances, increased dependence on the commercialization efforts and regulatory compliance of third-party distributors or strategic
            partners;</div>
        </td>

  </tr>


</table>
  <table cellspacing="0" cellpadding="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">


  <tr>

    <td style="width: 36pt;"></td>

    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">foreign government taxes, regulations and permit requirements;</div>
        </td>

  </tr>


</table>
  <table cellspacing="0" cellpadding="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">


  <tr>

    <td style="width: 36pt;"></td>

    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">U.S. and foreign government tariffs, trade restrictions, price and exchange controls and other regulatory requirements;</div>
        </td>

  </tr>


</table>
  <table cellspacing="0" cellpadding="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">


  <tr>

    <td style="width: 36pt;"></td>

    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">anti-corruption laws, including the Foreign Corrupt Practices Act, or the FCPA, and its equivalent in foreign jurisdictions;</div>
        </td>

  </tr>


</table>
  <table cellspacing="0" cellpadding="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">


  <tr>

    <td style="width: 36pt;"></td>

    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">economic weakness, including inflation, natural disasters, war, events of terrorism, political instability or public health issues or pandemics, such as
            the current COVID-19 Pandemic, in particular foreign countries or globally;</div>
        </td>

  </tr>


</table>
  <table cellspacing="0" cellpadding="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">


  <tr>

    <td style="width: 36pt;"></td>

    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">fluctuations in currency exchange rates, which could result in increased operating expenses and reduced revenue, and other obligations related to doing
            business in another country;</div>
        </td>

  </tr>


</table>
  <table cellspacing="0" cellpadding="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">


  <tr>

    <td style="width: 36pt;"></td>

    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">compliance with tax, employment, privacy, immigration and labor laws, regulations and restrictions for employees living or traveling abroad;</div>
        </td>

  </tr>


</table>
  <table cellspacing="0" cellpadding="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">


  <tr>

    <td style="width: 36pt;"></td>

    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">workforce uncertainty in countries where labor unrest is more common than in the U.S.; and</div>
        </td>

  </tr>


</table>
  <table cellspacing="0" cellpadding="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">


  <tr>

    <td style="width: 36pt;"></td>

    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">changes in diplomatic and trade relationships.</div>
        </td>

  </tr>


</table>
  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">The United Kingdom&#8217;s exit from the E.U. could increase these risks.</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Our business activities outside of the U.S. are subject to the FCPA and similar anti-bribery or anti-corruption laws, regulations or rules
    of other countries in which we operate, including the United Kingdom&#8217;s Bribery Act 2010. In many other countries, the healthcare providers who prescribe pharmaceuticals are employed by their government, and the purchasers of pharmaceuticals are
    government entities; therefore, any dealings with these prescribers and purchasers may be subject to regulation under the FCPA. There is no certainty that all employees and third-party business partners (including our distributors, wholesalers, agents,
    contractors and other partners) will comply with anti-bribery laws. In particular, we do not control the actions of manufacturers and other third-party agents, although we may be liable for their actions. Violation of these laws may result in civil or
    criminal sanctions, which could include monetary fines, criminal penalties, and disgorgement of past profits, which could have an adverse impact on our business and financial condition<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">.</span><a id="_Hlk53488840"><!--Anchor--></a></div>

  <div><br />
  </div>

  <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">The impact on us of the vote by the United Kingdom to leave the European Union cannot be predicted.</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">The withdrawal of the UK from the EU, commonly referred to as &#8220;Brexit,&#8221; may adversely impact our ability to obtain regulatory approvals of
    our medicines in the EU, result in restrictions or imposition of taxes and duties for importing our medicines into the EU, and may require us to incur additional expenses in order to develop, manufacture and commercialize our medicines in the EU.</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Following the result of a referendum in 2016, the UK left the EU on January 31, 2020. Pursuant to the formal withdrawal arrangements
    agreed between the UK and the EU, the UK was subject to a transition period that ended December 31, 2020, or the Transition Period, during which EU rules continued to apply. A trade and cooperation agreement, or the Trade and Cooperation Agreement,
    that outlines the future trading relationship between the UK and the EU was signed in December 2020.</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Since a significant proportion of the regulatory framework in the UK applicable to our business and our medicines is derived from EU
    directives and regulations, Brexit has had, and may continue to have, a material impact upon the regulatory regime with respect to the development, manufacture, importation, approval and commercialization of our medicines in the UK or the EU. For
    example, Great Britain is no longer covered by the centralized procedures for obtaining EU-wide marketing authorization from the EMA, and a separate marketing authorization will be required to market our medicines in Great Britain. It is currently
    unclear whether the Medicines &amp; Healthcare products Regulatory Agency in the UK is sufficiently prepared to handle the increased volume of marketing authorization applications that it is likely to receive. Any delay in obtaining, or an inability to
    obtain, any marketing approvals, as a result of Brexit or otherwise, would delay or prevent us from commercializing our medicines in the UK or the EU.</div>

  <div><br />
  </div>

  <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" class="DSPFPageBreakArea">
    <div class="DSPFPageFooter">
      <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span class="DSPFPageNumber">65</span></div>

    </div>

    <div style="page-break-after:always;" class="DSPFPageBreak">
      <hr style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;" /></div>


  </div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">While the Trade and Cooperation Agreement provides for the tariff-free trade of medicinal products between the UK and the EU, there may be
    additional non-tariff costs to such trade which did not exist prior to the end of the Transition Period. Further, should the UK diverge from the EU from a regulatory perspective in relation to medicinal products, tariffs could be put into place in the
    future. We could therefore, both now and in the future, face significant additional expenses (when compared to the position prior to the end of the Transition Period) to operate our business<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">.</span></div>

  <div><br />
  </div>

  <div><br />
  </div>

  <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Item 1B. Unresolved Staff Comments</div>

  <div><br />
  </div>

  <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Not applicable.</div>

  <div><br />
  </div>

  <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Item 2. Properties</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">As of February 16, 2022,
    the following are the primary facilities in which we operate:</div>

  <div><br />
  </div>

  <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; border-collapse: collapse; text-align: left; color: #000000;">


  <tr>

    <td style="width: 19.66%; vertical-align: bottom; border-bottom: #000000 2px solid;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Property Description</div>
        </td>

    <td style="width: 2.18%; vertical-align: top;">&#160;</td>

    <td style="width: 12.55%; vertical-align: bottom; border-bottom: #000000 2px solid;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Location</div>
        </td>

    <td style="width: 2.18%; vertical-align: top;">&#160;</td>

    <td style="width: 9.77%; vertical-align: bottom; border-bottom: #000000 2px solid;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Square</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Footage</div>
        </td>

    <td style="width: 2.18%; vertical-align: top;">&#160;</td>

    <td style="width: 10.38%; vertical-align: bottom; border-bottom: #000000 2px solid;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Owned</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">or Leased</div>
        </td>

    <td style="width: 2.18%; vertical-align: top;">&#160;</td>

    <td style="width: 14.52%; vertical-align: bottom; border-bottom: #000000 2px solid;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Initial Lease</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Term End Date</div>
        </td>

    <td style="width: 2.18%; vertical-align: top;">&#160;</td>

    <td style="width: 22.22%; vertical-align: bottom; border-bottom: #000000 2px solid;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Lease</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Extension Options</div>
        </td>

  </tr>

  <tr>

    <td style="width: 19.66%; vertical-align: bottom; background-color: #CCEEFF;">
          <div style="text-align: left; text-indent: -10pt; margin-left: 10pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Laboratory and office space facility</div>
        </td>

    <td style="width: 2.18%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 12.55%; vertical-align: bottom; background-color: #CCEEFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Carlsbad, CA</div>
        </td>

    <td style="width: 2.18%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 9.77%; vertical-align: bottom; background-color: #CCEEFF;">
          <div style="text-align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">176,000</div>
        </td>

    <td style="width: 2.18%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 10.38%; vertical-align: bottom; background-color: #CCEEFF;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Owned</div>
        </td>

    <td style="width: 2.18%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 14.52%; vertical-align: bottom; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 2.18%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 22.22%; vertical-align: bottom; background-color: #CCEEFF;">&#160;</td>

  </tr>

  <tr>

    <td style="width: 19.66%; vertical-align: bottom; background-color: #FFFFFF;">
          <div style="text-align: left; text-indent: -10pt; margin-left: 10pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Office and meeting space facility</div>
        </td>

    <td style="width: 2.18%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 12.55%; vertical-align: bottom; background-color: #FFFFFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Carlsbad, CA</div>
        </td>

    <td style="width: 2.18%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 9.77%; vertical-align: bottom; background-color: #FFFFFF;">
          <div style="text-align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">74,000</div>
        </td>

    <td style="width: 2.18%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 10.38%; vertical-align: bottom; background-color: #FFFFFF;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Owned</div>
        </td>

    <td style="width: 2.18%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 14.52%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 2.18%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 22.22%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>

  </tr>

  <tr>

    <td style="width: 19.66%; vertical-align: bottom; background-color: #CCEEFF;">
          <div style="text-align: left; text-indent: -10pt; margin-left: 10pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Manufacturing facility</div>
        </td>

    <td style="width: 2.18%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 12.55%; vertical-align: bottom; background-color: #CCEEFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Carlsbad, CA</div>
        </td>

    <td style="width: 2.18%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 9.77%; vertical-align: bottom; background-color: #CCEEFF;">
          <div style="text-align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">26,800</div>
        </td>

    <td style="width: 2.18%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 10.38%; vertical-align: bottom; background-color: #CCEEFF;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Owned</div>
        </td>

    <td style="width: 2.18%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 14.52%; vertical-align: bottom; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 2.18%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 22.22%; vertical-align: bottom; background-color: #CCEEFF;">&#160;</td>

  </tr>

  <tr>

    <td style="width: 19.66%; vertical-align: bottom; background-color: #FFFFFF;">
          <div style="text-align: left; text-indent: -10pt; margin-left: 10pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Manufacturing support facility</div>
        </td>

    <td style="width: 2.18%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 12.55%; vertical-align: bottom; background-color: #FFFFFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Carlsbad, CA</div>
        </td>

    <td style="width: 2.18%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 9.77%; vertical-align: bottom; background-color: #FFFFFF;">
          <div style="text-align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">25,800</div>
        </td>

    <td style="width: 2.18%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 10.38%; vertical-align: bottom; background-color: #FFFFFF;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Leased</div>
        </td>

    <td style="width: 2.18%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 14.52%; vertical-align: bottom; background-color: #FFFFFF;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">2026</div>
        </td>

    <td style="width: 2.18%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 22.22%; vertical-align: bottom; background-color: #FFFFFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">One, five-year option to extend</div>
        </td>

  </tr>

  <tr>

    <td style="width: 19.66%; vertical-align: bottom; background-color: #CCEEFF;">
          <div style="text-align: left; text-indent: -10pt; margin-left: 10pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Office and storage space facility</div>
        </td>

    <td style="width: 2.18%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 12.55%; vertical-align: bottom; background-color: #CCEEFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Carlsbad, CA</div>
        </td>

    <td style="width: 2.18%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 9.77%; vertical-align: bottom; background-color: #CCEEFF;">
          <div style="text-align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">18,700</div>
        </td>

    <td style="width: 2.18%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 10.38%; vertical-align: bottom; background-color: #CCEEFF;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Leased</div>
        </td>

    <td style="width: 2.18%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 14.52%; vertical-align: bottom; background-color: #CCEEFF;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">2023</div>
        </td>

    <td style="width: 2.18%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 22.22%; vertical-align: bottom; background-color: #CCEEFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">One, five-year option to extend</div>
        </td>

  </tr>

  <tr>

    <td style="width: 19.66%; vertical-align: bottom; background-color: #FFFFFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Office space facility</div>
        </td>

    <td style="width: 2.18%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 12.55%; vertical-align: bottom; background-color: #FFFFFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Boston, MA</div>
        </td>

    <td style="width: 2.18%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 9.77%; vertical-align: bottom; background-color: #FFFFFF;">
          <div style="text-align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">14,300</div>
        </td>

    <td style="width: 2.18%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 10.38%; vertical-align: bottom; background-color: #FFFFFF;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Leased</div>
        </td>

    <td style="width: 2.18%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 14.52%; vertical-align: bottom; background-color: #FFFFFF;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">2029</div>
        </td>

    <td style="width: 2.18%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 22.22%; vertical-align: bottom; background-color: #FFFFFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">One, five-year option to extend</div>
        </td>

  </tr>

  <tr>

    <td style="width: 19.66%; vertical-align: bottom; background-color: #CCEEFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Office space facility</div>
        </td>

    <td style="width: 2.18%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 12.55%; vertical-align: bottom; background-color: #CCEEFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Carlsbad, CA</div>
        </td>

    <td style="width: 2.18%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 9.77%; vertical-align: bottom; border-bottom: #000000 2px solid; background-color: #CCEEFF;">
          <div style="text-align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">5,800</div>
        </td>

    <td style="width: 2.18%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 10.38%; vertical-align: bottom; background-color: #CCEEFF;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Leased</div>
        </td>

    <td style="width: 2.18%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 14.52%; vertical-align: bottom; background-color: #CCEEFF;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">2023</div>
        </td>

    <td style="width: 2.18%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 22.22%; vertical-align: bottom; background-color: #CCEEFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">One, five-year option to extend</div>
        </td>

  </tr>

  <tr>

    <td style="width: 19.66%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 2.18%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 12.55%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 2.18%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 9.77%; vertical-align: bottom; border-bottom: #000000 4px double; background-color: #FFFFFF;">
          <div style="text-align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">341,400</div>
        </td>

    <td style="width: 2.18%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 10.38%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 2.18%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 14.52%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 2.18%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 22.22%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>

  </tr>


</table>
  <div><br />
  </div>

  <div style="text-align: left; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We believe that our current and future facilities will be adequate for the foreseeable future.</div>

  <div><br />
  </div>

  <div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Item 3. Legal Proceedings</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">For details of legal proceedings, see Note 10, <span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Legal Proceedings,</span> in the Notes to the Consolidated Financial Statements.</div>

  <div><br />
  </div>

  <div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Item 4. Mine Safety Disclosures</div>

  <div><br />
  </div>

  <div style="text-align: left; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Not applicable.</div>

  <div><br />
  </div>

  <div><br />
  </div>

  <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" class="DSPFPageBreakArea">
    <div class="DSPFPageFooter">
      <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span class="DSPFPageNumber">66</span></div>

    </div>

    <div style="page-break-after:always;" class="DSPFPageBreak">
      <hr style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;" /></div>


  </div>

  <div><br />
  </div>

  <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">PART II</div>

  <div><br />
  </div>

  <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Item 5. Market for Registrant</span>&#8217;<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">s Common Equity, Related Stockholder Matters and Issuer Purchases of Equity Securities</span></div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Market Information and Dividends</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Our common stock is traded publicly through The Nasdaq Global Select Market under the symbol &#8220;IONS.&#8221; As of February 16, 2022, there were approximately 495 stockholders of record of our common stock. Because many of our shares are held by brokers and other
    institutions on behalf of stockholders, we are unable to estimate the total number of stockholders represented by these record holders.</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We have never paid dividends and do not anticipate paying any dividends in the foreseeable future.</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Performance Graph (1)</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Set forth below is a table and chart comparing the total return on an indexed basis of $100 invested on December 31, 2016
    in our common stock, the Nasdaq Composite Index (total return) and the Nasdaq Biotechnology Index. The total return assumes reinvestment of dividends.</div>

  <div><br />
  </div>

  <div style="text-align: center;"><img width="710" height="590" src="image03.jpg" alt="graphic" /></div>

  <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">*&#160; $100 invested on December 31, 2016 in stock or index, including reinvestment of dividends. Fiscal year ending December 31.</div>

  <div><br />
  </div>

  <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" class="DSPFPageBreakArea">
    <div class="DSPFPageFooter">
      <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span class="DSPFPageNumber">67</span></div>

    </div>

    <div style="page-break-after:always;" class="DSPFPageBreak">
      <hr style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;" /></div>


  </div>

  <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">COMPARISON OF 5 YEAR CUMULATIVE TOTAL RETURN</div>

  <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Among Ionis Pharmaceuticals, Inc., the Nasdaq Composite Index,</div>

  <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">and the Nasdaq Biotechnology Index</div>

  <div style="text-align: center;"><br />
  </div>

  <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;" class="cfttable">


  <tr>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">

        </td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" colspan="2">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Dec-16</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" colspan="2">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Dec-17</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" colspan="2">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Dec-18</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" colspan="2">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Dec-19</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" colspan="2">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Dec-20</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" colspan="2">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Dec-21</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 28%; background-color: #CCEEFF;">
          <div style="text-align: left; text-indent: -10pt; margin-left: 10pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Ionis Pharmaceuticals, Inc.</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">100.00</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">105.16</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">113.03</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">126.30</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">118.21</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">63.62</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 28%; background-color: #FFFFFF;">
          <div style="text-align: left; text-indent: -10pt; margin-left: 10pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Nasdaq Composite Index</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">100.00</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">129.64</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">125.96</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">172.17</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">249.51</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">304.85</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 28%; background-color: #CCEEFF;">
          <div style="text-align: left; text-indent: -10pt; margin-left: 10pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Nasdaq Biotechnology Index</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">100.00</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">121.63</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">110.85</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">138.69</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">175.33</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">175.37</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>


</table>
  <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">________________</div>

  <table cellspacing="0" cellpadding="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">


  <tr>

    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(1)</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">This section is not &#8220;soliciting material,&#8221; is not deemed &#8220;filed&#8221; with the SEC, is not subject to the liabilities of Section 18 of the Exchange Act and is
            not to be incorporated by reference in any of our filings under the Securities Act or the Exchange Act, whether made before or after the date hereof and irrespective of any general incorporation language in any such filing.</div>
        </td>

  </tr>


</table>
  <div><br />
  </div>

  <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Item 6. Selected Financial Data</div>

  <div><br />
  </div>

  <div style="text-align: left; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Refer to our financial data contained within Item 7, <span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Management&#8217;s Discussion and Analysis</span>, our financial statements and within other parts of this document.</div>

  <div><br />
  </div>

  <div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Item 7. Management</span>&#8217;<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">s Discussion and Analysis of Financial Condition and Results of Operations</span></div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">This financial review presents our operating results for each of the two years in the period ended December 31, 2021, and our financial condition at December 31, 2021.
    Refer to our 2020 Form 10-K for our results of operations for 2020 compared to 2019. Except for the historical information contained herein, the following discussion contains forward-looking statements that are subject to known and unknown risks,
    uncertainties and other factors that may cause our actual results to differ materially from those expressed or implied by such forward-looking statements. We discuss such risks, uncertainties and other factors throughout this report and specifically
    under Item 1A of Part I of this report, &#8220;Risk Factors.&#8221; In addition, the following review should be read in conjunction with the information presented in our consolidated financial statements and the related notes to our consolidated financial
    statements as indexed on page F-1.</div>

  <div><br />
  </div>

  <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Overview</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><a id="_Hlk63852862"><!--Anchor--></a>As noted in our Business Overview in Part I of this report, we are a leader in RNA-targeted
    therapeutics. We believe our medicines, which are based on our novel antisense technology, have the potential to pioneer new markets, change standards of care and transform the lives of people with devastating diseases. We currently have three marketed
    medicines- SPINRAZA, TEGSEDI and WAYLIVRA. We also have a rich late-stage pipeline of medicines, primarily focused on our cardiovascular and neurology franchises. Within our late-stage pipeline, we have six medicines in Phase 3 development for eight
    indications. For further details on our business refer to the Business section of Part I of this report.</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic; font-weight: bold;">Financial Highlights</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic; font-weight: bold;">The following is a summary of our financial results (in millions):</div>

  <div><br />
  </div>

  <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;" class="cfttable">


  <tr>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" colspan="6">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Year Ended December 31,</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">

        </td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" colspan="2">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2021</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" colspan="2">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2020</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom;">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="2">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="2">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">(as revised*)</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 76%; background-color: #CCEEFF;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Total revenue</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">810.5</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">729.3</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 76%;">
          <div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Total operating expenses</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">840.6</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">901.3</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 76%; background-color: #CCEEFF;">
          <div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Loss from operations</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(30.2</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(172.1</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 76%;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Net loss attributable to Ionis Pharmaceuticals, Inc. common stockholders</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(28.6</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(479.7</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 76%; background-color: #CCEEFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Cash, cash equivalents and short-term investments</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">2,115.0</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">1,892.4</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>


</table>
  <div><br />
  </div>

  <table cellspacing="0" cellpadding="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">


  <tr>

    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">*</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We revised our 2020 amounts to reflect the simplified convertible instruments accounting guidance, which we adopted retrospectively. Refer to Note 1, <span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Organization and Significant Accounting Policies</span>, for further information.</div>
        </td>

  </tr>


</table>
  <div><br />
  </div>

  <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" class="DSPFPageBreakArea">
    <div class="DSPFPageFooter">
      <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span class="DSPFPageNumber">68</span></div>

    </div>

    <div style="page-break-after:always;" class="DSPFPageBreak">
      <hr style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;" /></div>


  </div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Our revenue for 2021 increased compared to 2020 due to significant partner payments across our cardiology and neurology
    franchises. Our commercial revenue for 2021 included SPINRAZA royalties, TEGSEDI and WAYLIVRA revenue and licensing and other royalty revenue. As a result of our distribution agreements with Sobi for TEGSEDI and WAYLIVRA, our commercial revenue from
    product sales shifted to revenue from distribution fees based on net sales generated by Sobi. We completed the transition of our TEGSEDI and WAYLIVRA commercial operations in Europe and our TEGSEDI commercial operations in North America to Sobi in the
    first and second quarters of 2021, respectively.</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We earn our R&amp;D revenue from multiple sources that can fluctuate depending on the timing of events. Our R&amp;D
    revenue increased in 2021 compared to 2020 primarily due to the joint development and commercialization collaboration we entered into with AstraZeneca in 2021.</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Our operating expenses, excluding $90 million of expenses related to the Akcea Merger and restructured European operations we incurred in
    2020, increased in 2021 compared to 2020 due to an increase in R&amp;D expenses, partially offset by a decrease in SG&amp;A expenses. Higher R&amp;D expenses were primarily driven by our ongoing investments in advancing our Phase 3 programs, expanding
    the number of Phase 3 studies and advancing and expanding our mid-stage pipeline. Additionally, we invested in our technology resulting in higher R&amp;D expenses, which was primarily driven by the $35 million we paid in 2021 to license Bicycle&#8217;s
    technology. As anticipated, our SG&amp;A expenses were lower in 2021 compared to 2020 due to operating efficiencies we achieved from integrating Akcea and restructuring our commercial operations.</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">At December 31, 2021, we had $2.1 billion in cash and short-term investments, compared with $1.9 billion as of December 31, 2020, enabling us to accelerate investments in our strategic priorities, while maintaining a strong
    financial foundation.</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: -18pt; margin-left: 54pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic; font-weight: bold;">Business Segment</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">In 2021, we began operating as a single segment, Ionis operations, because our chief decision maker reviews operating
    results on an aggregate basis and manages our operations as a single operating segment. Previously, we had operated as two operating segments, Ionis Core and Akcea Therapeutics. We completed the Akcea Merger in October 2020 and fully integrated Akcea&#8217;s
    operations into ours as of January 1, 2021<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">.</span></div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic; font-weight: bold;">Critical Accounting Estimates</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We prepare our consolidated financial statements in conformity with accounting principles generally accepted in the U.S.
    As such, we make certain estimates, judgments and assumptions that we believe are reasonable, based upon the information available to us. These judgments involve making estimates about the effect of matters that are inherently uncertain and may
    significantly impact our quarterly or annual results of operations and financial condition. Each quarter, our senior management reviews the development, selection and disclosure of such estimates with the audit committee of our board of directors. In
    the following paragraphs, we describe the specific risks associated with these critical accounting estimates and we caution that future events rarely develop exactly as one may expect, and that best estimates may require adjustment. Our significant
    accounting policies are outlined in Note 1, <span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Organization and Significant Accounting Policies</span>, in the Notes to the Consolidated Financial
    Statements.</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">The following are our significant accounting estimates, which we believe are the most critical to aid in fully
    understanding and evaluating our reported financial results:</div>

  <div><br />
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    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Assessing the propriety of revenue recognition and associated deferred revenue; and</div>
        </td>

  </tr>


</table>
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    <td style="width: 36pt;"></td>

    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Determining the appropriate cost estimates for unbilled preclinical studies and clinical development activities</div>
        </td>

  </tr>


</table>
  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">In 2021, we determined the estimation of our income taxes was no longer a critical accounting estimate because we
      recorded a valuation allowance against the entirety of our net deferred tax assets in the fourth quarter of 2020.</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">The following are descriptions of our critical accounting estimates.</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: -18pt; margin-left: 54pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic; font-weight: bold;">Revenue Recognition</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We earn revenue from several sources. The judgements and estimates we make vary between each source of our revenue. At
    contract inception, we analyze our collaboration arrangements to assess whether such arrangements involve joint operating activities performed by parties that are both active participants in the activities and exposed to significant risks and rewards
    dependent on the commercial success of such activities and therefore within the scope of ASC Topic 808, Collaborative Arrangements (ASC 808). For collaboration arrangements within the scope of ASC 808 that contain multiple elements, we first determine
    which elements of the collaboration reflect a vendor-customer relationship and therefore within the scope of ASC 606. When we determine elements of a collaboration do not reflect a vendor-customer relationship, we consistently apply the reasonable and
    rational policy election we made by analogizing to authoritative accounting literature.</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We evaluate the income statement classification for presentation of amounts due from or owed to other participants
    associated with multiple activities in a collaboration arrangement based on the nature of each separate activity. For example, in our eplontersen collaboration with AstraZeneca, we recognize funding received from AstraZeneca for co-development
    activities as revenue. While, we recognize cost sharing payments to and from AstraZeneca associated with co-commercialization activities and co-medical affairs activities as SG&amp;A expense and research and development expense, respectively</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">The following is a summary of the critical accounting estimates we make with respect to each of our significant revenue
    sources.</div>

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  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;">Commercial Revenue: SPINRAZA royalties and Licensing and other royalty revenue</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We estimate our commercial revenue from SPINRAZA royalties based on reporting we receive from Biogen each quarter. We use
    this reporting to calculate our royalty revenue based on our tiered contractual royalty rate for the given period based on annual cumulative net sales. We record our royalty revenue in the same period in which Biogen sells SPINRAZA. We also estimate
    commercial revenue from licensing and other royalty revenue.</div>

  <div><br />
  </div>

  <div style="text-align: left; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;">Commercial Revenue: TEGSEDI and WAYLIVRA revenue, net</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We recognize product sales in the period when our customer obtains control of our products. Prior to our distribution
    agreements with Sobi, we recorded TEGSEDI and WAYLIVRA commercial revenue at our net sales price, or transaction price, which included estimated reserves for discounts, returns, chargebacks, rebates and other allowances that we offered within contracts
    between us and our customers, wholesalers, distributors, health care providers and other indirect customers. Our reserves reflected our best estimates under the terms of our respective contracts. Our historical reserve estimates have not been
    materially different from our actual amounts. Under our agreements with Sobi, we transferred all reserves to Sobi and Sobi is responsible for any applicable reserves.</div>

  <div><br />
  </div>

  <div style="text-align: left; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;">Research and development revenue under collaborative agreements</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We recognize R&amp;D revenue from numerous collaboration agreements. Our collaboration agreements typically contain
    multiple elements, or performance obligations, including technology licenses or options to obtain technology licenses, R&amp;D services, and manufacturing services. Upon entering into a collaboration agreement, we are required to make the following
    judgements:</div>

  <div><br />
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    <td style="width: 36pt;"></td>

    <td style="width: 18pt; vertical-align: top; align: right; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Identifying the performance obligations contained in the agreement</div>
        </td>

  </tr>


</table>
  <div><br />
  </div>

  <div style="text-align: justify; margin-left: 54pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">Our assessment of what constitutes a separate
      performance obligation requires us to apply judgement.</span> Specifically, we have to identify which goods and services we are required to provide under the contract are distinct.</div>

  <div><br />
  </div>

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    <td style="width: 36pt;"></td>

    <td style="width: 18pt; vertical-align: top; align: right; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Determining the transaction price, including any variable consideration</div>
        </td>

  </tr>


</table>
  <div><br />
  </div>

  <div style="text-align: justify; margin-left: 54pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">To determine the transaction price, we review the amount of consideration we are eligible to earn under the agreement. We
    do not typically include any payments we may receive in the future in our initial transaction price since the payments are typically not probable because they are contingent upon certain future events.</div>

  <div><br />
  </div>

  <div style="text-align: justify; margin-left: 54pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We are required to reassess the total transaction price at each reporting period to determine if we should include
    additional payments in the transaction price that have become probable. For example, in the fourth quarter of 2021, we achieved a milestone payment for $7.5 million under our 2018 strategic neurology collaboration with Biogen. Prior to achieving this
    milestone payment, we did not consider this payment probable. Upon achieving the milestone payment, we reassessed the total transaction price of our 2018 strategic neurology collaboration. We added this milestone payment to our total transaction price
    under our collaboration.</div>

  <div><br />
  </div>

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    <td style="width: 36pt;"></td>

    <td style="width: 18pt; vertical-align: top; align: right; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Allocating the transaction price to each of our performance obligations</div>
        </td>

  </tr>


</table>
  <div><br />
  </div>

  <div style="text-align: justify; margin-left: 54pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">When we allocate the transaction price to more than one performance obligation, we make estimates of the relative stand-alone selling
    price of each performance obligation because we do not typically sell our goods or services on a stand-alone basis. The estimate of the relative stand-alone selling price requires us in some cases to make significant judgements. For example, when we
    deliver a license at the start of an agreement, we use valuation methodologies, such as the relief from royalty method, to value the license. Under this method we are required to make estimates including: future sales, royalties on future product
    sales, contractual milestones, expenses, income taxes and discount rates. Additionally, when we estimate the selling price for R&amp;D services, we make estimates, including: the number of internal hours we will spend on the services, the cost of work
    we and third parties will perform and the cost of clinical trial material we will use.</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">The R&amp;D revenue we recognize each period is comprised of several types of revenue, including amortization from upfront
    payments, milestone payments, license fees and other services. Each of these types of revenue require us to make various judgements and estimates.</div>

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  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;">Amortization from Upfront Payments</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><a id="_Hlk62375152"><!--Anchor--></a>We recognize revenue from the amortization of upfront payments as we perform R&amp;D services. We
    use an input method to estimate the amount of revenue to recognize each period. This method requires us to make estimates of the total costs we expect to incur to complete our R&amp;D services performance obligation or the total length of time it will
    take us to complete our R&amp;D services performance obligation. If we change our estimates, we may have to adjust our revenue. <span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">Refer to Note 6, </span><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic; color: #000000;">Collaborative Arrangements and Licensing Agreements</span><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">, for further discussion of the cumulative catch up adjustment we made.</span></div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;">Milestone Payments</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">When recognizing revenue related to milestone payments we typically make the following judgements and estimates:</div>

  <div><br />
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    <td style="width: 36pt;"></td>

    <td style="width: 18pt; vertical-align: top; align: right; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Whether the milestone payment is probable (discussed in detail above under &#8220;Determining the<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> transaction price, including any variable consideration&#8221;</span>); and</div>
        </td>

  </tr>


</table>
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    <td style="width: 36pt;"></td>

    <td style="width: 18pt; vertical-align: top; align: right; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Whether the milestone payment relates to services we are performing or if our partner is performing the services:</div>
        </td>

  </tr>


</table>
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    <td style="width: 36pt;"></td>

    <td style="width: 18pt; vertical-align: top; align: right; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;">If we are performing services, we recognize revenue over our estimated period of performance in a similar manner to the amortization of upfront payments (discussed above
            under &#8220;Amortization of Upfront payments&#8221;).</div>
        </td>

  </tr>


</table>
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    <td style="width: 36pt;"></td>

    <td style="width: 18pt; vertical-align: top; align: right; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Conversely, we recognize in full those milestone payments that we earn based on our partners&#8217; activities when our partner achieves the milestone event and we do not have
            a performance obligation.</div>
        </td>

  </tr>


</table>
  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;">License Fees</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">When we grant a license for a medicine in clinical development, we generally recognize as R&amp;D revenue the total amount
    we determine to be the relative stand-alone selling price of a license when we deliver the license to our partner. For example, in 2021, we received a $200 million upfront payment when we entered into an agreement with AstraZeneca to jointly develop
    and commercialize eplontersen. Refer to Note 1, <span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Organization and Significant Accounting Policies</span>, for our revenue recognition policy. We discuss
    the estimates we make related to the relative stand-alone selling price of a license in detail above under &#8220;Allocating the transaction price to each of our performance obligations.&#8221;</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: -18pt; margin-left: 54pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic; font-weight: bold;">Estimated Liability for Clinical Development Costs</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We have numerous medicines in preclinical studies and/or clinical trials at clinical sites throughout the world. On at
    least a quarterly basis, we estimate our liability for preclinical and clinical development costs we have incurred and services that we have received but for which we have not yet been billed and maintain an accrual to cover these costs. These costs
    primarily relate to third-party clinical management costs, laboratory and analysis costs, toxicology studies and investigator grants. We estimate our liability using assumptions about study and patient activities and the related expected expenses for
    those activities determined based on the contracted fees with our service providers. The assumptions we use represent our best estimates of the activity and expenses at the time of our accrual and involve inherent uncertainties and the application of
    our judgment. Upon settlement, these costs may differ materially from the amounts accrued in our consolidated financial statements. Our historical accrual estimates have not been materially different from our actual amounts.</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">As of December 31, 2021, a hypothetical 10.0 percent increase in our liability for preclinical and clinical development
    costs would have resulted in an increase in our loss before income tax benefit and accrued liabilities by approximately $6.6 million.</div>

  <div><br />
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  <div><br />
  </div>

  <div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Results of Operations</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Below we have included our results of operations for 2021 compared to 2020. Refer to our 2020 Form 10-K for our results of
    operations for 2020 compared to 2019.</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: -18pt; margin-left: 54pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;">Years Ended December 31, 2021 and December 31, 2020</div>

  <div><br />
  </div>

  <div style="text-align: left; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Revenue</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Total revenue for 2021
    was $810.5 million compared to $729.3
    million in 2020 and was comprised of the following (amounts in millions):</div>

  <div><br />
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    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">

        </td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" colspan="6">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Year Ended December 31,</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" colspan="2">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2021</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" colspan="2">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2020</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Revenue:</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="2">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="2">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 18pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Commercial revenue:</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="2">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="2">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 76%; background-color: #CCEEFF;">
          <div style="text-align: left; text-indent: -27pt; margin-left: 45pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">SPINRAZA royalties</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">267.8</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">286.6</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 76%;">
          <div style="text-align: left; text-indent: -27pt; margin-left: 45pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">TEGSEDI and WAYLIVRA revenue, net</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">55.5</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">70.0</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 76%; padding-bottom: 2px; background-color: #CCEEFF;">
          <div style="text-align: left; text-indent: -27pt; margin-left: 45pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Licensing and other royalty revenue</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">19.1</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">8.1</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 76%;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 45pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Total commercial revenue</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">342.4</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">364.7</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 76%; background-color: #CCEEFF;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 18pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">R&amp;D revenue:</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 76%;">
          <div style="text-align: left; margin-left: 18pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Amortization from upfront payments</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">77.5</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">79.6</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 76%; background-color: #CCEEFF;">
          <div style="text-align: left; margin-left: 18pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Milestone payments</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">88.3</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">182.6</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 76%;">
          <div style="text-align: left; margin-left: 18pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">License fees</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">291.3</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">86.0</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 76%; padding-bottom: 2px; background-color: #CCEEFF;">
          <div style="text-align: left; margin-left: 18pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Other services</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">11.0</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">16.4</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 76%; padding-bottom: 2px;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 45pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Total R&amp;D revenue</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">468.1</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">364.6</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 76%; padding-bottom: 4px; background-color: #CCEEFF;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 81pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Total revenue</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">810.5</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">729.3</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>


</table>
  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Our revenue for 2021 increased compared to 2020 due to significant partner payments across our cardiology and neurology franchises. Our
    commercial revenue for 2021 included SPINRAZA royalties, TEGSEDI and WAYLIVRA revenue and licensing and other royalty revenue. As a result of our distribution agreements with Sobi for TEGSEDI and WAYLIVRA, our commercial revenue from product sales
    shifted to revenue from distribution fees based on net sales generated by Sobi. We completed the transition of our TEGSEDI and WAYLIVRA commercial operations in Europe and our TEGSEDI commercial operations in North America to Sobi in the first and
    second quarters of 2021, respectively.</div>

  <div><br />
  </div>

  <div>
    <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We earn our R&amp;D revenue from multiple
        sources that can fluctuate depending on the timing of events. Our R&amp;D revenue increased in 2021 compared to 2020 primarily because we earned more revenue from license fees in 2021 than in 2020. Our R&amp;D revenue in 2021 was comprised of $252
        million from our cardiovascular franchise, including $200 million from AstraZeneca for its license of eplontersen and a $25 million milestone payment from Novartis when Novartis achieved 50 percent enrollment in the Phase 3 Lp(a) HORIZON study of
        pelacarsen. Additionally, our R&amp;D revenue in 2021 included $168 million from our neurology franchise, </span><a id="_Hlk95418609"><!--Anchor--></a><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">with $60 million
        from Biogen for advancing ION306, our medicine in development for SMA based on new Ionis chemistry, and from advancing several other neurology targets.</span>&#160;</div>

  </div>

  <div><br />
  </div>

  <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" class="DSPFPageBreakArea">
    <div class="DSPFPageFooter">
      <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span class="DSPFPageNumber">72</span></div>

    </div>

    <div style="page-break-after:always;" class="DSPFPageBreak">
      <hr style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;" /></div>


  </div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Operating Expenses</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Operating expenses for 2021
    were $840.6 million, and decreased compared to $901.3
    million for 2020. <span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">The decrease was principally due to $89.6
      million of operating expenses related to the Akcea Merger and restructured European operations we incurred in 2020</span>. Excluding expenses related to the Akcea Merger and restructured European operations, our operating expenses for 2021 increased
    compared to 2020 due to an increase in R&amp;D expenses, partially offset by a decrease in SG&amp;A expenses. Higher R&amp;D expenses were primarily driven by our investments in advancing our Phase 3 programs. Additionally, we recognized $35 million in
    R&amp;D expense in 2021 for licensing Bicycle&#8217;s technology. Lower SG&amp;A expenses primarily reflected operating efficiencies achieved from integrating Akcea and restructuring our commercial operations<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">.</span></div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Our operating expenses were as follows (in millions):</div>

  <div><br />
  </div>

  <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;" class="cfttable">


  <tr>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">

        </td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" colspan="6">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Year Ended December 31,</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" colspan="2">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2021</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" colspan="2">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2020</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 76%; background-color: #CCEEFF;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Operating expenses, excluding non-cash compensation expense related to equity awards</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">696.0</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">640.9</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 76%; padding-bottom: 2px;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Restructuring expenses</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">23.9</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">30.3</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 76%; background-color: #CCEEFF;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Total operating expenses, excluding non-cash compensation expense related to equity awards</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">719.9</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">671.2</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 76%;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Non-cash compensation expense related to equity awards</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">120.7</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">170.8</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 76%; padding-bottom: 2px; background-color: #CCEEFF;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Restructuring expenses related to acceleration of Akcea&#8217;s stock-based compensation expense due to
            Akcea Merger</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#8212;</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">59.3</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 76%; padding-bottom: 4px;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Total operating expenses</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">840.6</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">901.3</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>


</table>
  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">In order to analyze and compare our results of operations to other similar companies, we believe it is important to
    exclude non-cash compensation expense related to equity awards from our operating expenses. We believe non-cash compensation expense related to equity awards is not indicative of our operating results or cash flows from our operations. Further, we
    internally evaluate the performance of our operations excluding it.</div>

  <div><br />
  </div>

  <div style="text-align: left; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic; font-weight: bold;">Cost of Sales</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Our cost of sales consisted of manufacturing costs, including certain fixed costs, transportation and freight,
      indirect overhead costs associated with the manufacturing and distribution of TEGSEDI and WAYLIVRA and certain associated period costs.</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Our cost of sales were as follows (in millions):</div>

  <div><br />
  </div>

  <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;" class="cfttable">


  <tr>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">

        </td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" colspan="6">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Year Ended December 31,</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" colspan="2">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2021</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" colspan="2">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2020</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 76%; background-color: #CCEEFF;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Cost of sales, excluding non-cash compensation expense related to equity awards</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">10.4</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">10.0</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 76%; padding-bottom: 2px;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Non-cash compensation expense related to equity awards</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">0.4</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">1.9</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 76%; padding-bottom: 4px; background-color: #CCEEFF;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Total cost of sales</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">10.8</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">11.9</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>


</table>
  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Our cost of sales, excluding non-cash compensation expense related to equity awards, for 2021 were consistent with
      2020.</div>

  <div><br />
  </div>

  <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" class="DSPFPageBreakArea">
    <div class="DSPFPageFooter">
      <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span class="DSPFPageNumber">73</span></div>

    </div>

    <div style="page-break-after:always;" class="DSPFPageBreak">
      <hr style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;" /></div>


  </div>

  <div><br />
  </div>

  <div style="text-align: left; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic; font-weight: bold;">Research, Development and Patent Expenses</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Our research, development and patent expenses consist of expenses for antisense drug discovery, antisense drug
    development, manufacturing and development chemistry and R&amp;D support expenses.</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">The following table sets forth information on research, development and patent expenses (in millions):</div>

  <div><br />
  </div>

  <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;" class="cfttable">


  <tr>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">

        </td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" colspan="6">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Year Ended December 31,</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" colspan="2">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2021</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" colspan="2">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2020</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 76%; background-color: #CCEEFF;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Research, development and patent expenses, excluding non-cash compensation expense related to
            equity awards</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">547.4</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">411.3</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 76%; padding-bottom: 2px; background-color: #FFFFFF;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Restructuring expenses</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">8.5</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">8.2</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 76%; background-color: #CCEEFF;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Total research, development and patent expenses, excluding non-cash compensation expense related to
            equity awards</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">555.9</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">419.5</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 76%; padding-bottom: 2px; background-color: #FFFFFF;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Non-cash compensation expense related to equity awards</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">87.6</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">115.6</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 76%; padding-bottom: 4px; background-color: #CCEEFF;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Total research, development and patent expenses</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">643.5</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">535.1</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>


</table>
  <div><br />
  </div>

  <div style="text-align: left; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="text-decoration: underline;">Antisense Drug Discovery</span></div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We use our proprietary antisense technology to generate information about the function of genes and to determine the value
    of genes as drug discovery targets. We use this information to direct our own antisense drug discovery research, and that of our partners. Antisense drug discovery is also the function that is responsible for advancing our antisense core technology.
    This function is also responsible for making investments in complementary technologies to expand the reach of antisense technology.</div>

  <div><br />
  </div>

  <div style="text-align: left; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Our antisense drug discovery expenses were as follows (in millions):</div>

  <div><br />
  </div>

  <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;" class="cfttable">


  <tr>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">

        </td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" colspan="6">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Year Ended December 31,</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" colspan="2">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2021</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" colspan="2">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2020</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 76%; background-color: #CCEEFF;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Antisense drug discovery expenses, excluding non-cash compensation expense related to equity awards</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">136.6</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">89.2</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 76%; padding-bottom: 2px;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Non-cash compensation expense related to equity awards</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">21.4</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">24.2</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 76%; padding-bottom: 4px; background-color: #CCEEFF;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Total antisense drug discovery expenses</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">158.0</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">113.4</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>


</table>
  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Antisense drug discovery expenses, excluding non-cash compensation expense related to equity awards, increased in 2021
    compared to 2020 primarily due to $35 million in R&amp;D expense that we recognized in 2021 for licensing Bicycle&#8217;s technology as discussed above.</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="text-decoration: underline;">Antisense Drug Development</span></div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">The following table sets forth drug development expenses, including expenses for our marketed medicines and those in Phase
    3 development for which we have incurred significant costs (in millions):</div>

  <div><br />
  </div>

  <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;" class="cfttable">


  <tr>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">

        </td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" colspan="6">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Year Ended December 31,</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" colspan="2">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2021</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" colspan="2">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2020</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 76%; background-color: #CCEEFF;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">TEGSEDI and WAYLIVRA</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">11.4</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">20.3</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 76%;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Eplontersen</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">79.1</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">34.0</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 76%; background-color: #CCEEFF;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Olezarsen</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">22.0</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">5.6</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 76%;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Donidalorsen</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">6.7</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">6.4</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 76%; background-color: #CCEEFF;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">ION363</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">7.7</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">2.6</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 76%;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Other antisense development projects</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">104.5</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">69.9</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 76%; background-color: #CCEEFF;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Development overhead expenses</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">83.7</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">85.9</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 76%; padding-bottom: 2px;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Restructuring expenses</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">7.7</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">8.0</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 76%; background-color: #CCEEFF;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Total antisense drug development, excluding non-cash compensation expense related to equity awards</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">322.8</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">232.7</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 76%; padding-bottom: 2px;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Non-cash compensation expense related to equity awards</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">39.2</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">63.7</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 76%; padding-bottom: 4px; background-color: #CCEEFF;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Total antisense drug development expenses</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">362.0</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">296.4</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>


</table>
  <div><br />
  </div>

  <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" class="DSPFPageBreakArea">
    <div class="DSPFPageFooter">
      <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span class="DSPFPageNumber">74</span></div>

    </div>

    <div style="page-break-after:always;" class="DSPFPageBreak">
      <hr style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;" /></div>


  </div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Our development expenses, excluding non-cash compensation expense related to equity awards, increased in 2021 compared to
    2020 primarily due to our numerous ongoing Phase 3 programs in addition to our advancing and expanding mid-stage pipeline.</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We may conduct multiple clinical trials on a drug candidate, including multiple clinical trials for the various
    indications we may be studying. Furthermore, as we obtain results from trials, we may elect to discontinue clinical trials for certain drug candidates in certain indications in order to focus our resources on more promising drug candidates or
    indications. Our Phase 1 and Phase 2 programs are clinical research programs that fuel our Phase 3 pipeline. When our medicines are in Phase 1 or Phase 2 clinical trials, they are in a dynamic state in which we may adjust the development strategy for
    each medicine. Although we may characterize a medicine as &#8220;in Phase 1&#8221; or &#8220;in Phase 2,&#8221; it does not mean that we are conducting a single, well-defined study with dedicated resources. Instead, we allocate our internal resources on a shared basis across
    numerous medicines based on each medicine&#8217;s particular needs at that time. This means we are constantly shifting resources among medicines. Therefore, what we spend on each medicine during a particular period is usually a function of what is required
    to keep the medicines progressing in clinical development, not what medicines we think are most important. For example, the number of people required to start a new study is large, the number of people required to keep a study going is modest and the
    number of people required to finish a study is large. However, such fluctuations are not indicative of a shift in our emphasis from one medicine to another and cannot be used to accurately predict future costs for each medicine. And, because we always
    have numerous medicines in preclinical and early stage clinical research, the fluctuations in expenses from medicine to medicine, in large part, offset one another. If we partner a medicine, it may affect the size of a trial, its timing, its total cost
    and the timing of the related costs.</div>

  <div><br />
  </div>

  <div style="text-align: left; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="text-decoration: underline;">Manufacturing and Development Chemistry</span></div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Expenditures in our manufacturing and development chemistry function consist primarily of personnel costs, specialized
    chemicals for oligonucleotide manufacturing, laboratory supplies and outside services. Our manufacturing and development chemistry function is responsible for providing drug supplies to antisense drug development and our collaboration partners. Our
    manufacturing procedures include testing to satisfy good laboratory and good manufacturing practice requirements.</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Our manufacturing and development chemistry expenses were as follows (in millions):</div>

  <div><br />
  </div>

  <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;" class="cfttable">


  <tr>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">

        </td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" colspan="6">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Year Ended December 31,</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" colspan="2">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2021</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" colspan="2">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2020</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 76%; background-color: #CCEEFF;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Manufacturing and development chemistry expenses, excluding non-cash compensation expense related
            to equity awards</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">47.2</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">55.7</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 76%; padding-bottom: 2px;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Restructuring expenses</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">0.8</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">0.2</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 76%; background-color: #CCEEFF;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Total manufacturing and development chemistry expenses, excluding non-cash compensation expense
            related to equity awards</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">48.0</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">55.9</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 76%; padding-bottom: 2px;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Non-cash compensation expense related to equity awards</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">11.5</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">10.9</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 76%; padding-bottom: 4px; background-color: #CCEEFF;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Total manufacturing and development chemistry expenses</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">59.5</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">66.8</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>


</table>
  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Manufacturing and development chemistry expenses, excluding non-cash compensation expense related to equity awards,
      decreased in 2021 compared to 2020 due to costs we incurred to manufacture API for olezarsen and eplontersen in 2020.</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="text-decoration: underline;">R&amp;D Support</span></div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">In our research, development and patent expenses, we include support costs such as rent, repair and maintenance for
    buildings and equipment, utilities, depreciation of laboratory equipment and facilities, amortization of our intellectual property, informatics costs, procurement costs and waste disposal costs. We call these costs R&amp;D support expenses.</div>

  <div><br />
  </div>

  <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" class="DSPFPageBreakArea">
    <div class="DSPFPageFooter">
      <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span class="DSPFPageNumber">75</span></div>

    </div>

    <div style="page-break-after:always;" class="DSPFPageBreak">
      <hr style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;" /></div>


  </div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">The following table sets forth information on R&amp;D support expenses (in millions):</div>

  <div><br />
  </div>

  <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;" class="cfttable">


  <tr>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">

        </td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" colspan="6">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Year Ended December 31,</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" colspan="2">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2021</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" colspan="2">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2020</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 76%; background-color: #CCEEFF;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Personnel costs</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">17.7</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">14.7</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 76%;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Occupancy</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">13.1</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">10.2</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 76%; background-color: #CCEEFF;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Patent expenses</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">5.3</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">4.1</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 76%;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Insurance</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">3.2</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">2.4</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 76%; background-color: #CCEEFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Computer software and licenses</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">1.8</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">2.9</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 76%;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Other</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">7.3</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">7.4</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 76%; padding-bottom: 2px; background-color: #CCEEFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Restructuring expenses</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">0.1</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#8212;</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 76%;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Total R&amp;D support expenses, excluding non-cash compensation expense related to equity awards</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">48.5</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">41.7</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 76%; padding-bottom: 2px; background-color: #CCEEFF;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Non-cash compensation expense related to equity awards</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">15.5</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">16.8</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 76%; padding-bottom: 4px;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Total R&amp;D support expenses</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">64.0</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">58.5</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>


</table>
  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">R&amp;D support expenses, excluding non-cash compensation expense related to equity awards, increased in 2021 compared to
    2020. The increase was primarily related to increased personnel and occupancy costs to support advancing our pipeline and our technology.</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic; font-weight: bold;">Selling, General and Administrative Expenses</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Selling, general and administrative, or SG&amp;A, expenses include personnel and outside costs associated with the
    pre-commercialization and commercialization activities for our medicines and costs to support our company, our employees and our stockholders including, legal, human resources, investor relations, and finance. Additionally, we include in selling,
    general and administrative expenses such costs as rent, repair and maintenance of buildings and equipment, depreciation and utilities costs that we need to support the corporate functions listed above. We also include fees we owe under our in-licensing
    agreements related to SPINRAZA.</div>

  <div><br />
  </div>

  <div style="text-align: left; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">The following table sets forth information on SG&amp;A expenses (in millions):</div>

  <div><br />
  </div>

  <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;" class="cfttable">


  <tr>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">

        </td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" colspan="6">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Year Ended December 31,</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" colspan="2">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2021</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" colspan="2">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2020</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 76%; background-color: #CCEEFF;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Selling, general and administrative expenses, excluding non-cash compensation expense related to
            equity awards</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">138.1</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">219.7</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 76%; padding-bottom: 2px;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Restructuring expenses</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">15.4</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">22.1</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 76%; background-color: #CCEEFF;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Total selling, general and administrative expenses, excluding non-cash compensation related to
            equity awards</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">153.5</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">241.8</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 76%; padding-bottom: 2px;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Non-cash compensation expense related to equity awards</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">32.8</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">112.5</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 76%; padding-bottom: 4px; background-color: #CCEEFF;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Total selling, general and administrative expenses</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">186.3</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">354.3</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>


</table>
  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">SG&amp;A expenses, excluding non-cash compensation expense related to equity awards, decreased in 2021 compared to 2020 due to operating
    efficiencies achieved from the Akcea Merger and restructuring our commercial operations. Non-cash compensation expense related to equity awards decreased in 2021 compared to 2020 due to reduced headcount as a result of the Akcea Merger and
    restructuring our commercial operations<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">. In addition, our SG&amp;A expenses in 2020 included non-cash stock-based compensation expense of $42.0 million related
      to the Akcea Merger and restructured European operations.</span></div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic; font-weight: bold;">Investment Income</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Investment income for 2021
    was $10.0 million compared to $30.6
    million for 2020. The decrease in investment income was primarily due to a decrease in interest rates during 2021 compared to 2020.</div>

  <div><br />
  </div>

  <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" class="DSPFPageBreakArea">
    <div class="DSPFPageFooter">
      <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span class="DSPFPageNumber">76</span></div>

    </div>

    <div style="page-break-after:always;" class="DSPFPageBreak">
      <hr style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;" /></div>


  </div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic; font-weight: bold;">Interest Expense</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">The following table sets forth information on interest expense (in millions):</div>

  <div><br />
  </div>

  <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;" class="cfttable">


  <tr>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">

        </td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" colspan="6">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Year Ended December 31,</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" colspan="2">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2021</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" colspan="2">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2020</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom;">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="2">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="2">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">(as revised*)</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Convertible senior notes:</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="2">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="2">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 76%; background-color: #CCEEFF;">
          <div style="text-align: left; margin-left: 18pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Non-cash amortization of the debt discounts and debt issuance costs</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">4.9</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">3.2</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 76%;">
          <div style="text-align: left; text-indent: 9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Interest expense payable in cash</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">1.9</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">3.8</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 76%; background-color: #CCEEFF;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Interest on mortgage for primary R&amp;D and manufacturing facilities</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">2.4</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">2.4</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 76%; padding-bottom: 2px;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Other</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">0.1</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">0.1</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 76%; padding-bottom: 4px; background-color: #CCEEFF;">
          <div style="text-align: left; text-indent: 9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Total interest expense</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">9.3</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">9.5</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>


</table>
  <div><br />
  </div>

  <table cellspacing="0" cellpadding="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">


  <tr>

    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">*</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We revised our 2020 amounts to reflect the simplified convertible instruments accounting guidance, which we adopted retrospectively. Refer to Note 1, <span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Organization and Significant Accounting Policies</span>, for further information.</div>
        </td>

  </tr>


</table>
  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic; font-weight: bold;">Gain on Investments</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Gain on investments for 2021 was $10.1 million compared to $16.5 million for 2020. During 2021, we revalued our investments in Bicycle and ProQR because we recognize publicly traded equity securities at fair value and recognized gains of $7.1 million and
    $1.8 million on our investments, respectively. <span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">During 2020, we revalued our investments in three privately held companies, Dynacure, Suzhou-Ribo and Aro Biotherapeutics
      because the companies sold additional equity securities that were similar to the equity we own. As a result of these observable price changes in 2020, we recognized a total gain of $14.8 million on our investments in these companies during 2020
      because the sales were at higher prices compared to our recorded value.</span></div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic; font-weight: bold;">Early Retirement of Debt</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">As a result of the debt offering and debt repurchase completed in April 2021, we recorded an $8.6 million loss on early
    retirement of debt, reflecting the early retirement of a portion of our 1% Notes. The loss on the early retirement of our debt is the difference between the amount we paid to retire our 1% Notes and the net carrying balance of the liability at the time
    that we retired the debt.</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic; font-weight: bold;">Income Tax Expense (Benefit)</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We recorded an income tax benefit of $0.6 million for 2021 compared to an income tax expense of $345.2 million for 2020.
    Our 2020 income tax expense included a non-cash tax expense of $341 million related to an increase in the valuation allowance recorded against Ionis&#8217; U.S. federal net deferred tax assets in 2020. We now maintain a valuation allowance against all our
    consolidated U.S. federal and state net deferred tax assets. Refer to Note 5, <span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Income Taxes</span>, in the Notes to our consolidated financial statements
    for further details on our valuation allowance.</div>

  <div><br />
  </div>

  <div style="text-align: left; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic; font-weight: bold;">Net Loss</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We generated a net loss of $28.6
    million for 2021 compared to $479.7
    million for 2020. Our net loss decreased for 2021 compared to 2020 primarily due to the valuation allowance we recorded in 2020 as a result of
    the Akcea Merger, as discussed above in the income tax expense (benefit) section. In addition, our revenue increased and expenses decreased year-over-year, as discussed above in the revenue and expenses sections, respectively<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">.</span></div>

  <div><br />
  </div>

  <div style="text-align: left; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic; font-weight: bold;">Net Loss Attributable to Noncontrolling Interest in Akcea Therapeutics, Inc.</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Our noncontrolling interest in Akcea on our statement of operations for 2020 was a net loss of $35.5 million.<span style="font-size: 12pt; font-family: 'Times New Roman', Times, serif;">&#160;</span>This amount represents the portion of Akcea&#8217;s net loss that third parties owned for the period from January 1, 2020 until we acquired 100 percent of Akcea in October 2020.
    After we completed the Akcea Merger in October 2020, we no longer recorded any adjustment related to noncontrolling interest for Akcea&#8217;s net loss.</div>

  <div><br />
  </div>

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    <div class="DSPFPageFooter">
      <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span class="DSPFPageNumber">77</span></div>

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  <div><br />
  </div>

  <div style="text-align: left; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic; font-weight: bold;">Net Loss Attributable to Ionis Pharmaceuticals, Inc. Common Stockholders<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> and Net Loss per Share</span></div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We had a net loss attributable to our common stockholders of $28.6 million for 2021 compared to $444.3 million in 2020. <span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">Basic and diluted net loss per share for </span>2021<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> were each $</span>0.20<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">. Basic and diluted net loss per share for 2020 were each $</span>3.18<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">.</span></div>

  <div><br />
  </div>

  <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Liquidity and Capital Resources</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">We have financed our operations primarily
      from research and development collaborative agreements. </span>We also finance our operations from commercial revenue from SPINRAZA royalties and TEGSEDI and WAYLIVRA commercial revenue. <span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">From our inception through December 31, </span>2021, we have earned approximately $5.8 billion<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> in revenue. We have also financed our operations
      through the sale of our equity securities and the issuance of long-term debt. From the time we were founded through December 31, </span>2021<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">, we have raised net proceeds of approximately $</span>2.0&#160;<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">billion from the sale of our equity securities. Additionally, we borrowed approximately $</span>2.1<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> billion under long-term debt arrangements to finance a portion of our operations over the same
      time period.</span></div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">Our cash, cash equivalents and short-term
      investments, debt obligations and working capital increased from 2020 to 2021, primarily as a result of receiving more than $760 million in payments from partners in 2021 and issuing $632.5 million of 0% Notes (due in April 2026). This increase was
      partially offset by our repurchase of $247.9 million of our 1% Notes in April 2021 and payment of the remaining principal balance of our 1% Notes with $62.0 million of cash at maturity in November 2021. At December 31, 2021, we had $2.1 billion of
      cash and short-term investments on hand. We believe our cash and short-term investment balance is sufficient to fund our operations in the short-term and in the longer-term. </span>In 2021 our working capital increased because our cash and
    investments increased as discussed above.</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">The following table summarizes our contractual obligations as of December 31, 2021. The table provides a breakdown of when obligations become due. We provide a more detailed description of the major components of our debt in <span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Note 3, </span><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Long-Term Obligations and Commitments</span><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">.</span></div>

  <div><br />
  </div>

  <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;" class="cfttable">


  <tr>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Contractual Obligations</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" colspan="10">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Payments Due by Period</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">(in millions)</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">(selected balances described below)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" colspan="2">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Total</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" colspan="2">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Less than 1 year</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" colspan="2">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">More than 1 year</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;">
          <div style="text-align: left; text-indent: -10pt; margin-left: 10pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">0% Notes (principal payable)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">632.5</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#8212;</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">632.5</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 64%;">
          <div style="text-align: left; text-indent: -10pt; margin-left: 10pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">0.125% Notes (principal and interest payable)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">550.9</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">0.7</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">550.2</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;">
          <div style="text-align: left; text-indent: -10pt; margin-left: 10pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Building mortgage payments (principal and interest payable)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">73.4</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">2.7</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">70.7</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 64%;">
          <div style="text-align: left; text-indent: -10pt; margin-left: 10pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Operating leases</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">27.5</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">4.1</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">23.4</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #CCEEFF;">
          <div style="text-align: left; text-indent: -10pt; margin-left: 10pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Other obligations (principal and interest payable)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">0.8</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">0.1</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">0.7</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 4px;">
          <div style="text-align: left; text-indent: -10pt; margin-left: 10pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Total</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">1,285.1</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">7.6</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">1,277.5</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>


</table>
  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Our contractual obligations consist primarily of our convertible debt. In addition, we also have facility mortgages, facility leases,
    equipment financing arrangements and other obligations. Due to the uncertainty with respect to the timing of future cash flows associated with our unrecognized tax benefits, we are unable to make reasonably reliable estimates of the period of cash
    settlement with the respective taxing authorities. Therefore, we have excluded our gross unrecognized tax benefits from our contractual obligations table above. We have not entered into, nor do we currently have, any off-balance sheet arrangements (as
    defined under SEC rules<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">).</span></div>

  <div><br />
  </div>

  <div style="text-align: left; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic; font-weight: bold;"><a id="_Hlk63502267"><!--Anchor--></a>Convertible Debt and Call Spread</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Refer to our Convertible Debt and Call Spread accounting
      policies in Note 1, </span><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Organization and Significant Accounting Policies</span><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">, and Note 3, </span><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Long-Term Obligations and Commitments</span><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">,
      in the Notes to our consolidated financial statements for the significant terms of each convertible debt instrument.</span></div>

  <div><br />
  </div>

  <div style="text-align: left; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic; font-weight: bold;">Research and Development and Manufacturing Facilities</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Refer to Note 3, <span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Long-Term Obligations
      and Commitments</span>, in the Notes to our consolidated financial statements for further details on our research and development and manufacturing facilities.</div>

  <div><br />
  </div>

  <div style="text-align: left; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic; font-weight: bold;">Operating Leases</div>

  <div><br />
  </div>

  <div style="text-align: left; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Refer to Note 3, <span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Long-Term Obligations and
      Commitments</span>, in the Notes to our consolidated financial statements for further details on our operating leases<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">.</span></div>

  <div><br />
  </div>

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      <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span class="DSPFPageNumber">78</span></div>

    </div>

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  </div>

  <div><br />
  </div>

  <div style="text-align: left; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic; font-weight: bold;">Other Obligations</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">In addition to contractual obligations, we had outstanding purchase orders as of December 31, 2021 for the purchase of
    services, capital equipment and materials as part of our normal course of business.</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We may enter into additional collaborations with partners which could provide for additional revenue to us and we may
    incur additional cash expenditures related to our obligations under any of the new agreements we may enter into. We currently intend to use our cash, cash equivalents and short-term investments to finance our activities. However, we may also pursue
    other financing alternatives, like issuing additional shares of our common stock, issuing debt instruments, refinancing our existing debt, or securing lines of credit. Whether we use our existing capital resources or choose to obtain financing will
    depend on various factors, including the future success of our business, the prevailing interest rate environment and the condition of financial markets generally.</div>

  <div><br />
  </div>

  <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Item 7A. Quantitative and Qualitative Disclosures About Market Risk</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We are exposed to changes in interest rates
      primarily from our investments in certain short-term investments. We primarily invest our excess cash in highly liquid short-term investments of the U.S. Treasury and reputable financial institutions, corporations, and U.S. government agencies with
      strong credit ratings. We typically hold our investments for the duration of the term of the respective instrument. We do not utilize derivative financial instruments, derivative commodity instruments or other market risk sensitive instruments,
      positions or transactions to manage exposure to interest rate changes. Accordingly, we believe that, while the securities we hold are subject to changes in the financial standing of the issuer of such securities, we were not subject to any material
      risks arising from changes in interest rates, foreign currency exchange rates, commodity prices, equity prices or other market changes that affect market risk sensitive instruments as of December 31, 2021 and will not be subject to any material risks
      arising from these changes in the foreseeable future</span>.</div>

  <div><br />
  </div>

  <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Item 8. Financial Statements and Supplementary Data</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We filed our consolidated financial statements and supplementary data required by this item as exhibits hereto, and listed
    them under Item 15(a)(1) and (2), and incorporate them herein by reference.</div>

  <div><br />
  </div>

  <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Item 9. Changes in and Disagreements with Accountants on Accounting and Financial Disclosure</div>

  <div><br />
  </div>

  <div style="text-align: left; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">None.</div>

  <div><br />
  </div>

  <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Item 9A. Controls and Procedures</div>

  <div><br />
  </div>

  <div style="text-align: left; text-indent: -18pt; margin-left: 54pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Disclosure Controls and Procedures</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We maintain disclosure controls and procedures (as defined in Rules 13a-15(e) and 15d-15(e) under the Securities Exchange
    Act of 1934, as amended, or Exchange Act) that are designed to ensure that information we are required to disclose in our Exchange Act reports is recorded, processed, summarized and reported within the time periods specified in the SEC&#8217;s rules and
    forms, and that such information is accumulated and communicated to our management, including our Chief Executive Officer and Chief Financial Officer, as appropriate, to allow timely decisions regarding required disclosure. We designed and evaluate our
    disclosure controls and procedures recognizing that any controls and procedures, no matter how well designed and operated, can provide only reasonable assurance and not absolute assurance of achieving the desired control objectives.</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">As of the end of the period covered by this report on Form 10-K, we carried out an evaluation of our disclosure controls
    and procedures under the supervision of, and with the participation of our management, including our Chief Executive Officer and Chief Financial Officer. Based on our evaluation, our Chief Executive Officer and Chief Financial Officer concluded that
    our disclosure controls and procedures were effective as of December 31, 2021.</div>

  <div><br />
  </div>

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    <div class="DSPFPageFooter">
      <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span class="DSPFPageNumber">79</span></div>

    </div>

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  </div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: -18pt; margin-left: 54pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Management</span>&#8217;<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">s Report on Internal Control over Financial Reporting</span></div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Our management is responsible for establishing and maintaining adequate internal control over financial reporting, as
    defined in Exchange Act Rules 13a-15(f). Our internal control over financial reporting is a process designed under the supervision of our Chief Executive Officer and Chief Financial Officer to provide reasonable assurance regarding the reliability of
    financial reporting and the preparation of our financial statements for external purposes in accordance with U.S. generally accepted accounting principles.</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">As of December 31, 2021,
    we assessed the effectiveness of our internal control over financial reporting based on the criteria for effective internal control over financial reporting under the 2013 &#8220;Internal Control&#8212;Integrated Framework,&#8221; issued by the Committee of Sponsoring
    Organizations, or COSO, of the Treadway Commission, under the supervision of, and with the participation of our management, including our Chief Executive Officer and Chief Financial Officer. Based on that assessment, our management concluded that we
    maintained effective internal control over financial reporting as of December 31, 2021.</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Ernst &amp; Young LLP, an independent registered public accounting firm, audited the effectiveness of our internal control
    over financial reporting as of December 31, 2021, as stated in their attestation report, which is included elsewhere herein.</div>

  <div><br />
  </div>

  <div style="text-align: left; text-indent: -18pt; margin-left: 54pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Changes in Internal Control over Financial Reporting</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">The above assessment did not identify any change in our internal control over financial reporting that occurred during our
    latest fiscal quarter and that has materially affected, or is reasonably likely to materially affect, our internal control over financial reporting.</div>

  <div><br />
  </div>

  <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" class="DSPFPageBreakArea">
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      <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span class="DSPFPageNumber">80</span></div>

    </div>

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  </div>

  <div><br />
  </div>

  <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">REPORT OF INDEPENDENT REGISTERED PUBLIC ACCOUNTING FIRM</div>

  <div><br />
  </div>

  <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">To the Stockholders and Board of Directors of Ionis Pharmaceuticals, Inc.</div>

  <div><br />
  </div>

  <div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Opinion on Internal Control over Financial Reporting</div>

  <div><br />
  </div>

  <div style="text-align: justify; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We have audited Ionis Pharmaceuticals, Inc.&#8217;s internal control over financial reporting as of December 31, 2021, based on criteria established in Internal
    Control&#8212;Integrated Framework issued by the Committee of Sponsoring Organizations of the Treadway Commission (2013 framework) (the COSO criteria). In our opinion, Ionis Pharmaceuticals, Inc. (the Company) maintained, in all material respects, effective
    internal control over financial reporting as of December 31, 2021, based on the COSO criteria.</div>

  <div>&#160;</div>

  <div style="text-align: justify; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We also have audited, in accordance with the standards of the Public Company Accounting Oversight Board (United States) (PCAOB), the consolidated balance
    sheets of the Company as of December 31, 2021 and 2020, the related consolidated statements of operations, comprehensive income (loss), stockholders&#8217; equity and cash flows for each of the three years in the period ended December 31, 2021, and the
    related notes and our report dated February 24, 2022 expressed an unqualified opinion thereon.</div>

  <div>&#160;</div>

  <div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Basis for Opinion</div>

  <div><br />
  </div>

  <div style="text-align: justify; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">The Company&#8217;s management is responsible for maintaining effective internal control over financial reporting and for its assessment of the effectiveness of
    internal control over financial reporting included in the accompanying Management&#8217;s Report on Internal Control over Financial Reporting. Our responsibility is to express an opinion on the Company&#8217;s internal control over financial reporting based on our
    audit. We are a public accounting firm registered with the PCAOB and are required to be independent with respect to the Company in accordance with the U.S. federal securities laws and the applicable rules and regulations of the Securities and Exchange
    Commission and the PCAOB.</div>

  <div>&#160;</div>

  <div style="text-align: justify; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We conducted our audit in accordance with the standards of the PCAOB. Those standards require that we plan and perform the audit to obtain reasonable
    assurance about whether effective internal control over financial reporting was maintained in all material respects.</div>

  <div>&#160;</div>

  <div style="text-align: justify; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Our audit included obtaining an understanding of internal control over financial reporting, assessing the risk that a material weakness exists, testing and
    evaluating the design and operating effectiveness of internal control based on the assessed risk, and performing such other procedures as we considered necessary in the circumstances. We believe that our audit provides a reasonable basis for our
    opinion.</div>

  <div>&#160;</div>

  <div style="text-align: justify; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Definition and Limitations of Internal Control Over Financial Reporting</div>

  <div><br />
  </div>

  <div style="text-align: justify; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">A company&#8217;s internal control over financial reporting is a process designed to provide reasonable assurance regarding the reliability of financial reporting
    and the preparation of financial statements for external purposes in accordance with generally accepted accounting principles. A company&#8217;s internal control over financial reporting includes those policies and procedures that (1) pertain to the
    maintenance of records that, in reasonable detail, accurately and fairly reflect the transactions and dispositions of the assets of the company; (2) provide reasonable assurance that transactions are recorded as necessary to permit preparation of
    financial statements in accordance with generally accepted accounting principles, and that receipts and expenditures of the company are being made only in accordance with authorizations of management and directors of the company; and (3) provide
    reasonable assurance regarding prevention or timely detection of unauthorized acquisition, use, or disposition of the company&#8217;s assets that could have a material effect on the financial statements.</div>

  <div>&#160;</div>

  <div style="text-align: justify; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Because of its inherent limitations, internal control over financial reporting may not prevent or detect misstatements. Also, projections of any evaluation
    of effectiveness to future periods are subject to the risk that controls may become inadequate because of changes in conditions, or that the degree of compliance with the policies or procedures may deteriorate.</div>

  <div>&#160;</div>

  <div><br />
  </div>

  <div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">/s/ Ernst &amp; Young LLP</div>

  <div><br />
  </div>

  <div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">San Diego, California</div>

  <div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">February 24, 2022</div>

  <div><br />
  </div>

  <div><br />
  </div>

  <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" class="DSPFPageBreakArea">
    <div class="DSPFPageFooter">
      <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span class="DSPFPageNumber">81</span></div>

    </div>

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  </div>

  <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Item 9B. Other Information</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Not applicable.</div>

  <div><br />
  </div>

  <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Item 9C. Disclosure Regarding Foreign Jurisdictions that Prevent Inspections</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Not applicable.</div>

  <div><br />
  </div>

  <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">PART III</div>

  <div><br />
  </div>

  <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Item 10. Directors, Executive Officers and Corporate Governance</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">We incorporate by reference the information
      required by this Item with respect to directors and the Audit Committee from the information under the caption &#8220;ELECTION OF DIRECTORS,&#8221; including in particular the information under &#8220;Nominating, Governance and Review Committee&#8221; and &#8220;Audit Committee,&#8221;
      contained in our definitive Proxy Statement, which we will file with the Securities and Exchange Commission within 120 days after the end of the fiscal year ended </span>December 31, 2021<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">, or the Proxy Statement.</span></div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We include information concerning our executive officers in the section titled, <span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Information about our Executive Officers</span>, in this report on the Form 10-K in Item 1 titled &#8220;Business.&#8221;</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We incorporate by reference the required information concerning our Code of Ethics from the information under the caption
    &#8220;Code of Ethics and Business Conduct&#8221; contained in the Proxy Statement. Our Code of Ethics and Business Conduct is posted on our website at www.ionispharma.com<sup>(1)</sup>. We intend to disclose future amendments to, or waivers from, our Code of
    Ethics and Business Conduct on our website.</div>

  <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">________________</div>

  <div>
    <table cellspacing="0" cellpadding="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">


  <tr>

    <td style="width: 18pt; vertical-align: top; align: right;">
            <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(1)</div>
          </td>

    <td style="width: auto; vertical-align: top;">
            <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Any information that is included on or linked to our website is not part of this Form 10-K.</div>
          </td>

  </tr>


</table>
  </div>

  <div><br />
  </div>

  <div style="text-align: left; text-indent: 18pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;">Delinquent Section 16(a) Reports</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Item 1, Part I of this Report contains information concerning our executive officers. We incorporate by reference the
    information required by this Item concerning compliance with Section 16(a) of the Exchange Act from the information under the caption &#8220;Delinquent Section 16(a) Reports&#8221; contained in the Proxy Statement.</div>

  <div><br />
  </div>

  <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Item 11. Executive Compensation</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We incorporate by reference the information required by this item to the information under the caption &#8220;EXECUTIVE
    COMPENSATION,&#8221; &#8220;Compensation Committee Interlocks and Insider Participation&#8221; and &#8220;COMPENSATION COMMITTEE REPORT&#8221; contained in the Proxy Statement.</div>

  <div><br />
  </div>

  <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" class="DSPFPageBreakArea">
    <div class="DSPFPageFooter">
      <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span class="DSPFPageNumber">82</span></div>

    </div>

    <div style="page-break-after:always;" class="DSPFPageBreak">
      <hr style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;" /></div>


  </div>

  <div><br />
  </div>

  <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Item 12. Security Ownership of Certain Beneficial Owners and Management and Related Stockholder Matters</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We incorporate by reference the information required by this item to the information under the captions &#8220;SECURITY
    OWNERSHIP OF CERTAIN BENEFICIAL OWNERS AND MANAGEMENT&#8221; contained in the Proxy Statement.</div>

  <div><br />
  </div>

  <div style="text-align: left; margin-left: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Securities Authorized for Issuance under Equity Compensation Plans</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">The following table sets forth information regarding outstanding options and shares reserved for future issuance under our
    equity compensation plans as of December 31, 2021.</div>

  <div style="text-align: left;"><br />
  </div>

  <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; border-collapse: collapse; text-align: left; color: #000000;">


  <tr>

    <td style="width: 41.45%; vertical-align: bottom; border-bottom: #000000 2px solid;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Plan Category</div>
        </td>

    <td style="width: 1%; vertical-align: bottom;">&#160;</td>

    <td style="width: 19.85%; vertical-align: bottom; border-bottom: #000000 2px solid;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Number of Shares to</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">be Issued Upon Exercise</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">of Outstanding Options</div>
        </td>

    <td style="width: 0.75%; vertical-align: bottom;">&#160;</td>

    <td style="width: 17.48%; vertical-align: bottom; border-bottom: #000000 2px solid;" colspan="2">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Weighted Average</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Exercise Price of</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Outstanding Options</div>
        </td>

    <td style="width: 0.87%; vertical-align: bottom;">&#160;</td>

    <td style="width: 16.36%; vertical-align: bottom; border-bottom: #000000 2px solid;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Number of Shares</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Remaining Available</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">for Future Issuance</div>
        </td>

    <td style="width: 2.24%; vertical-align: bottom;">&#160;</td>

  </tr>

  <tr>

    <td style="width: 41.45%; vertical-align: bottom; background-color: #CCEEFF;">
          <div style="text-align: left; text-indent: -10pt; margin-left: 10pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Equity compensation plans approved by stockholders (a)</div>
        </td>

    <td style="width: 1%; vertical-align: bottom; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 19.85%; vertical-align: bottom; border-bottom: #000000 2px solid; background-color: #CCEEFF;">
          <div style="text-align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">14,088,816</div>
        </td>

    <td style="width: 0.75%; vertical-align: bottom; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 2.87%; vertical-align: bottom; background-color: #CCEEFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td style="width: 14.61%; vertical-align: bottom; background-color: #CCEEFF;">
          <div style="text-align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">54.04</div>
        </td>

    <td style="width: 0.87%; vertical-align: bottom; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 16.36%; vertical-align: bottom; border-bottom: #000000 2px solid; background-color: #CCEEFF;">
          <div style="text-align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">11,102,267</div>
        </td>

    <td style="width: 2.24%; vertical-align: bottom; background-color: #CCEEFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(b)</div>
        </td>

  </tr>

  <tr>

    <td style="width: 41.45%; vertical-align: bottom; background-color: #FFFFFF;">
          <div style="text-align: left; text-indent: -10pt; margin-left: 10pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Total</div>
        </td>

    <td style="width: 1%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 19.85%; vertical-align: bottom; border-bottom: #000000 4px double; background-color: #FFFFFF;">
          <div style="text-align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">14,088,816</div>
        </td>

    <td style="width: 0.75%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 2.87%; vertical-align: bottom; background-color: #FFFFFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td style="width: 14.61%; vertical-align: bottom; background-color: #FFFFFF;">
          <div style="text-align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">54.04</div>
        </td>

    <td style="width: 0.87%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 16.36%; vertical-align: bottom; border-bottom: #000000 4px double; background-color: #FFFFFF;">
          <div style="text-align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">11,102,267</div>
        </td>

    <td style="width: 2.24%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>

  </tr>


</table>
  <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">________________</div>

  <table cellspacing="0" cellpadding="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">


  <tr>

    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(a)</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Consists of five Ionis plans: 1989 Stock Option Plan, Amended and Restated 2002 Non-Employee Directors&#8217; Stock Option Plan, 2011 Equity Incentive Plan,
            2020 Equity Incentive Plan and Employee Stock Purchase Plan, or ESPP.</div>
        </td>

  </tr>


</table>
  <table cellspacing="0" cellpadding="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">


  <tr>

    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(b)</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Of these shares, 588,529 were available for purchase under the ESPP as of December 31, 2021.</div>
        </td>

  </tr>


</table>
  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">For additional details about our equity compensation plans, including a description of each plan, see Note 4, <span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Stockholders&#8217; Equity</span>, in the Notes to the Consolidated Financial Statements.</div>

  <div><br />
  </div>

  <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Item 13. Certain Relationships and Related Transactions, and Director Independence</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We incorporate by reference the information required by this item to the information under the captions &#8220;Independence of
    the Board of Directors&#8221; and &#8220;Certain Relationships and Related Transactions&#8221; contained in the Proxy Statement.</div>

  <div><br />
  </div>

  <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Item 14. Principal Accountant Fees and Services</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We incorporate by reference the information required by this item to the information under the caption &#8220;Ratification of
    Selection of Independent Auditors&#8221; contained in the Proxy Statement.</div>

  <div><br />
  </div>

  <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">PART IV</div>

  <div style="text-align: center;"><br />
  </div>

  <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Item 15. Exhibits, Financial Statement Schedules</div>

  <div style="text-align: left;"><br />
  </div>

  <div style="text-align: left; text-indent: -36pt; margin-left: 72pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">(a)(1) Index to Financial Statements</div>

  <div style="text-align: justify; text-indent: -36pt; margin-left: 72pt;"><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We submitted the consolidated financial statements required by this item in a separate section beginning on page F-1 of
    this Report.</div>

  <div style="text-align: left; text-indent: 36pt;"><br />
  </div>

  <div style="text-align: left; text-indent: -36pt; margin-left: 72pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">(a)(2) Index to Financial Statement Schedules</div>

  <div style="text-align: left; text-indent: -36pt; margin-left: 72pt;"><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We omitted these schedules because they are not required, or are not applicable, or the required information is shown in
    the consolidated financial statements or notes thereto.</div>

  <div style="text-align: left; text-indent: 36pt;"><br />
  </div>

  <div style="text-align: left; text-indent: -36pt; margin-left: 72pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">(a)(3) Index to Exhibits</div>

  <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" class="DSPFPageBreakArea">
    <div class="DSPFPageFooter">
      <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span class="DSPFPageNumber">83</span></div>

    </div>

    <div style="page-break-after:always;" class="DSPFPageBreak">
      <hr style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;" /></div>


  </div>

  <div><br />
  </div>

  <div><br />
  </div>

  <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">INDEX TO EXHIBITS</div>

  <div><br />
  </div>

  <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; border-collapse: collapse; text-align: left; color: #000000;">


  <tr>

    <td style="width: 7.41%; vertical-align: bottom; border-bottom: #000000 2px solid;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Exhibit Number</div>
        </td>

    <td style="width: 2.17%; vertical-align: bottom;">&#160;</td>

    <td style="width: 90.43%; vertical-align: bottom; border-bottom: #000000 2px solid;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Description of Document</div>
        </td>

  </tr>

  <tr>

    <td style="width: 7.41%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">2.1</div>
        </td>

    <td style="width: 2.17%; vertical-align: bottom; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 90.43%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: justify; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><a style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;" href="https://www.sec.gov/Archives/edgar/data/874015/000119312520235408/d75253dex21.htm">Agreement and Plan of Merger, dated as of August 30, 2020, among Akcea Therapeutics, Inc., Ionis Pharmaceuticals, Inc. and Avalanche Merger Sub, Inc.</a><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">, filed as an exhibit to the Registrant&#8217;s Current Report on Form 8-K filed August 31, 2020 and incorporated herein by reference.</span></div>
        </td>

  </tr>

  <tr>

    <td style="width: 7.41%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 2.17%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 90.43%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

  </tr>

  <tr>

    <td style="width: 7.41%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">3.1</div>
        </td>

    <td style="width: 2.17%; vertical-align: bottom; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 90.43%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: justify; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><a style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;" href="https://www.sec.gov/Archives/edgar/data/874015/000087401518000047/exhibit3_1.htm">Amended and Restated Certificate of Incorporation filed June 19, 1991</a><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">, filed as an exhibit to the Registrant&#8217;s Annual Report on Form 10-K for the year ended December 31, 2017 and incorporated herein by reference.</span></div>
        </td>

  </tr>

  <tr>

    <td style="width: 7.41%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 2.17%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 90.43%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

  </tr>

  <tr>

    <td style="width: 7.41%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">3.2</div>
        </td>

    <td style="width: 2.17%; vertical-align: bottom; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 90.43%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: justify; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><a style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;" href="https://www.sec.gov/Archives/edgar/data/874015/000114036114017588/formdef14a.htm">Certificate of Amendment to Restated Certificate of Incorporation</a><span style="font-size: 12pt; font-family: 'Times New Roman', Times, serif; color: #000000;">, </span><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">filed as an exhibit to the Registrant&#8217;s Notice of Annual Meeting and Proxy Statement, for the 2014 Annual Meeting of
              Stockholders, filed on April 25, 2014 and incorporated herein by reference.</span></div>
        </td>

  </tr>

  <tr>

    <td style="width: 7.41%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 2.17%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 90.43%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

  </tr>

  <tr>

    <td style="width: 7.41%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">3.3</div>
        </td>

    <td style="width: 2.17%; vertical-align: bottom; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 90.43%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: justify; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><a style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;" href="https://www.sec.gov/Archives/edgar/data/874015/000114036115045083/ex3_1.htm">Certificate of Amendment to Restated Certificate of Incorporation</a><span style="font-size: 12pt; font-family: 'Times New Roman', Times, serif; color: #000000;">, </span><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">filed as an exhibit to the Registrant&#8217;s Current Report on Form 8-K filed December 18, 2015 and incorporated herein by reference.</span></div>
        </td>

  </tr>

  <tr>

    <td style="width: 7.41%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 2.17%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 90.43%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

  </tr>

  <tr>

    <td style="width: 7.41%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">3.4</div>
        </td>

    <td style="width: 2.17%; vertical-align: bottom; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 90.43%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: justify; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><a style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;" href="https://www.sec.gov/Archives/edgar/data/874015/000114036121010402/brhc10022399_ex3-1.htm">Amended and Restated Bylaws</a><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">, filed as an exhibit
              to the Registrant&#8217;s Current Report on Form 8-K filed March 29, 2021 and incorporated herein by reference.</span></div>
        </td>

  </tr>

  <tr>

    <td style="width: 7.41%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 2.17%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 90.43%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

  </tr>

  <tr>

    <td style="width: 7.41%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">4.1</div>
        </td>

    <td style="width: 2.17%; vertical-align: bottom; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 90.43%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: justify; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><a style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;" href="https://www.sec.gov/Archives/edgar/data/874015/000091205700053343/a2032851zex-4_2.txt">Certificate of Designation of the Series C Junior Participating Preferred Stock</a><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">, filed as an exhibit to Registrant&#8217;s Current Report on Form 8-K filed December 13, 2000 and incorporated herein by reference.</span></div>
        </td>

  </tr>

  <tr>

    <td style="width: 7.41%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 2.17%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 90.43%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

  </tr>

  <tr>

    <td style="width: 7.41%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">4.2</div>
        </td>

    <td style="width: 2.17%; vertical-align: bottom; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 90.43%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: justify; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><a style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;" href="https://www.sec.gov/Archives/edgar/data/874015/000087401518000047/exhibit4_2.htm">Specimen Common Stock Certificate</a><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">, filed as an exhibit to
              the Registrant&#8217;s Annual Report on Form 10-K for the year ended December 31, 2017 and incorporated herein by reference.</span></div>
        </td>

  </tr>

  <tr>

    <td style="width: 7.41%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 2.17%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 90.43%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

  </tr>

  <tr>

    <td style="width: 7.41%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">4.3</div>
        </td>

    <td style="width: 2.17%; vertical-align: bottom; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 90.43%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: justify; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><a style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;" href="https://www.sec.gov/Archives/edgar/data/874015/000110465914082750/a14-24885_18k.htm">Indenture, dated as of November 17, 2014, between the Registrant and Wells Fargo Bank, National Association, as trustee, including Form of 1.00 percent
              Convertible Senior Note due 2021</a><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">, filed as an exhibit to the Registrant&#8217;s Current Report on Form 8-K filed November 21, 2014 and incorporated
              herein by reference.</span></div>
        </td>

  </tr>

  <tr>

    <td style="width: 7.41%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 2.17%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 90.43%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

  </tr>

  <tr>

    <td style="width: 7.41%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">4.4</div>
        </td>

    <td style="width: 2.17%; vertical-align: bottom; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 90.43%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: justify; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><a style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;" href="https://www.sec.gov/Archives/edgar/data/874015/000114036119023019/ex4_1.htm">Indenture, dated as of December 19, 2019, by and between the Registrant&#160; and U.S. Bank National Association, as trustee, including Form of 0.125 percent
              Convertible Senior Note due 2024</a><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">, filed as an exhibit to the Registrant&#8217;s Current Report on Form 8-K filed December 23, 2019 and incorporated
              herein by reference.</span></div>
        </td>

  </tr>

  <tr>

    <td style="width: 7.41%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 2.17%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 90.43%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

  </tr>

  <tr>

    <td style="width: 7.41%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">4.5</div>
        </td>

    <td style="width: 2.17%; vertical-align: bottom; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 90.43%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: justify; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><a style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;" href="https://www.sec.gov/Archives/edgar/data/874015/000119312521113586/d158901dex41.htm">Indenture, dated as of April 12, 2021, by and between the Registrant and U.S. Bank National Association, as trustee, including Form of 0 percent
              Convertible Senior Note due 2026</a><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">, filed as an exhibit to the Registrant&#8217;s Current Report on Form 8-K filed April 13, 2021 and incorporated herein
              by reference.</span></div>
        </td>

  </tr>

  <tr>

    <td style="width: 7.41%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 2.17%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 90.43%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

  </tr>

  <tr>

    <td style="width: 7.41%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">4.6</div>
        </td>

    <td style="width: 2.17%; vertical-align: bottom; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 90.43%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: justify; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><a style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;" href="https://www.sec.gov/Archives/edgar/data/874015/000114036119022393/ex99_1.htm">Form of Exchange and/or Subscription Agreement for Convertible Senior Notes due 2024</a><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">, filed as an exhibit to the Registrant&#8217;s Current Report on Form 8-K filed December 12, 2019 and incorporated herein by reference.</span></div>
        </td>

  </tr>

  <tr>

    <td style="width: 7.41%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 2.17%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 90.43%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

  </tr>

  <tr>

    <td style="width: 7.41%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">4.7</div>
        </td>

    <td style="width: 2.17%; vertical-align: bottom; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 90.43%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: justify; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><a style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;" href="https://www.sec.gov/Archives/edgar/data/874015/000114036119022393/ex99_2.htm">Form of Convertible Note Hedge Transactions Confirmation</a><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #0000FF;"><span style="text-decoration: underline;">
                for Convertible Senior Notes due 2024</span></span><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">, filed as an exhibit to the Registrant&#8217;s Current Report on Form 8-K filed December 12, 2019 and
              incorporated herein by reference.</span></div>
        </td>

  </tr>

  <tr>

    <td style="width: 7.41%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 2.17%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 90.43%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

  </tr>

  <tr>

    <td style="width: 7.41%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">4.8</div>
        </td>

    <td style="width: 2.17%; vertical-align: bottom; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 90.43%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: justify; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><a style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;" href="https://www.sec.gov/Archives/edgar/data/874015/000119312521113586/d158901dex101.htm">Form of Convertible Note Hedge Confirmation for Convertible Senior Notes due 2026</a><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">, filed as an exhibit to the Registrant&#8217;s Current Report on Form 8-K filed April 13, 2021 and incorporated herein by reference.</span></div>
        </td>

  </tr>

  <tr>

    <td style="width: 7.41%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 2.17%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 90.43%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

  </tr>

  <tr>

    <td style="width: 7.41%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">4.9</div>
        </td>

    <td style="width: 2.17%; vertical-align: bottom; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 90.43%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: justify; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><a style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;" href="https://www.sec.gov/Archives/edgar/data/874015/000114036119022393/ex99_3.htm">Form of Warrant Transactions Confirmation</a><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #0000FF;"><span style="text-decoration: underline;"> for Convertible
                Senior Notes due 2024</span></span><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">, filed as an exhibit to the Registrant&#8217;s Current Report on Form 8-K filed December 12, 2019 and incorporated
              herein by reference.</span></div>
        </td>

  </tr>

  <tr>

    <td style="width: 7.41%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 2.17%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 90.43%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

  </tr>

  <tr>

    <td style="width: 7.41%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">4.10</div>
        </td>

    <td style="width: 2.17%; vertical-align: bottom; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 90.43%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: justify; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><a style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;" href="https://www.sec.gov/Archives/edgar/data/874015/000119312521113586/d158901dex102.htm">Form of Warrant Confirmation for Convertible Senior Notes due 2026</a><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">, filed as an exhibit to the Registrant&#8217;s Current Report on Form 8-K filed April 13, 2021 and incorporated herein by reference.</span></div>
        </td>

  </tr>

  <tr>

    <td style="width: 7.41%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 2.17%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 90.43%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

  </tr>

  <tr>

    <td style="width: 7.41%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: left; color: #0000FF; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><a href="exhibit4-11.htm">4.11</a></div>
        </td>

    <td style="width: 2.17%; vertical-align: bottom; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 90.43%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: justify; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #0000FF;">Description of the Registrant&#8217;s Securities</span><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">.</span></div>
        </td>

  </tr>

  <tr>

    <td style="width: 7.41%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 2.17%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 90.43%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

  </tr>

  <tr>

    <td style="width: 7.41%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">10.1</div>
        </td>

    <td style="width: 2.17%; vertical-align: bottom; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 90.43%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: justify; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><a style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;" href="https://www.sec.gov/Archives/edgar/data/874015/000087401521000144/ex10-1.htm">Amended Board Compensation Policy</a><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">, filed as an exhibit to the
              Registrant&#8217;s Quarterly Report on Form 10-Q for the quarter ended June 30, 2021 and incorporated herein by reference.</span></div>
        </td>

  </tr>

  <tr>

    <td style="width: 7.41%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 2.17%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 90.43%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

  </tr>


</table>
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  <tr>

    <td style="width: 7.41%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">10.2</div>
        </td>

    <td style="width: 2.17%; vertical-align: bottom; background-color: #CCEEFF;" colspan="2">&#160;</td>

    <td style="width: 90.43%; vertical-align: top; background-color: #CCEEFF;" colspan="2">
          <div style="text-align: justify; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><a style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;" href="https://www.sec.gov/Archives/edgar/data/874015/000110465913016208/a12-28450_1ex10d1.htm">Form of Indemnity Agreement entered into between the Registrant and its Directors and Officers with related schedule</a><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">, filed as an exhibit to the Registrant&#8217;s Annual Report on Form 10-K for the year ended December 31, 2012 and incorporated herein by reference.</span></div>
        </td>

  </tr>

  <tr>

    <td style="width: 7.41%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 2.17%; vertical-align: bottom; background-color: #FFFFFF;" colspan="2">&#160;</td>

    <td style="width: 90.43%; vertical-align: top; background-color: #FFFFFF;" colspan="2">&#160;</td>

  </tr>

  <tr>

    <td style="width: 7.41%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">10.3*</div>
        </td>

    <td style="width: 2.17%; vertical-align: bottom; background-color: #CCEEFF;" colspan="2">&#160;</td>

    <td style="width: 90.43%; vertical-align: top; background-color: #CCEEFF;" colspan="2">
          <div style="text-align: justify; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><a style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;" href="https://www.sec.gov/Archives/edgar/data/874015/000110465912025639/a12-1729_1def14a.htm">Registrant&#8217;s 1989 Stock Option Plan, as amended</a><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">,
              filed as an exhibit to Registrant&#8217;s Notice of Annual Meeting and Proxy Statement for the 2012 Annual Meeting of Stockholders, filed on April 16, 2012 and incorporated herein by reference.</span></div>
        </td>

  </tr>

  <tr>

    <td style="width: 7.41%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 2.17%; vertical-align: bottom; background-color: #FFFFFF;" colspan="2">&#160;</td>

    <td style="width: 90.43%; vertical-align: top; background-color: #FFFFFF;" colspan="2">&#160;</td>

  </tr>

  <tr>

    <td style="width: 7.41%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">10.4*</div>
        </td>

    <td style="width: 2.17%; vertical-align: bottom; background-color: #CCEEFF;" colspan="2">&#160;</td>

    <td style="width: 90.43%; vertical-align: top; background-color: #CCEEFF;" colspan="2">
          <div style="text-align: justify; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><a style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;" href="https://www.sec.gov/Archives/edgar/data/874015/000114036119005627/ex10_2.htm">Registrant&#8217;s Amended and Restated 2000 Employee Stock Purchase Plan</a><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">, filed as an exhibit to Registrant&#8217;s Current Report on Form 8-K filed on March 26, 2019 and incorporated herein by reference.</span></div>
        </td>

  </tr>

  <tr>

    <td style="width: 7.41%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 2.17%; vertical-align: bottom; background-color: #FFFFFF;" colspan="2">&#160;</td>

    <td style="width: 90.43%; vertical-align: top; background-color: #FFFFFF;" colspan="2">&#160;</td>

  </tr>

  <tr>

    <td style="width: 7.5%; vertical-align: top; background-color: #CCEEFF;" colspan="2">
          <div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">10.5</div>
        </td>

    <td style="width: 2.07%; vertical-align: bottom; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 90.43%; vertical-align: top; background-color: #CCEEFF;" colspan="2">
          <div style="text-align: justify; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><a style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;" href="https://www.sec.gov/Archives/edgar/data/874015/000087401518000047/exhibit10_4.htm">Form of Employee Confidential Information and Inventions Agreement</a><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">, filed as an exhibit to the Registrant&#8217;s Annual Report on Form 10-K for the year ended December 31, 2017 and incorporated herein by reference.</span></div>
        </td>

  </tr>

  <tr>

    <td style="width: 7.5%; vertical-align: top; background-color: #FFFFFF;" colspan="2">&#160;</td>

    <td style="width: 2.07%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 90.43%; vertical-align: top; background-color: #FFFFFF;" colspan="2">&#160;</td>

  </tr>

  <tr>

    <td style="width: 7.5%; vertical-align: top; background-color: #CCEEFF;" colspan="2">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">10.6</div>
        </td>

    <td style="width: 2.07%; vertical-align: bottom; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 90.43%; vertical-align: top; background-color: #CCEEFF;" colspan="2">
          <div style="text-align: justify; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><a style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;" href="https://www.sec.gov/Archives/edgar/data/874015/000110465911044376/a11-13864_1ex10d1.htm">Amendment #1 to the Research, Development and License Agreement dated May 11, 2011 by and between the Registrant and Glaxo Group Limited</a><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">, filed as an exhibit to the Registrant&#8217;s Quarterly Report on Form 10-Q for the quarter ended June 30, 2011 and incorporated herein by reference. Portions
              of this exhibit have been omitted and separately filed with the SEC with a request for confidential treatment.</span></div>
        </td>

  </tr>

  <tr>

    <td style="width: 7.5%; vertical-align: top; background-color: #FFFFFF;" colspan="2">&#160;</td>

    <td style="width: 2.07%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 90.43%; vertical-align: top; background-color: #FFFFFF;" colspan="2">&#160;</td>

  </tr>

  <tr>

    <td style="width: 7.5%; vertical-align: top; background-color: #CCEEFF;" colspan="2">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">10.7</div>
        </td>

    <td style="width: 2.07%; vertical-align: bottom; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 90.43%; vertical-align: top; background-color: #CCEEFF;" colspan="2">
          <div style="text-align: justify; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><a style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;" href="https://www.sec.gov/Archives/edgar/data/874015/000110465908032466/a08-11587_1ex10d2.htm">Amended and Restated Collaboration and License Agreement between the Registrant and Antisense Therapeutics Ltd dated February 8, 2008</a><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">, filed as an exhibit to the Registrant&#8217;s Quarterly Report on Form 10-Q for the quarter ended March 31, 2008 and incorporated herein by reference. Portions
              of this exhibit have been omitted and separately filed with the SEC with a request for confidential treatment.</span></div>
        </td>

  </tr>

  <tr>

    <td style="width: 7.5%; vertical-align: top; background-color: #FFFFFF;" colspan="2">&#160;</td>

    <td style="width: 2.07%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 90.43%; vertical-align: top; background-color: #FFFFFF;" colspan="2">&#160;</td>

  </tr>

  <tr>

    <td style="width: 7.5%; vertical-align: top; background-color: #CCEEFF;" colspan="2">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">10.8</div>
        </td>

    <td style="width: 2.07%; vertical-align: bottom; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 90.43%; vertical-align: top; background-color: #CCEEFF;" colspan="2">
          <div style="text-align: justify; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><a style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;" href="https://www.sec.gov/Archives/edgar/data/1662524/000104746917001995/a2231300zex-10_7.htm">Strategic Collaboration, Option and License Agreement by and among Akcea Therapeutics, Inc. and Novartis Pharma AG, dated January 5, 2017</a>,
            filed as an exhibit to Akcea Therapeutics, Inc.&#8217;s Form S-1 filed March 27, 2017 and incorporated herein by reference.</div>
        </td>

  </tr>

  <tr>

    <td style="width: 7.5%; vertical-align: top; background-color: #FFFFFF;" colspan="2">&#160;</td>

    <td style="width: 2.07%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 90.43%; vertical-align: top; background-color: #FFFFFF;" colspan="2">&#160;</td>

  </tr>

  <tr>

    <td style="width: 7.5%; vertical-align: top; background-color: #CCEEFF;" colspan="2">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">10.9</div>
        </td>

    <td style="width: 2.07%; vertical-align: bottom; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 90.43%; vertical-align: top; background-color: #CCEEFF;" colspan="2">
          <div style="text-align: justify; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><a style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;" href="https://www.sec.gov/Archives/edgar/data/1662524/000156459019018117/akca-ex101_176.htm">Amendment No. 1 to the Strategic Collaboration, Option and License Agreement between Akcea Therapeutics, Inc. and Novartis Pharma AG dated February
              22, 2019</a>, filed as an exhibit to Akcea Therapeutics, Inc.&#8217;s Quarterly Report on Form 10-Q for the quarter ended March 30, 2019 and incorporated herein by reference.</div>
        </td>

  </tr>

  <tr>

    <td style="width: 7.5%; vertical-align: top; background-color: #FFFFFF;" colspan="2">&#160;</td>

    <td style="width: 2.07%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 90.43%; vertical-align: top; background-color: #FFFFFF;" colspan="2">&#160;</td>

  </tr>

  <tr>

    <td style="width: 7.5%; vertical-align: top; background-color: #CCEEFF;" colspan="2">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">10.10</div>
        </td>

    <td style="width: 2.07%; vertical-align: bottom; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 90.43%; vertical-align: top; background-color: #CCEEFF;" colspan="2">
          <div style="text-align: justify; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><a style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;" href="https://www.sec.gov/Archives/edgar/data/874015/000087401517000033/ex10_2.htm">Stock Purchase Agreement among the Registrant, Akcea Therapeutics, Inc. and Novartis Pharma AG</a><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> dated January 5, 2017, filed as an exhibit to the Registrant&#8217;s Quarterly Report on Form 10-Q for the quarter ended March 31, 2017 and incorporated herein by reference.</span></div>
        </td>

  </tr>

  <tr>

    <td style="width: 7.5%; vertical-align: top; background-color: #FFFFFF;" colspan="2">&#160;</td>

    <td style="width: 2.07%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 90.43%; vertical-align: top; background-color: #FFFFFF;" colspan="2">&#160;</td>

  </tr>

  <tr>

    <td style="width: 7.5%; vertical-align: top; background-color: #CCEEFF;" colspan="2">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">10.11</div>
        </td>

    <td style="width: 2.07%; vertical-align: bottom; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 90.43%; vertical-align: top; background-color: #CCEEFF;" colspan="2">
          <div style="text-align: justify; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><a style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;" href="https://www.sec.gov/Archives/edgar/data/874015/000087401517000033/ex10_3.htm">Amendment #1 between the Registrant and Bayer AG dated February 10, 2017</a><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">, filed as an exhibit to the Registrant&#8217;s Quarterly Report on Form 10-Q for the quarter ended March 31, 2017 and incorporated herein by reference. Portions of this exhibit have been omitted and separately filed with the SEC with a
              request for confidential treatment.</span></div>
        </td>

  </tr>

  <tr>

    <td style="width: 7.5%; vertical-align: top; background-color: #FFFFFF;" colspan="2">&#160;</td>

    <td style="width: 2.07%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 90.43%; vertical-align: top; background-color: #FFFFFF;" colspan="2">&#160;</td>

  </tr>

  <tr>

    <td style="width: 7.5%; vertical-align: top; background-color: #CCEEFF;" colspan="2">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">10.12</div>
        </td>

    <td style="width: 2.07%; vertical-align: bottom; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 90.43%; vertical-align: top; background-color: #CCEEFF;" colspan="2">
          <div style="text-align: justify; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><a style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;" href="https://www.sec.gov/Archives/edgar/data/874015/000110465913081234/a13-19600_1ex10d4.htm">Registrant&#8217;s Amended and Restated 10b5-1 Trading Plan dated September 12, 2013</a><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">, filed as an exhibit to the Registrant&#8217;s Quarterly Report on Form 10-Q for the quarter ended September 30, 2013 and incorporated herein by reference.</span></div>
          <div>&#160;</div>
        </td>

  </tr>

  <tr>

    <td style="width: 7.5%; vertical-align: top; background-color: #FFFFFF;" colspan="2">&#160;</td>

    <td style="width: 2.07%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 90.43%; vertical-align: top; background-color: #FFFFFF;" colspan="2">&#160;</td>

  </tr>

  <tr>

    <td style="width: 7.5%; vertical-align: top; background-color: #CCEEFF;" colspan="2">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">10.13*</div>
        </td>

    <td style="width: 2.07%; vertical-align: bottom; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 90.43%; vertical-align: top; background-color: #CCEEFF;" colspan="2">
          <div style="text-align: justify; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><a style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;" href="https://www.sec.gov/Archives/edgar/data/874015/000114036120009606/nc10007589x2_def14a.htm">Registrant&#8217;s Amended and Restated 2002 Non-Employee Directors&#8217; Stock Option Plan, as amended</a><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">, filed as an exhibit to the Registrant&#8217;s Notice of Annual Meeting and Proxy Statement for the 2020 Annual Meeting of Stockholders, filed on April 24, 2020 and incorporated herein by reference.</span></div>
        </td>

  </tr>

  <tr>

    <td style="width: 7.5%; vertical-align: top; background-color: #FFFFFF;" colspan="2">&#160;</td>

    <td style="width: 2.07%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 90.43%; vertical-align: top; background-color: #FFFFFF;" colspan="2">&#160;</td>

  </tr>

  <tr>

    <td style="width: 7.5%; vertical-align: top; background-color: #CCEEFF;" colspan="2">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">10.14*</div>
        </td>

    <td style="width: 2.23%; vertical-align: bottom; background-color: #CCEEFF;" colspan="2">&#160;</td>

    <td style="width: 90.27%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: justify; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><a style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;" href="https://www.sec.gov/Archives/edgar/data/874015/000114036120017841/nt10014191x2_ex99-3.htm">Form of Restricted Stock Unit Agreement for Restricted Stock Units granted under the Ionis Pharmaceuticals, Inc. Amended and Restated 2002
              Non-Employee Directors&#8217; Stock Option Plan</a><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">, filed as an exhibit to the Registrant&#8217;s Registration Statement on Form S-8 filed on August 7, 2020 and
              incorporated herein by reference.</span></div>
        </td>

  </tr>

  <tr>

    <td style="width: 7.5%; vertical-align: top; background-color: #FFFFFF;" colspan="2">&#160;</td>

    <td style="width: 2.23%; vertical-align: bottom; background-color: #FFFFFF;" colspan="2">&#160;</td>

    <td style="width: 90.27%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

  </tr>

  <tr>

    <td style="width: 7.5%; vertical-align: top; background-color: #CCEEFF;" colspan="2">
          <div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">10.15</div>
        </td>

    <td style="width: 2.23%; vertical-align: bottom; background-color: #CCEEFF;" colspan="2">&#160;</td>

    <td style="width: 90.27%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: justify; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><a style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;" href="https://www.sec.gov/Archives/edgar/data/874015/000087401518000047/exhibit10_17.htm">Research Collaboration, Option and License Agreement between the Registrant and Biogen MA Inc.</a><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> dated December 19, 2017, filed as an exhibit to the Registrant&#8217;s Annual Report on Form 10-K for the year ended December 31, 2017 and incorporated herein by reference. Portions of this exhibit have been
              omitted and separately filed with the SEC with a request for confidential treatment.</span></div>
        </td>

  </tr>

  <tr>

    <td style="width: 7.5%; vertical-align: top; background-color: #FFFFFF;" colspan="2">&#160;</td>

    <td style="width: 2.23%; vertical-align: bottom; background-color: #FFFFFF;" colspan="2">&#160;</td>

    <td style="width: 90.27%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

  </tr>

  <tr>

    <td style="width: 7.5%; vertical-align: top; background-color: #CCEEFF;" colspan="2">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">10.16*</div>
        </td>

    <td style="width: 2.23%; vertical-align: bottom; background-color: #CCEEFF;" colspan="2">&#160;</td>

    <td style="width: 90.27%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: justify; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><a style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;" href="https://www.sec.gov/Archives/edgar/data/874015/000114036121013999/nc10023262x1_def14a.htm">Amended and Restated Ionis Pharmaceuticals, Inc. 2011 Equity Incentive Plan</a><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">, filed as an exhibit to the Registrant&#8217;s Notice of 2021 Annual Meeting of Stockholders and Proxy Statement filed on April 23, 2021 and incorporated herein by reference.</span></div>
        </td>

  </tr>


</table>
  <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" class="DSPFPageBreakArea">
    <div class="DSPFPageFooter">
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  <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; border-collapse: collapse; text-align: left; color: #000000;">


  <tr>

    <td style="width: 7.5%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">10.17*</div>
        </td>

    <td style="width: 2.23%; vertical-align: bottom; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 90.27%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: justify; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><a style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;" href="https://www.sec.gov/Archives/edgar/data/874015/000087401515000082/ex10_4.htm">Form of Option Agreement under the 2011 Equity Incentive Plan</a><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">,
              filed as an exhibit to the Registrant&#8217;s Quarterly Report on Form 10-Q for the quarter ended September 30, 2015 and incorporated herein by reference.</span></div>
        </td>

  </tr>

  <tr>

    <td style="width: 7.5%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 2.23%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 90.27%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

  </tr>

  <tr>

    <td style="width: 7.5%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">10.18*</div>
        </td>

    <td style="width: 2.23%; vertical-align: bottom; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 90.27%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: justify; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><a style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;" href="https://www.sec.gov/Archives/edgar/data/874015/000110465911044856/a11-23763_1ex99d3.htm">Form of Time-Vested Restricted Stock Unit Agreement for Restricted Stock Units granted under the 2011 Equity Incentive Plan</a><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">, filed as an exhibit to the Registrant&#8217;s Registration Statement on Form S-8 filed on August 8, 2011 and incorporated herein by reference.</span></div>
        </td>

  </tr>

  <tr>

    <td style="width: 7.5%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 2.23%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 90.27%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

  </tr>

  <tr>

    <td style="width: 7.5%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><a style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;" href="exhibit10-19.htm">10.19</a><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">*</span></div>
        </td>

    <td style="width: 2.23%; vertical-align: bottom; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 90.27%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: justify; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #0000FF;">Forms of Performance Based Restricted Stock Unit Grant
              Notice and Performance Based Restricted Stock Unit Agreement for Performance Based Restricted Stock Units granted under the 2011 Equity Incentive Plan</span><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">.</span></div>
        </td>

  </tr>

  <tr>

    <td style="width: 7.5%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 2.23%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 90.27%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

  </tr>

  <tr>

    <td style="width: 7.5%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">10.20*</div>
        </td>

    <td style="width: 2.23%; vertical-align: bottom; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 90.27%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: justify; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><a style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;" href="https://www.sec.gov/Archives/edgar/data/874015/000114036120030055/brhc10018560_ex99-1.htm">Ionis Pharmaceuticals, Inc. 2020 Equity Incentive Plan</a><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">, filed as an exhibit to the Registrant&#8217;s Registration Statement on Form S-8 filed on December 31, 2020 and incorporated herein by reference.</span></div>
        </td>

  </tr>

  <tr>

    <td style="width: 7.5%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 2.23%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 90.27%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

  </tr>

  <tr>

    <td style="width: 7.5%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">10.21*</div>
        </td>

    <td style="width: 2.23%; vertical-align: bottom; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 90.27%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: justify; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><a style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;" href="https://www.sec.gov/Archives/edgar/data/874015/000114036120030055/brhc10018560_ex99-2.htm">Form of Global Option Agreement for options granted under the Ionis Pharmaceuticals, Inc. 2020 Equity Incentive Plan</a><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">, filed as an exhibit to the Registrant&#8217;s Registration Statement on Form S-8 filed on December 31, 2020 and incorporated herein by reference.</span></div>
        </td>

  </tr>

  <tr>

    <td style="width: 7.5%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 2.23%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 90.27%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

  </tr>

  <tr>

    <td style="width: 7.5%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">10.22*</div>
        </td>

    <td style="width: 2.23%; vertical-align: bottom; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 90.27%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: justify; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><a style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;" href="https://www.sec.gov/Archives/edgar/data/874015/000114036120030055/brhc10018560_ex99-3.htm">Form of Global Restricted Stock Unit Agreement for restricted stock units granted under the Ionis Pharmaceuticals, Inc. 2020 Equity
                Incentive Plan</a><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">, filed as an exhibit to the Registrant&#8217;s Registration Statement on Form S-8 filed on December 31, 2020 and incorporated
              herein by reference.</span></div>
        </td>

  </tr>

  <tr>

    <td style="width: 7.5%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 2.23%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 90.27%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

  </tr>

  <tr>

    <td style="width: 7.5%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">10.23*</div>
        </td>

    <td style="width: 2.23%; vertical-align: bottom; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 90.27%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: justify; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><a style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;" href="https://www.sec.gov/Archives/edgar/data/874015/000114036120030055/brhc10018560_ex99-4.htm">Forms of Restricted Stock Unit Grant Notice, Stock Option Grant Notice and Stock Option Exercise Notice for options granted under the Ionis
              Pharmaceuticals, Inc. 2020 Equity Incentive Plan</a><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">, filed as an exhibit to the Registrant&#8217;s Registration Statement on Form S-8 filed on December
              31, 2020 and incorporated herein by reference.</span></div>
        </td>

  </tr>

  <tr>

    <td style="width: 7.5%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 2.23%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 90.27%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

  </tr>

  <tr>

    <td style="width: 7.5%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">10.24</div>
        </td>

    <td style="width: 2.23%; vertical-align: bottom; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 90.27%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: justify; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><a style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;" href="https://www.sec.gov/Archives/edgar/data/874015/000114036117028398/ex10_1.htm">Loan Agreement between Ionis Gazelle, LLC and UBS AG dated July 18, 2017</a><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">, filed as an exhibit to the Registrant&#8217;s Current Report on Form 8-K filed July 21, 2017 and incorporated herein by reference.</span></div>
        </td>

  </tr>

  <tr>

    <td style="width: 7.5%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 2.23%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 90.27%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

  </tr>

  <tr>

    <td style="width: 7.5%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">10.25*</div>
        </td>

    <td style="width: 2.23%; vertical-align: bottom; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 90.27%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: justify; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><a style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;" href="https://www.sec.gov/Archives/edgar/data/874015/000087401515000082/ex10_5.htm">Form of Option Agreement under the 1989 Stock Option Plan</a><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">,
              filed as an exhibit to the Registrant&#8217;s Quarterly Report on Form 10-Q for the quarter ended September 30, 2015 and incorporated herein by reference.</span></div>
        </td>

  </tr>

  <tr>

    <td style="width: 7.5%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 2.23%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 90.27%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

  </tr>

  <tr>

    <td style="width: 7.5%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">10.26*</div>
        </td>

    <td style="width: 2.23%; vertical-align: bottom; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 90.27%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: justify; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><a style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;" href="https://www.sec.gov/Archives/edgar/data/874015/000114036120017841/nt10014191x2_ex99-2.htm">Form of Option Agreement for Options granted under the 2002 Non-Employee Director&#8217;s Stock Option Plan</a><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">, filed as an exhibit to the Registrant&#8217;s Registration Statement on Form S-8 filed on August 7, 2020 and incorporated herein by reference.</span></div>
        </td>

  </tr>

  <tr>

    <td style="width: 7.5%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 2.23%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 90.27%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

  </tr>

  <tr>

    <td style="width: 7.5%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">10.27</div>
        </td>

    <td style="width: 2.23%; vertical-align: bottom; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 90.27%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: justify; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><a style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;" href="https://www.sec.gov/Archives/edgar/data/874015/000110465910026849/a10-5958_1ex10d5.htm">Research, Development and License Agreement between the Registrant and Glaxo Group Limited dated March 30, 2010</a><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">, filed as an exhibit to the Registrant&#8217;s Quarterly Report on Form 10-Q for the quarter ended March 31, 2010 and incorporated herein by reference. Portions of this exhibit have
              been omitted and separately filed with the SEC with a request for confidential treatment.</span></div>
        </td>

  </tr>

  <tr>

    <td style="width: 7.5%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 2.23%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 90.27%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

  </tr>

  <tr>

    <td style="width: 7.5%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">10.28</div>
        </td>

    <td style="width: 2.23%; vertical-align: bottom; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 90.27%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: justify; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><a style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;" href="https://www.sec.gov/Archives/edgar/data/874015/000114036117028398/ex10_2.htm">Loan Agreement between Ionis Faraday, LLC and UBS AG</a><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> dated
              July 18, 2017, filed as an exhibit to the Registrant&#8217;s Current Report on Form 8-K filed July 21, 2017 and incorporated herein by reference.</span></div>
        </td>

  </tr>

  <tr>

    <td style="width: 7.5%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 2.23%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 90.27%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

  </tr>

  <tr>

    <td style="width: 7.5%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">10.29</div>
        </td>

    <td style="width: 2.23%; vertical-align: bottom; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 90.27%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: justify; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><a style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;" href="https://www.sec.gov/Archives/edgar/data/874015/000110465911061713/a11-25667_1ex10d1.htm">Research Agreement dated August 10, 2011 between the Registrant and CHDI Foundation, Inc</a><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">, filed as an exhibit to the Registrant&#8217;s Quarterly Report on Form 10-Q for the quarter ended September 30, 2011 and incorporated herein by reference. Portions of this exhibit have been omitted and
              separately filed with the SEC with a request for confidential treatment.</span></div>
        </td>

  </tr>

  <tr>

    <td style="width: 7.5%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 2.23%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 90.27%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

  </tr>

  <tr>

    <td style="width: 7.5%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">10.30</div>
        </td>

    <td style="width: 2.23%; vertical-align: bottom; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 90.27%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: justify; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><a style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;" href="https://www.sec.gov/Archives/edgar/data/874015/000114036117028398/ex10_3.htm">Guaranty between the Registrant and UBS AG</a><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> dated July 18,
              2017, filed as an exhibit to the Registrant&#8217;s Current Report on Form 8-K filed July 21, 2017 and incorporated herein by reference.</span></div>
        </td>

  </tr>

  <tr>

    <td style="width: 7.5%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 2.23%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 90.27%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

  </tr>

  <tr>

    <td style="width: 7.5%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">10.31</div>
        </td>

    <td style="width: 2.23%; vertical-align: bottom; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 90.27%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: justify; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><a style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;" href="https://www.sec.gov/Archives/edgar/data/874015/000110465912034636/a12-6491_1ex10d1.htm">Development, Option and License Agreement between the Registrant and Biogen Idec International Holding Ltd. dated January 3, 2012</a><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">, filed as an exhibit to the Registrant&#8217;s Quarterly Report on Form 10-Q for the quarter ended March 31, 2012 and incorporated herein by reference. Portions
              of this exhibit have been omitted and separately filed with the SEC with a request for confidential treatment.</span></div>
        </td>

  </tr>

  <tr>

    <td style="width: 7.5%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 2.23%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 90.27%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

  </tr>

  <tr>

    <td style="width: 7.5%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">10.32</div>
        </td>

    <td style="width: 2.23%; vertical-align: bottom; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 90.27%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: justify; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><a style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;" href="https://www.sec.gov/Archives/edgar/data/874015/000110465912054509/a12-13652_1ex10d1.htm">DMPK Research, Development, Option and License Agreement between the Registrant and Biogen Idec MA Inc. dated June 27, 2012</a><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">, filed as an exhibit to the Registrant&#8217;s Quarterly Report on Form 10-Q for the quarter ended June 30, 2012 and incorporated herein by reference. Portions
              of this exhibit have been omitted and separately filed with the SEC with a request for confidential treatment.</span></div>
        </td>

  </tr>


</table>
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    <div class="DSPFPageFooter">
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    <div style="page-break-after:always;" class="DSPFPageBreak">
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  <tr>

    <td style="width: 7.5%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">10.33</div>
        </td>

    <td style="width: 2.23%; vertical-align: bottom; background-color: #CCEEFF;" colspan="2">&#160;</td>

    <td style="width: 90.27%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: justify; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><a style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;" href="https://www.sec.gov/Archives/edgar/data/874015/000110465913016208/a12-28450_1ex10d44.htm">Amendment #2 to Research, Development and License Agreement between the Registrant and Glaxo Group Limited dated October 30, 2012</a><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">, filed as an exhibit to the Registrant&#8217;s Annual Report on Form 10-K for the year ended December 31, 2012 and incorporated herein by reference. Portions of
              this exhibit have been omitted and separately filed with the SEC with a request for confidential treatment.</span></div>
        </td>

  </tr>

  <tr>

    <td style="width: 7.5%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 2.23%; vertical-align: bottom; background-color: #FFFFFF;" colspan="2">&#160;</td>

    <td style="width: 90.27%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

  </tr>

  <tr>

    <td style="width: 7.5%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">10.34</div>
        </td>

    <td style="width: 2.23%; vertical-align: bottom; background-color: #CCEEFF;" colspan="2">&#160;</td>

    <td style="width: 90.27%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: justify; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><a style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;" href="https://www.sec.gov/Archives/edgar/data/874015/000110465913016208/a12-28450_1ex10d45.htm">Collaboration, License and Development Agreement between the Registrant and AstraZeneca AB dated December 7, 2012</a><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">, filed as an exhibit to the Registrant&#8217;s Annual Report on Form 10-K for the year ended December 31, 2012 and incorporated herein by reference. Portions of this exhibit have been
              omitted and separately filed with the SEC with a request for confidential treatment.</span></div>
        </td>

  </tr>

  <tr>

    <td style="width: 7.5%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 2.23%; vertical-align: bottom; background-color: #FFFFFF;" colspan="2">&#160;</td>

    <td style="width: 90.27%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

  </tr>

  <tr>

    <td style="width: 7.64%; vertical-align: top; background-color: #CCEEFF;" colspan="2">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">10.35</div>
        </td>

    <td style="width: 2.09%; vertical-align: bottom; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 90.27%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: justify; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><a style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;" href="https://www.sec.gov/Archives/edgar/data/874015/000087401521000166/ex10-1.htm">Amended and Restated Neurology Drug Discovery and Development Collaboration, Option and License Agreement by and between the Registrant and Biogen MA Inc.
              dated July 12, 2021</a><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">, filed as an exhibit to the Registrant&#8217;s Quarterly Report on Form 10-Q for the quarter ended September 30, 2021 and
              incorporated herein by reference. Portions of this exhibit have been omitted because they are both (i) not material and (ii) would be competitively harmful if publicly disclosed.</span></div>
        </td>

  </tr>

  <tr>

    <td style="width: 7.64%; vertical-align: top; background-color: #FFFFFF;" colspan="2">&#160;</td>

    <td style="width: 2.09%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 90.27%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

  </tr>

  <tr>

    <td style="width: 7.64%; vertical-align: top; background-color: #CCEEFF;" colspan="2">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">10.36</div>
        </td>

    <td style="width: 2.09%; vertical-align: bottom; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 90.27%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: justify; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><a style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;" href="https://www.sec.gov/Archives/edgar/data/874015/000110465913060361/a13-13715_1ex10d1.htm">HTT Research, Development, Option and License Agreement among the Registrant, F. Hoffmann-La Roche Ltd and Hoffman-La Roche Inc. dated April 8,
              2013</a><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">, filed as an exhibit to the Registrant&#8217;s Quarterly Report on Form 10-Q for the quarter ended June 30, 2013 and incorporated herein by
              reference. Portions of this exhibit have been omitted and separately filed with the SEC with a request for confidential treatment.</span></div>
        </td>

  </tr>

  <tr>

    <td style="width: 7.64%; vertical-align: top; background-color: #FFFFFF;" colspan="2">&#160;</td>

    <td style="width: 2.09%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 90.27%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

  </tr>

  <tr>

    <td style="width: 7.64%; vertical-align: top; background-color: #CCEEFF;" colspan="2">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">10.37</div>
        </td>

    <td style="width: 2.09%; vertical-align: bottom; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 90.27%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: justify; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><a style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;" href="https://www.sec.gov/Archives/edgar/data/874015/000110465913060361/a13-13715_1ex10d2.htm">Letter Agreement between the Registrant and CHDI Foundation, Inc. dated April 8, 2013</a><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">, filed as an exhibit to the Registrant&#8217;s Quarterly Report on Form 10-Q for the quarter ended June 30, 2013 and incorporated herein by reference. Portions of this exhibit have been omitted and separately
              filed with the SEC with a request for confidential treatment.</span></div>
        </td>

  </tr>

  <tr>

    <td style="width: 7.64%; vertical-align: top; background-color: #FFFFFF;" colspan="2">&#160;</td>

    <td style="width: 2.09%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 90.27%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

  </tr>

  <tr>

    <td style="width: 7.64%; vertical-align: top; background-color: #CCEEFF;" colspan="2">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">10.38</div>
        </td>

    <td style="width: 2.09%; vertical-align: bottom; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 90.27%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: justify; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><a style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;" href="https://www.sec.gov/Archives/edgar/data/874015/000110465913081234/a13-19600_1ex10d2.htm">Amendment #1 to Collaboration, License and Development Agreement between the Registrant and AstraZeneca AB dated August 13, 2013</a><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">, filed as an exhibit to the Registrant&#8217;s Quarterly Report on Form 10-Q for the quarter ended September 30, 2013 and incorporated herein by reference.
              Portions of this exhibit have been omitted and separately filed with the SEC with a request for confidential treatment.</span></div>
        </td>

  </tr>

  <tr>

    <td style="width: 7.64%; vertical-align: top; background-color: #FFFFFF;" colspan="2">&#160;</td>

    <td style="width: 2.09%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 90.27%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

  </tr>

  <tr>

    <td style="width: 7.64%; vertical-align: top; background-color: #CCEEFF;" colspan="2">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">10.39</div>
        </td>

    <td style="width: 2.09%; vertical-align: bottom; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 90.27%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: justify; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><a style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;" href="https://www.sec.gov/Archives/edgar/data/874015/000114036114030549/ex10_1.htm">Amendment No. 3 to the Research, Development and License Agreement between the Registrant and Glaxo Group Limited dated July 10, 2013</a><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">, filed as an exhibit to the Registrant&#8217;s Quarterly Report on Form 10-Q for the quarter ended June 30, 2014 and incorporated herein by reference. Portions
              of this exhibit have been omitted and separately filed with the SEC with a request for confidential treatment.</span></div>
        </td>

  </tr>

  <tr>

    <td style="width: 7.64%; vertical-align: top; background-color: #FFFFFF;" colspan="2">&#160;</td>

    <td style="width: 2.09%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 90.27%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

  </tr>

  <tr>

    <td style="width: 7.64%; vertical-align: top; background-color: #CCEEFF;" colspan="2">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">10.40</div>
        </td>

    <td style="width: 2.09%; vertical-align: bottom; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 90.27%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: justify; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><a style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;" href="https://www.sec.gov/Archives/edgar/data/874015/000114036114030549/ex10_2.htm">Amendment #4 to the Research, Development and License Agreement between the Registrant and Glaxo Group Limited dated April 10, 2014</a><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">, filed as an exhibit to the Registrant&#8217;s Quarterly Report on Form 10-Q for the quarter ended June 30, 2014 and incorporated herein by reference. Portions of this exhibit
              have been omitted and separately filed with the SEC with a request for confidential treatment.</span></div>
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  </tr>

  <tr>

    <td style="width: 7.64%; vertical-align: top; background-color: #FFFFFF;" colspan="2">&#160;</td>

    <td style="width: 2.09%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 90.27%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

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  <tr>

    <td style="width: 7.64%; vertical-align: top; background-color: #CCEEFF;" colspan="2">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">10.41</div>
        </td>

    <td style="width: 2.09%; vertical-align: bottom; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 90.27%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: justify; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><a style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;" href="https://www.sec.gov/Archives/edgar/data/874015/000114036114030549/ex10_3.htm">Amendment #5 to the Research, Development and License Agreement among the Registrant, Glaxo Group Limited and GlaxoSmithKline Intellectual Property
              Development Limited dated June 27, 2014</a><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">, filed as an exhibit to the Registrant&#8217;s Quarterly Report on Form 10-Q for the quarter ended June 30,
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        </td>

  </tr>

  <tr>

    <td style="width: 7.64%; vertical-align: top; background-color: #FFFFFF;" colspan="2">&#160;</td>

    <td style="width: 2.09%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 90.27%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

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  <tr>

    <td style="width: 7.64%; vertical-align: top; background-color: #CCEEFF;" colspan="2">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">10.42</div>
        </td>

    <td style="width: 2.09%; vertical-align: bottom; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 90.27%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: justify; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><a style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;" href="https://www.sec.gov/Archives/edgar/data/874015/000087401514000095/ex10_1.htm">Exclusive License Agreement between the Registrant and the University of Massachusetts dated January 14, 2010</a><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">, filed as an exhibit to the Registrant&#8217;s Quarterly Report on Form 10-Q for the quarter ended September 30, 2014 and incorporated herein by reference. Portions of this exhibit have been
              omitted and separately filed with the SEC with a request for confidential treatment.</span></div>
        </td>

  </tr>

  <tr>

    <td style="width: 7.64%; vertical-align: top; background-color: #FFFFFF;" colspan="2">&#160;</td>

    <td style="width: 2.09%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 90.27%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

  </tr>

  <tr>

    <td style="width: 7.64%; vertical-align: top; background-color: #CCEEFF;" colspan="2">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">10.43</div>
        </td>

    <td style="width: 2.09%; vertical-align: bottom; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 90.27%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: justify; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><a style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;" href="https://www.sec.gov/Archives/edgar/data/874015/000087401514000095/ex10_2.htm">Amended and Restated Collaboration and License Agreement between the Registrant and Cold Spring Harbor Laboratory dated October 26, 2011</a><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">, filed as an exhibit to the Registrant&#8217;s Quarterly Report on Form 10-Q for the quarter ended September 30, 2014 and incorporated herein by reference.
              Portions of this exhibit have been omitted and separately filed with the SEC with a request for confidential treatment.</span></div>
        </td>

  </tr>

  <tr>

    <td style="width: 7.64%; vertical-align: top; background-color: #FFFFFF;" colspan="2">&#160;</td>

    <td style="width: 2.09%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 90.27%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

  </tr>

  <tr>

    <td style="width: 7.64%; vertical-align: top; background-color: #CCEEFF;" colspan="2">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">10.44</div>
        </td>

    <td style="width: 2.09%; vertical-align: bottom; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 90.27%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: justify; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><a style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;" href="https://www.sec.gov/Archives/edgar/data/874015/000087401514000095/ex10_3.htm">Amendment to Amended and Restated Collaboration and License Agreement between the Registrant and Cold Spring Harbor Laboratory dated March 14, 2014</a><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">, filed as an exhibit to the Registrant&#8217;s Quarterly Report on Form 10-Q for the quarter ended September 30, 2014 and incorporated herein by reference.
              Portions of this exhibit have been omitted and separately filed with the SEC with a request for confidential treatment.</span></div>
        </td>

  </tr>

  <tr>

    <td style="width: 7.64%; vertical-align: top; background-color: #FFFFFF;" colspan="2">&#160;</td>

    <td style="width: 2.09%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 90.27%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

  </tr>


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    <div class="DSPFPageFooter">
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  <tr>

    <td style="width: 7.64%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">10.45</div>
        </td>

    <td style="width: 2.09%; vertical-align: bottom; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 90.27%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: justify; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><a style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;" href="https://www.sec.gov/Archives/edgar/data/874015/000087401521000056/exhibit10_46.htm">Research Collaboration, Option and License Agreement between the Registrant and Janssen Biotech Inc. dated December 22, 2014</a><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #0000FF;">, </span>filed as an exhibit to the<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #0000FF;">&#160;</span><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">Registrant&#8217;s Annual Report on Form 10-K for the year ended December 31, 2020 and incorporated herein by reference. Portions of this exhibit have been omitted because they are both
              (i) not material and (ii) would be competitively harmful if publicly disclosed.</span></div>
        </td>

  </tr>

  <tr>

    <td style="width: 7.64%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 2.09%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 90.27%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

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  <tr>

    <td style="width: 7.64%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">10.46</div>
        </td>

    <td style="width: 2.09%; vertical-align: bottom; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 90.27%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: justify; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><a style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;" href="https://www.sec.gov/Archives/edgar/data/874015/000114036115009498/exhibit10_61.htm">Amendment No.2 to the Collaboration, License and Development Agreement between the Registrant and AstraZeneca AB dated October 15, 2014</a><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">, filed as an exhibit to the Registrant&#8217;s Annual Report on Form 10-K for the year ended December 31, 2014 and incorporated herein by reference. Portions of
              this exhibit have been omitted and separately filed with the SEC with a request for confidential treatment.</span></div>
        </td>

  </tr>

  <tr>

    <td style="width: 7.64%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 2.09%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 90.27%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

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  <tr>

    <td style="width: 7.64%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">10.47</div>
        </td>

    <td style="width: 2.09%; vertical-align: bottom; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 90.27%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: justify; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><a style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;" href="https://www.sec.gov/Archives/edgar/data/874015/000087401515000082/ex10_1.htm">Strategic Collaboration Agreement between the Registrant and AstraZeneca AB dated July 31, 2015</a><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">, filed as an exhibit to the Registrant&#8217;s Quarterly Report on Form 10-Q for the quarter ended September 30, 2015 and incorporated herein by reference. Portions of this exhibit have been omitted and
              separately filed with the SEC with a request for confidential treatment.</span></div>
        </td>

  </tr>

  <tr>

    <td style="width: 7.64%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 2.09%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 90.27%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

  </tr>

  <tr>

    <td style="width: 7.64%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">10.48</div>
        </td>

    <td style="width: 2.09%; vertical-align: bottom; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 90.27%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: justify; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><a style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;" href="https://www.sec.gov/Archives/edgar/data/874015/000087401515000082/ex10_2.htm">Amendment #6 to Research, Development and License Agreement between the Registrant, Glaxo Group Limited and GlaxoSmithKline Intellectual Property Development
              Limited dated September 2, 2015</a><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">, filed as an exhibit to the Registrant&#8217;s Quarterly Report on Form 10-Q for the quarter ended September 30, 2015
              and incorporated herein by reference. Portions of this exhibit have been omitted and separately filed with the SEC with a request for confidential treatment.</span></div>
        </td>

  </tr>

  <tr>

    <td style="width: 7.64%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 2.09%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 90.27%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

  </tr>

  <tr>

    <td style="width: 7.64%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">10.49</div>
        </td>

    <td style="width: 2.09%; vertical-align: bottom; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 90.27%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: justify; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><a style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;" href="https://www.sec.gov/Archives/edgar/data/874015/000087401515000082/ex10_3.htm">Amendment Number One to the Second Amended and Restated Strategic Collaboration and License Agreement between the Registrant and Alnylam Pharmaceuticals, Inc.
              dated July 13, 2015</a><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">, filed as an exhibit to the Registrant&#8217;s Quarterly Report on Form 10-Q for the quarter ended September 30, 2015 and
              incorporated herein by reference. Portions of this exhibit have been omitted and separately filed with the SEC with a request for confidential treatment.</span></div>
        </td>

  </tr>

  <tr>

    <td style="width: 7.64%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 2.09%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 90.27%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

  </tr>

  <tr>

    <td style="width: 7.64%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">10.50</div>
        </td>

    <td style="width: 2.09%; vertical-align: bottom; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 90.27%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: justify; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><a style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;" href="https://www.sec.gov/Archives/edgar/data/874015/000087401515000077/ex10_1.htm">License Agreement between the Registrant and Bayer Pharma AG dated May 1, 2015</a><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">, filed as an exhibit to the Registrant&#8217;s Quarterly Report on Form 10-Q for the quarter ended June 30, 2015 and incorporated herein by reference. Portions of this exhibit have been omitted and separately filed with the SEC
              with a request for confidential treatment.</span></div>
        </td>

  </tr>

  <tr>

    <td style="width: 7.64%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 2.09%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 90.27%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

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  <tr>

    <td style="width: 7.64%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">10.51</div>
        </td>

    <td style="width: 2.09%; vertical-align: bottom; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 90.27%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: justify; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><a style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;" href="https://www.sec.gov/Archives/edgar/data/874015/000087401515000057/ex10_1.htm">Second Amended and Restated Strategic Collaboration and License Agreement between the Registrant and Alnylam Pharmaceuticals, Inc. dated January 8, 2015</a><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">, filed as an exhibit to the Registrant&#8217;s Quarterly Report on Form 10-Q for the quarter ended March 31, 2015 and incorporated herein by reference. Portions
              of this exhibit have been omitted and separately filed with the SEC with a request for confidential treatment.</span></div>
        </td>

  </tr>

  <tr>

    <td style="width: 7.64%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 2.09%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 90.27%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

  </tr>

  <tr>

    <td style="width: 7.64%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">10.52</div>
        </td>

    <td style="width: 2.09%; vertical-align: bottom; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 90.27%; vertical-align: top; background-color: #CCEEFF;">
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              herein by reference. Portions of this exhibit have been omitted and separately filed with the SEC with a request for confidential treatment.</span></div>
        </td>

  </tr>

  <tr>

    <td style="width: 7.64%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 2.09%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 90.27%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

  </tr>

  <tr>

    <td style="width: 7.64%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">10.53</div>
        </td>

    <td style="width: 2.09%; vertical-align: bottom; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 90.27%; vertical-align: top; background-color: #CCEEFF;">
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              of this exhibit have been omitted and separately filed with the SEC with a request for confidential treatment.</span></div>
        </td>

  </tr>

  <tr>

    <td style="width: 7.64%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 2.09%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 90.27%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

  </tr>

  <tr>

    <td style="width: 7.64%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">10.54</div>
        </td>

    <td style="width: 2.09%; vertical-align: bottom; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 90.27%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: justify; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><a style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;" href="https://www.sec.gov/Archives/edgar/data/874015/000087401516000118/ex10_2.htm">Amendment #7 to the Research, Development and License Agreement among the Registrant, Glaxo Group Limited and GlaxoSmithKline Intellectual Property
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        </td>

  </tr>

  <tr>

    <td style="width: 7.64%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 2.09%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 90.27%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

  </tr>

  <tr>

    <td style="width: 7.64%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">10.55</div>
        </td>

    <td style="width: 2.09%; vertical-align: bottom; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 90.27%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: justify; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><a style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;" href="https://www.sec.gov/Archives/edgar/data/874015/000087401521000056/exhibit10_56.htm">First Amendment to Research Collaboration, Option and License Agreement between the Registrant and Janssen Biotech Inc. dated December 21, 2016</a><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #0000FF;">, </span>filed as an exhibit to the<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #0000FF;">&#160;</span><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">Registrant&#8217;s Annual Report on Form 10-K for the year ended December 31, 2020 and incorporated herein by reference. Portions of this exhibit have been
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        </td>

  </tr>

  <tr>

    <td style="width: 7.64%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 2.09%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 90.27%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

  </tr>

  <tr>

    <td style="width: 7.64%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">10.56</div>
        </td>

    <td style="width: 2.09%; vertical-align: bottom; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 90.27%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: justify; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><a style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;" href="https://www.sec.gov/Archives/edgar/data/874015/000114036117009823/exhibit10_61.htm">Letter Agreement between the Registrant and Biogen MA Inc. dated October 28, 2016</a><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">, filed as an exhibit to the Registrant&#8217;s Annual Report on Form 10-K for the year ended December 31, 2016 and incorporated herein by reference. Portions of this exhibit have been omitted and separately filed
              with the SEC with a request for confidential treatment.</span></div>
        </td>

  </tr>

  <tr>

    <td style="width: 7.64%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 2.09%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 90.27%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

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</table>
  <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" class="DSPFPageBreakArea">
    <div class="DSPFPageFooter">
      <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span class="DSPFPageNumber">88</span></div>

    </div>

    <div style="page-break-after:always;" class="DSPFPageBreak">
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  <tr>

    <td style="width: 7.64%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">10.57</div>
        </td>

    <td style="width: 1.94%; vertical-align: bottom; background-color: #CCEEFF;" colspan="2">&#160;</td>

    <td style="width: 90.42%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: justify; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><a style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;" href="https://www.sec.gov/Archives/edgar/data/874015/000114036117028398/ex10_4.htm">Guaranty between the Registrant and UBS AG dated July 18, 2017</a><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">,
              filed as an exhibit to the Registrant&#8217;s Current Report on Form 8-K filed July 21, 2017 and incorporated herein by reference.</span></div>
        </td>

  </tr>

  <tr>

    <td style="width: 7.64%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 1.94%; vertical-align: bottom; background-color: #FFFFFF;" colspan="2">&#160;</td>

    <td style="width: 90.42%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

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  <tr>

    <td style="width: 7.64%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">10.58</div>
        </td>

    <td style="width: 1.94%; vertical-align: bottom; background-color: #CCEEFF;" colspan="2">&#160;</td>

    <td style="width: 90.42%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: justify; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><a style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;" href="https://www.sec.gov/Archives/edgar/data/874015/000114036117028398/ex10_5.htm">Environmental Indemnity Agreement among the Registrant, Ionis Gazelle, LLC and UBS AG</a><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> dated July 18, 2017, filed as an exhibit to the Registrant&#8217;s Current Report on Form 8-K filed July 21, 2017 and incorporated herein by reference.</span></div>
        </td>

  </tr>

  <tr>

    <td style="width: 7.64%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 1.94%; vertical-align: bottom; background-color: #FFFFFF;" colspan="2">&#160;</td>

    <td style="width: 90.42%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

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  <tr>

    <td style="width: 7.64%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">10.59*</div>
        </td>

    <td style="width: 1.94%; vertical-align: bottom; background-color: #CCEEFF;" colspan="2">&#160;</td>

    <td style="width: 90.42%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: justify; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><a style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;" href="https://www.sec.gov/Archives/edgar/data/874015/000114036118040955/ex10_1.htm">Registrant&#8217;s Severance Benefit Plan and Summary Plan Description dated October 18, 2018</a><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">, filed as an exhibit to the Registrant&#8217;s Current Report on form 8-K filed October 18, 2018 and incorporated herein by reference.</span></div>
        </td>

  </tr>

  <tr>

    <td style="width: 7.64%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 1.94%; vertical-align: bottom; background-color: #FFFFFF;" colspan="2">&#160;</td>

    <td style="width: 90.42%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

  </tr>

  <tr>

    <td style="width: 7.64%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: left; color: #0000FF; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><a href="exhibit10-60.htm">10.60</a></div>
        </td>

    <td style="width: 1.94%; vertical-align: bottom; background-color: #CCEEFF;" colspan="2">&#160;</td>

    <td style="width: 90.42%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: justify; color: #0000FF; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Fourth Amended and Restated Strategic Advisory Services Agreement by and between the Registrant and B. Lynne Parshall, dated February
            22, 2022.</div>
        </td>

  </tr>

  <tr>

    <td style="width: 7.64%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 1.94%; vertical-align: bottom; background-color: #FFFFFF;" colspan="2">&#160;</td>

    <td style="width: 90.42%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

  </tr>

  <tr>

    <td style="width: 7.64%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">10.61</div>
        </td>

    <td style="width: 1.94%; vertical-align: bottom; background-color: #CCEEFF;" colspan="2">&#160;</td>

    <td style="width: 90.42%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: justify; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><a style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;" href="https://www.sec.gov/Archives/edgar/data/874015/000087401518000060/ex10_2.htm">Development, Commercialization, Collaboration, and License Agreement by and between the Registrant and Akcea Therapeutics, Inc.</a><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">, dated March 14, 2018, filed as an exhibit to the Registrant&#8217;s Quarterly Report on Form 10-Q for the quarter ended March 31, 2018 and incorporated herein by reference.</span></div>
        </td>

  </tr>

  <tr>

    <td style="width: 7.64%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 1.94%; vertical-align: bottom; background-color: #FFFFFF;" colspan="2">&#160;</td>

    <td style="width: 90.42%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

  </tr>

  <tr>

    <td style="width: 7.64%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">10.62</div>
        </td>

    <td style="width: 1.94%; vertical-align: bottom; background-color: #CCEEFF;" colspan="2">&#160;</td>

    <td style="width: 90.42%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: justify; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><a style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;" href="https://www.sec.gov/Archives/edgar/data/874015/000087401518000060/ex10_3.htm">Amended and Restated Services Agreement by and between the Registrant and Akcea Therapeutics, Inc.</a><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">, dated March 14, 2018, filed as an exhibit to the Registrant&#8217;s Quarterly Report on Form 10-Q for the quarter ended March 31, 2018 and incorporated herein by reference.</span></div>
        </td>

  </tr>

  <tr>

    <td style="width: 7.64%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 1.94%; vertical-align: bottom; background-color: #FFFFFF;" colspan="2">&#160;</td>

    <td style="width: 90.42%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

  </tr>

  <tr>

    <td style="width: 7.64%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">10.63</div>
        </td>

    <td style="width: 1.94%; vertical-align: bottom; background-color: #CCEEFF;" colspan="2">&#160;</td>

    <td style="width: 90.42%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: justify; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><a style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;" href="https://www.sec.gov/Archives/edgar/data/874015/000087401518000105/ex10_1.htm">New Strategic Neurology Drug Discovery and Development Collaboration, Option and License Agreement by and between the Registrant and Biogen MA Inc.</a><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">, dated April 19, 2018, filed as an exhibit to the Registrant&#8217;s Quarterly Report on Form 10-Q for the quarter ended June 30, 2018 and incorporated herein
              by reference. Portions of this exhibit have been omitted and separately filed with the SEC with a request for confidential treatment.</span></div>
        </td>

  </tr>

  <tr>

    <td style="width: 7.64%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 1.94%; vertical-align: bottom; background-color: #FFFFFF;" colspan="2">&#160;</td>

    <td style="width: 90.42%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

  </tr>

  <tr>

    <td style="width: 7.78%; vertical-align: top; background-color: #CCEEFF;" colspan="2">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">10.64</div>
        </td>

    <td style="width: 1.81%; vertical-align: bottom; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 90.42%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: justify; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><a style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;" href="https://www.sec.gov/Archives/edgar/data/874015/000087401518000105/ex10_2.htm">Stock Purchase Agreement by and between the Registrant and Biogen MA Inc.</a><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">, dated April 19, 2018, filed as an exhibit to the Registrant&#8217;s Quarterly Report on Form 10-Q for the quarter ended June 30, 2018 and incorporated herein by reference.</span></div>
        </td>

  </tr>

  <tr>

    <td style="width: 7.78%; vertical-align: top; background-color: #FFFFFF;" colspan="2">&#160;</td>

    <td style="width: 1.81%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 90.42%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

  </tr>

  <tr>

    <td style="width: 7.78%; vertical-align: top; background-color: #CCEEFF;" colspan="2">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">10.65</div>
        </td>

    <td style="width: 1.81%; vertical-align: bottom; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 90.42%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: justify; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><a style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;" href="https://www.sec.gov/Archives/edgar/data/874015/000087401518000128/ex10_1.htm">Second Amendment to Research, Collaboration, Option and License Agreement by and between the Registrant and Janssen Biotech Inc.</a><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">, dated August 7, 2018, filed as an exhibit to the Registrant&#8217;s Quarterly Report on Form 10-Q for the quarter ended September 30, 2018 and incorporated herein by reference.
              Portions of this exhibit have been omitted and separately filed with the SEC with a request for confidential treatment.</span></div>
        </td>

  </tr>

  <tr>

    <td style="width: 7.78%; vertical-align: top; background-color: #FFFFFF;" colspan="2">&#160;</td>

    <td style="width: 1.81%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 90.42%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

  </tr>

  <tr>

    <td style="width: 7.78%; vertical-align: top; background-color: #CCEEFF;" colspan="2">
          <div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">10.66</div>
        </td>

    <td style="width: 1.81%; vertical-align: bottom; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 90.42%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: justify; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><a style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;" href="https://www.sec.gov/Archives/edgar/data/874015/000087401519000045/exhibit10_67.htm">Factor B Development Collaboration, Option and License Agreement by and between the Registrant, F. Hoffmann-La Roche Ltd and Hoffmann-La Roche Inc.,
              dated October 9, 2018,</a><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> filed as an exhibit to the Registrant&#8217;s Annual Report on Form 10-K for the year ended December 31, 2018 and incorporated
              herein by reference. Portions of this exhibit have been omitted and separately filed with the SEC with a request for confidential treatment.</span></div>
        </td>

  </tr>

  <tr>

    <td style="width: 7.78%; vertical-align: top; background-color: #FFFFFF;" colspan="2">&#160;</td>

    <td style="width: 1.81%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 90.42%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

  </tr>

  <tr>

    <td style="width: 7.78%; vertical-align: top; background-color: #CCEEFF;" colspan="2">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">10.67</div>
        </td>

    <td style="width: 1.81%; vertical-align: bottom; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 90.42%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: justify; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><a style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;" href="https://www.sec.gov/Archives/edgar/data/874015/000087401519000045/exhibit10_68.htm">Second Amended and Restated Strategic Neurology Drug Discovery and Development Collaboration, Option and License Agreement by and between the Registrant
              and Biogen MA Inc., dated October 17, 2018</a><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">, filed as an exhibit to the Registrant&#8217;s Annual Report on Form 10-K for the year ended December 31,
              2018 and incorporated herein by reference. Portions of this exhibit have been omitted and separately filed with the SEC with a request for confidential treatment.</span></div>
        </td>

  </tr>

  <tr>

    <td style="width: 7.78%; vertical-align: top; background-color: #FFFFFF;" colspan="2">&#160;</td>

    <td style="width: 1.81%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 90.42%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

  </tr>

  <tr>

    <td style="width: 7.78%; vertical-align: top; background-color: #CCEEFF;" colspan="2">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">10.68</div>
        </td>

    <td style="width: 1.81%; vertical-align: bottom; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 90.42%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: justify; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><a style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;" href="https://www.sec.gov/Archives/edgar/data/874015/000087401519000045/exhibit10_69.htm">Amendment #1 to the Strategic Collaboration Agreement by and between the Registrant and AstraZeneca AB, dated October 18, 2018</a><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">, filed as an exhibit to the Registrant&#8217;s Annual Report on Form 10-K for the year ended December 31, 2018 and incorporated herein by reference. Portions of
              this exhibit have been omitted and separately filed with the SEC with a request for confidential treatment.</span></div>
        </td>

  </tr>

  <tr>

    <td style="width: 7.78%; vertical-align: top; background-color: #FFFFFF;" colspan="2">&#160;</td>

    <td style="width: 1.81%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 90.42%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

  </tr>

  <tr>

    <td style="width: 7.78%; vertical-align: top; background-color: #CCEEFF;" colspan="2">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">10.69</div>
        </td>

    <td style="width: 1.81%; vertical-align: bottom; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 90.42%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: justify; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><a style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;" href="https://www.sec.gov/Archives/edgar/data/874015/000087401519000045/exhibit10_70.htm">Amendment #4 to the Collaboration, License and Development Agreement by and between the Registrant and AstraZeneca AB, dated October 18, 2018</a><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">, filed as an exhibit to the Registrant&#8217;s Annual Report on Form 10-K for the year ended December 31, 2018 and incorporated herein by reference. Portions of
              this exhibit have been omitted and separately filed with the SEC with a request for confidential treatment.</span></div>
        </td>

  </tr>

  <tr>

    <td style="width: 7.78%; vertical-align: top; background-color: #FFFFFF;" colspan="2">&#160;</td>

    <td style="width: 1.81%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 90.42%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

  </tr>

  <tr>

    <td style="width: 7.78%; vertical-align: top; background-color: #CCEEFF;" colspan="2">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">10.70</div>
        </td>

    <td style="width: 1.81%; vertical-align: bottom; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 90.42%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: justify; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><a style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;" href="https://www.sec.gov/Archives/edgar/data/874015/000114036119014492/ex10_1.htm">Amendment #1 to Second Amended and Restated Strategic Neurology Drug Discovery and Development Collaboration, Option and License Agreement by and between the
              Registrant and Biogen MA Inc., dated May 2, 2019</a><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">, filed as an exhibit to the Registrant&#8217;s Quarterly Report on Form 10-Q for the quarter ended
              June 30, 2019 and incorporated herein by reference.</span></div>
        </td>

  </tr>

  <tr>

    <td style="width: 7.78%; vertical-align: top; background-color: #FFFFFF;" colspan="2">&#160;</td>

    <td style="width: 1.81%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 90.42%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

  </tr>


</table>
  <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" class="DSPFPageBreakArea">
    <div class="DSPFPageFooter">
      <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span class="DSPFPageNumber">89</span></div>

    </div>

    <div style="page-break-after:always;" class="DSPFPageBreak">
      <hr style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;" /></div>


  </div>

  <div><br />
  </div>

  <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; border-collapse: collapse; text-align: left; color: #000000;">


  <tr>

    <td style="width: 7.78%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">10.71</div>
        </td>

    <td style="width: 1.81%; vertical-align: bottom; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 90.42%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: justify; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><a style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;" href="https://www.sec.gov/Archives/edgar/data/874015/000087401519000130/ex10_1.htm">Amendment #1 to the New Strategic Neurology Drug Discovery and Development Collaboration, Option and License Agreement between the Registrant and Biogen MA
              Inc., dated August 16, 2019</a><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">, filed as an exhibit to the Registrant&#8217;s Quarterly Report on Form 10-Q for the quarter ended September 30, 2019 and
              incorporated herein by reference. Portions of this exhibit have been omitted because they are both (i) not material and (ii) would be competitively harmful if publicly disclosed.</span></div>
        </td>

  </tr>

  <tr>

    <td style="width: 7.78%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 1.81%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 90.42%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

  </tr>

  <tr>

    <td style="width: 7.78%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">10.72</div>
        </td>

    <td style="width: 1.81%; vertical-align: bottom; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 90.42%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: justify; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><a style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;" href="https://www.sec.gov/Archives/edgar/data/874015/000087401519000130/ex10_2.htm">Amendment #8 to the Research, Development and License Agreement between the Registrant, Glaxo Group Limited and Glaxosmithkline Intellectual Property
              Development Limited, dated July 29, 2019</a><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">, filed as an exhibit to the Registrant&#8217;s Quarterly Report on Form 10-Q for the quarter ended September
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        </td>

  </tr>

  <tr>

    <td style="width: 7.78%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 1.81%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 90.42%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

  </tr>

  <tr>

    <td style="width: 7.78%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">10.73</div>
        </td>

    <td style="width: 1.81%; vertical-align: bottom; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 90.42%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: justify; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><a style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;" href="https://www.sec.gov/Archives/edgar/data/874015/000087401519000130/ex10_3.htm">Consent to Collateral Addition and Amendment to Loan Documents between the Registrant, Ionis Gazelle, LLC, Wells Fargo Bank, National Association, as Trustee
              for the Benefit of the Registered Holders of UBS Commercial Mortgage Trust 2017-C3, Commercial Mortgage Pass-Through Certificates, Series 2017-C3, dated August 1, 2019</a><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">, filed as an exhibit to the Registrant&#8217;s Quarterly Report on Form 10-Q for the quarter ended September 30, 2019 and incorporated herein by reference.</span></div>
        </td>

  </tr>

  <tr>

    <td style="width: 7.78%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 1.81%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 90.42%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

  </tr>

  <tr>

    <td style="width: 7.78%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">10.74</div>
        </td>

    <td style="width: 1.81%; vertical-align: bottom; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 90.42%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: justify; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><a style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;" href="https://www.sec.gov/Archives/edgar/data/1662524/000156459020008119/akca-ex1015_357.htm">License Agreement by and among Akcea Therapeutics, Inc. and Pfizer Inc. dated October 4, 2019</a><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">, filed as an exhibit to Akcea Therapeutics, Inc.&#8217;s Annual Report on Form 10-K for the year ended December 31, 2019 and incorporated herein by reference.</span></div>
        </td>

  </tr>

  <tr>

    <td style="width: 7.78%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 1.81%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 90.42%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

  </tr>

  <tr>

    <td style="width: 7.78%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">10.75</div>
        </td>

    <td style="width: 1.81%; vertical-align: bottom; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 90.42%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: justify; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><a style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;" href="https://www.sec.gov/Archives/edgar/data/874015/000114036120004500/exhibit10_70.htm">Letter Agreement between the Registrant, Akcea Therapeutics, Inc., and Pfizer Inc., dated October 4, 2019</a><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">, filed as an exhibit to the Registrant&#8217;s Annual Report on Form 10-K for the year ended December 31, 2019 and incorporated herein by reference. Portions of this exhibit have been omitted
              because they are both (i) not material and (ii) would be competitively harmful if publicly disclosed.</span></div>
        </td>

  </tr>

  <tr>

    <td style="width: 7.78%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 1.81%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 90.42%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

  </tr>

  <tr>

    <td style="width: 7.78%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">10.76</div>
        </td>

    <td style="width: 1.81%; vertical-align: bottom; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 90.42%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: justify; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><a style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;" href="https://www.sec.gov/Archives/edgar/data/874015/000087401520000115/ex10_1.htm">Side Letter dated June 11, 2020 to the Second Amended and Restated Strategic Neurology Drug Discovery and Development Collaboration, Option and License
              Agreement by and between the Registrant and Biogen MA Inc. dated October 17, 2018</a><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">, filed as an exhibit to the Registrant&#8217;s Quarterly Report on
              Form 10-Q for the quarter ended June 30, 2020 and incorporated herein by reference. Portions of this exhibit have been omitted because they are both (i) not material and (ii) would be competitively harmful if publicly disclosed.</span></div>
        </td>

  </tr>

  <tr>

    <td style="width: 7.78%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 1.81%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 90.42%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

  </tr>

  <tr>

    <td style="width: 7.78%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">10.77</div>
        </td>

    <td style="width: 1.81%; vertical-align: bottom; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 90.42%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: justify; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><a style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;" href="https://www.sec.gov/Archives/edgar/data/874015/000087401520000115/ex10_2.htm">Amendment No. 2 dated April 30, 2020 to the Strategic Collaboration Agreement by and between the Registrant and AstraZeneca AB dated July 31, 2015</a><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">, filed as an exhibit to the Registrant&#8217;s Quarterly Report on Form 10-Q for the quarter ended June 30, 2020 and incorporated herein by reference. Portions
              of this exhibit have been omitted because they are both (i) not material and (ii) would be competitively harmful if publicly disclosed.</span></div>
        </td>

  </tr>

  <tr>

    <td style="width: 7.78%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 1.81%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 90.42%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

  </tr>

  <tr>

    <td style="width: 7.78%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">10.78</div>
        </td>

    <td style="width: 1.81%; vertical-align: bottom; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 90.42%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: justify; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><a style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;" href="https://www.sec.gov/Archives/edgar/data/874015/000087401521000074/ex10_1.htm">Letter agreement dated October 21, 2020 to the License Agreement by and among Akcea Therapeutics, Inc. and Pfizer Inc. dated October 4, 2019</a><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">, filed as an exhibit to the Registrant&#8217;s Quarterly Report on Form 10-Q for the quarter ended March 31, 2021 and incorporated herein by reference. Portions
              of this exhibit have been omitted because they are both (i) not material and (ii) would be competitively harmful if publicly disclosed.</span></div>
        </td>

  </tr>

  <tr>

    <td style="width: 7.78%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 1.81%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 90.42%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

  </tr>

  <tr>

    <td style="width: 7.78%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">10.79</div>
        </td>

    <td style="width: 1.81%; vertical-align: bottom; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 90.42%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: justify; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><a style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;" href="https://www.sec.gov/Archives/edgar/data/874015/000087401521000056/exhibit10_79.htm">Amendment No. 3 dated December 17, 2020 to the Strategic Collaboration Agreement by and between the Registrant and AstraZeneca AB dated July 31, 2015</a><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">, filed as an exhibit to the Registrant&#8217;s Annual Report on Form 10-K for the year ended December 31, 2020 and incorporated herein by reference. Portions of
              this exhibit have been omitted because they are both (i) not material and (ii) would be competitively harmful if publicly disclosed.</span></div>
        </td>

  </tr>

  <tr>

    <td style="width: 7.78%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 1.81%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 90.42%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

  </tr>

  <tr>

    <td style="width: 7.78%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">10.80</div>
        </td>

    <td style="width: 1.81%; vertical-align: bottom; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 90.42%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: justify; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><a style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;" href="https://www.sec.gov/Archives/edgar/data/874015/000087401521000056/exhibit10_80.htm">Strategic Advisory Services Agreement by and between the Registrant and Stanley T. Crooke, dated December 17, 2020</a><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">, filed as an exhibit to the Registrant&#8217;s Annual Report on Form 10-K for the year ended December 31, 2020 and incorporated herein by reference.</span></div>
        </td>

  </tr>

  <tr>

    <td style="width: 7.78%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 1.81%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 90.42%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

  </tr>

  <tr>

    <td style="width: 7.78%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">10.81</div>
        </td>

    <td style="width: 1.81%; vertical-align: bottom; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 90.42%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: justify; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><a style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;" href="https://www.sec.gov/Archives/edgar/data/874015/000087401521000056/exhibit10_81.htm">Side Letter dated December 31, 2020 to the New Strategic Neurology Drug Discovery and Development Collaboration, Option and License Agreement by and
              between the Registrant and Biogen MA Inc. dated April 19, 2018</a><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">, filed as an exhibit to the Registrant&#8217;s Annual Report on Form 10-K for the year
              ended December 31, 2020 and incorporated herein by reference. Portions of this exhibit have been omitted because they are both (i) not material and (ii) would be competitively harmful if publicly disclosed.</span></div>
        </td>

  </tr>

  <tr>

    <td style="width: 7.78%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 1.81%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 90.42%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

  </tr>


</table>
  <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" class="DSPFPageBreakArea">
    <div class="DSPFPageFooter">
      <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span class="DSPFPageNumber">90</span></div>

    </div>

    <div style="page-break-after:always;" class="DSPFPageBreak">
      <hr style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;" /></div>


  </div>

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  </div>

  <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; border-collapse: collapse; text-align: left; color: #000000;">


  <tr>

    <td style="width: 7.78%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">10.82</div>
        </td>

    <td style="width: 1.81%; vertical-align: bottom; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 90.42%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: justify; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><a style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;" href="https://www.sec.gov/Archives/edgar/data/874015/000087401521000166/ex10-2.htm">Collaboration and License Agreement by and between the Registrant and BicycleTX Limited dated July 9, 2021</a>, filed as an exhibit to the Registrant&#8217;s
            Quarterly Report on Form 10-Q for the quarter ended September 30, 2021 and incorporated herein by reference. Portions of this exhibit have been omitted because they are both (i) not material and (ii) would be competitively harmful if publicly
            disclosed.</div>
        </td>

  </tr>

  <tr>

    <td style="width: 7.78%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 1.81%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 90.42%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

  </tr>

  <tr>

    <td style="width: 7.78%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: left; color: #0000FF; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><a href="exhibit10-83.htm">10.83</a></div>
        </td>

    <td style="width: 1.81%; vertical-align: bottom; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 90.42%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Amendment No. 1 dated December 17, 2021 to the Collaboration and License Agreement by and between the Registrant and BicycleTX
            Limited dated July 9, 2021. Portions of this exhibit have been omitted because they are both (i) not material and (ii) would be competitively harmful if publicly disclosed.</div>
        </td>

  </tr>

  <tr>

    <td style="width: 7.78%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 1.81%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 90.42%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

  </tr>

  <tr>

    <td style="width: 7.78%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: left; color: #0000FF; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><a href="exhibit10-84.htm">10.84</a></div>
        </td>

    <td style="width: 1.81%; vertical-align: bottom; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 90.42%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Collaboration and License Agreement by and between Akcea Therapeutics, Inc. and AstraZeneca AB dated December 6, 2021.&#160; Portions of
            this exhibit have been omitted because they are both (i) not material and (ii) would be competitively harmful if publicly disclosed.</div>
        </td>

  </tr>

  <tr>

    <td style="width: 7.78%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 1.81%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 90.42%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

  </tr>

  <tr>

    <td style="width: 7.78%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: left; color: #0000FF; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><a href="exhibit21-1.htm">21.1</a></div>
        </td>

    <td style="width: 1.81%; vertical-align: bottom; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 90.42%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">List of Subsidiaries for the Registrant.</div>
        </td>

  </tr>

  <tr>

    <td style="width: 7.78%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 1.81%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 90.42%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

  </tr>

  <tr>

    <td style="width: 7.78%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: left; color: #0000FF; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><a href="exhibit23-1.htm">23.1</a></div>
        </td>

    <td style="width: 1.81%; vertical-align: bottom; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 90.42%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Consent of Independent Registered Public Accounting Firm.</div>
        </td>

  </tr>

  <tr>

    <td style="width: 7.78%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 1.81%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 90.42%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

  </tr>

  <tr>

    <td style="width: 7.78%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">24.1</div>
        </td>

    <td style="width: 1.81%; vertical-align: bottom; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 90.42%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Power of Attorney &#8211; Included on the signature page of this Annual Report on Form 10-K.</div>
        </td>

  </tr>

  <tr>

    <td style="width: 7.78%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 1.81%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 90.42%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

  </tr>

  <tr>

    <td style="width: 7.78%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: left; color: #0000FF; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><a href="exhibit31-1.htm">31.1</a></div>
        </td>

    <td style="width: 1.81%; vertical-align: bottom; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 90.42%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Certification by Chief Executive Officer Pursuant to 18 U.S.C. Section 1350 as Adopted Pursuant to Section 302 of the Sarbanes-Oxley
            Act of 2002.</div>
        </td>

  </tr>

  <tr>

    <td style="width: 7.78%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 1.81%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 90.42%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

  </tr>

  <tr>

    <td style="width: 7.78%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: left; color: #0000FF; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><a href="exhibit31-2.htm">31.2</a></div>
        </td>

    <td style="width: 1.81%; vertical-align: bottom; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 90.42%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Certification by Chief Financial Officer Pursuant to 18 U.S.C. Section 1350 as Adopted Pursuant to Section 302 of the Sarbanes-Oxley
            Act of 2002.</div>
        </td>

  </tr>

  <tr>

    <td style="width: 7.78%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 1.81%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 90.42%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

  </tr>

  <tr>

    <td style="width: 7.78%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><a style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;" href="exhibit32-1.htm">32.1</a><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">+</span></div>
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    <td style="width: 1.81%; vertical-align: bottom; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 90.42%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Certification Pursuant to 18 U.S.C. Section 1350 as Adopted Pursuant to Section 906 of the Sarbanes-Oxley Act of 2002.</div>
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    <td style="width: 7.78%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 1.81%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 90.42%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

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    <td style="width: 7.78%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">101</div>
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    <td style="width: 1.81%; vertical-align: bottom; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 90.42%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">The following financial statements from the Ionis Pharmaceuticals, Inc. Annual Report on Form 10-K for the year ended December 31, 2021, formatted in Extensive Business Reporting Language (XBRL): (i) consolidated balance sheets, (ii) consolidated statements of operations,
            (iii) consolidated statements of comprehensive income (loss), (iv) consolidated statements of stockholders&#8217; equity (v) consolidated statements of cash flows, and (vi) notes to consolidated financial statements (detail tagged).</div>
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    <td style="width: 7.78%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 1.81%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 90.42%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

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    <td style="width: 7.78%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">104</div>
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    <td style="width: 90.42%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Cover Page Interactive Data File (formatted in iXBRL and included in exhibit 101).</div>
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    <td style="width: 18pt; vertical-align: top; align: right; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">*</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Indicates management compensatory plans and arrangements as required to be filed as exhibits to this Report pursuant to Item 14(c).</div>
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    <td style="width: 18pt; vertical-align: top; align: right; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">+</td>

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          <div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;">This certification is deemed not filed for purposes of Section 18 of the Securities Exchange Act of 1934, as amended, or otherwise subject to the liability of that
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        </td>

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  <div><br />
  </div>

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  </div>

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      <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span class="DSPFPageNumber">91</span></div>

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  </div>

  <div><br />
  </div>

  <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">SIGNATURES</div>

  <div style="text-align: justify;"><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Pursuant to the requirements of Section 13 or 15(d) of the Securities Exchange Act of 1934, the Registrant has duly caused
    this report on Form 10-K to be signed on its behalf by the undersigned, thereunto duly authorized on the 24<sup>th</sup> day of February, 2022.</div>

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    <td style="width: 49.81%; vertical-align: top;">&#160;</td>

    <td style="width: 50.19%; vertical-align: top;" colspan="2">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">IONIS PHARMACEUTICALS, INC.</div>
        </td>

  </tr>

  <tr>

    <td style="width: 49.81%; vertical-align: top;">&#160;</td>

    <td style="width: 4.63%; vertical-align: top;">&#160;</td>

    <td style="width: 45.56%; vertical-align: top;">&#160;</td>

  </tr>

  <tr>

    <td style="width: 49.81%; vertical-align: top;">&#160;</td>

    <td style="width: 4.63%; vertical-align: top;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">By:</div>
        </td>

    <td style="width: 45.56%; vertical-align: top; border-bottom: #000000 2px solid;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">/s/ BRETT P. MONIA</div>
        </td>

  </tr>

  <tr>

    <td style="width: 49.81%; vertical-align: top;">&#160;</td>

    <td style="width: 4.63%; vertical-align: top;">&#160;</td>

    <td style="width: 45.56%; vertical-align: top;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Brett P. Monia, Ph.D.</div>
        </td>

  </tr>

  <tr>

    <td style="width: 49.81%; vertical-align: top;">&#160;</td>

    <td style="width: 4.63%; vertical-align: top;">&#160;</td>

    <td style="width: 45.56%; vertical-align: top;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;">Chief Executive Officer (Principal executive officer)</div>
        </td>

  </tr>


</table>
  <div style="text-align: center;"><br />
  </div>

  <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">POWER OF ATTORNEY</div>

  <div style="text-align: center;"><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">KNOW ALL MEN BY THESE PRESENTS, that each person whose signature appears below constitutes and appoints Brett P. Monia and
    Elizabeth L. Hougen, or any of them, his or her attorney-in-fact, each with the power of substitution, for him or her in any and all capacities, to sign any amendments to this Report, and to file the same, with exhibits thereto and other documents in
    connection therewith, with the Securities and Exchange Commission, hereby ratifying and confirming all that each of said attorneys-in-fact, or his or her substitute or substitutes, may do or cause to be done by virtue hereof.</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Pursuant to the requirements of the Securities Exchange Act of 1934, this report has been signed below by the following
    persons on behalf of the Registrant and in the capacities and on the dates indicated.</div>

  <div style="text-align: left;"><br />
  </div>

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    <td style="width: 2.05%; vertical-align: top;">&#160;</td>

    <td style="width: 49.28%; vertical-align: top; border-bottom: #000000 2px solid;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Title</div>
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    <td style="width: 2.22%; vertical-align: top;">&#160;</td>

    <td style="width: 16.06%; vertical-align: top; border-bottom: #000000 2px solid;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Date</div>
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    <td style="width: 30.39%; vertical-align: top;">&#160;</td>

    <td style="width: 2.05%; vertical-align: top;">&#160;</td>

    <td style="width: 49.28%; vertical-align: top;">&#160;</td>

    <td style="width: 2.22%; vertical-align: top;">&#160;</td>

    <td style="width: 16.06%; vertical-align: top;">&#160;</td>

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    <td style="width: 30.39%; vertical-align: top; border-bottom: #000000 2px solid;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">/s/ BRETT P. MONIA</div>
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    <td style="width: 49.28%; vertical-align: top;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Director and Chief Executive Officer</div>
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    <td style="width: 2.22%; vertical-align: top;">&#160;</td>

    <td style="width: 16.06%; vertical-align: top;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">February 24, 2022</div>
        </td>

  </tr>

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    <td style="width: 30.39%; vertical-align: top;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Brett P. Monia, Ph.D.</div>
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    <td style="width: 2.05%; vertical-align: top;">&#160;</td>

    <td style="width: 49.28%; vertical-align: top;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(Principal executive officer)</div>
        </td>

    <td style="width: 2.22%; vertical-align: top;">&#160;</td>

    <td style="width: 16.06%; vertical-align: top;">&#160;</td>

  </tr>

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    <td style="width: 30.39%; vertical-align: top;">&#160;</td>

    <td style="width: 2.05%; vertical-align: top;">&#160;</td>

    <td style="width: 49.28%; vertical-align: top;">&#160;</td>

    <td style="width: 2.22%; vertical-align: top;">&#160;</td>

    <td style="width: 16.06%; vertical-align: top;">&#160;</td>

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    <td style="width: 30.39%; vertical-align: top; border-bottom: #000000 2px solid;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">/s/ ELIZABETH L. HOUGEN</div>
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    <td style="width: 2.05%; vertical-align: top;">&#160;</td>

    <td style="width: 49.28%; vertical-align: top;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Executive Vice President, Finance and Chief Financial Officer</div>
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    <td style="width: 2.22%; vertical-align: top;">&#160;</td>

    <td style="width: 16.06%; vertical-align: top;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">February 24, 2022</div>
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    <td style="width: 30.39%; vertical-align: top;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Elizabeth L. Hougen</div>
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    <td style="width: 2.05%; vertical-align: top;">&#160;</td>

    <td style="width: 49.28%; vertical-align: top;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(Principal financial and accounting officer)</div>
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    <td style="width: 2.22%; vertical-align: top;">&#160;</td>

    <td style="width: 16.06%; vertical-align: top;">&#160;</td>

  </tr>

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    <td style="width: 30.39%; vertical-align: top;">&#160;</td>

    <td style="width: 2.05%; vertical-align: top;">&#160;</td>

    <td style="width: 49.28%; vertical-align: top;">&#160;</td>

    <td style="width: 2.22%; vertical-align: top;">&#160;</td>

    <td style="width: 16.06%; vertical-align: top;">&#160;</td>

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    <td style="width: 30.39%; vertical-align: top; border-bottom: #000000 2px solid;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">/s/ JOSEPH LOSCALZO</div>
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    <td style="width: 2.05%; vertical-align: top;">&#160;</td>

    <td style="width: 49.28%; vertical-align: top;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Chairman of the Board</div>
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    <td style="width: 2.22%; vertical-align: top;">&#160;</td>

    <td style="width: 16.06%; vertical-align: top;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">February 24, 2022</div>
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    <td style="width: 30.39%; vertical-align: top;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Joseph Loscalzo, M.D., Ph.D.</div>
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    <td style="width: 2.05%; vertical-align: top;">&#160;</td>

    <td style="width: 49.28%; vertical-align: top;">&#160;</td>

    <td style="width: 2.22%; vertical-align: top;">&#160;</td>

    <td style="width: 16.06%; vertical-align: top;">&#160;</td>

  </tr>

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    <td style="width: 30.39%; vertical-align: top;">&#160;</td>

    <td style="width: 2.05%; vertical-align: top;">&#160;</td>

    <td style="width: 49.28%; vertical-align: top;">&#160;</td>

    <td style="width: 2.22%; vertical-align: top;">&#160;</td>

    <td style="width: 16.06%; vertical-align: top;">&#160;</td>

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    <td style="width: 30.39%; vertical-align: top; border-bottom: #000000 2px solid;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">/s/ SPENCER R. BERTHELSEN</div>
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    <td style="width: 2.05%; vertical-align: top;">&#160;</td>

    <td style="width: 49.28%; vertical-align: top;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Director</div>
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    <td style="width: 2.22%; vertical-align: top;">&#160;</td>

    <td style="width: 16.06%; vertical-align: top;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">February 24, 2022</div>
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    <td style="width: 30.39%; vertical-align: top;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Spencer R. Berthelsen, M.D.</div>
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    <td style="width: 2.05%; vertical-align: top;">&#160;</td>

    <td style="width: 49.28%; vertical-align: top;">&#160;</td>

    <td style="width: 2.22%; vertical-align: top;">&#160;</td>

    <td style="width: 16.06%; vertical-align: top;">&#160;</td>

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    <td style="width: 30.39%; vertical-align: top;">&#160;</td>

    <td style="width: 2.05%; vertical-align: top;">&#160;</td>

    <td style="width: 49.28%; vertical-align: top;">&#160;</td>

    <td style="width: 2.22%; vertical-align: top;">&#160;</td>

    <td style="width: 16.06%; vertical-align: top;">&#160;</td>

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          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">/s/ ALLENE M. DIAZ</div>
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    <td style="width: 2.05%; vertical-align: top;">&#160;</td>

    <td style="width: 49.28%; vertical-align: top;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Director</div>
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    <td style="width: 2.22%; vertical-align: top;">&#160;</td>

    <td style="width: 16.06%; vertical-align: top;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">February 24, 2022</div>
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    <td style="width: 30.39%; vertical-align: top;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Allene M. Diaz</div>
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    <td style="width: 2.05%; vertical-align: top;">&#160;</td>

    <td style="width: 49.28%; vertical-align: top;">&#160;</td>

    <td style="width: 2.22%; vertical-align: top;">&#160;</td>

    <td style="width: 16.06%; vertical-align: top;">&#160;</td>

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    <td style="width: 30.39%; vertical-align: top;">&#160;</td>

    <td style="width: 2.05%; vertical-align: top;">&#160;</td>

    <td style="width: 49.28%; vertical-align: top;">&#160;</td>

    <td style="width: 2.22%; vertical-align: top;">&#160;</td>

    <td style="width: 16.06%; vertical-align: top;">&#160;</td>

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    <td style="width: 2.05%; vertical-align: top;">&#160;</td>

    <td style="width: 49.28%; vertical-align: top;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Director</div>
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    <td style="width: 2.22%; vertical-align: top;">&#160;</td>

    <td style="width: 16.06%; vertical-align: top;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">February 24, 2022</div>
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    <td style="width: 30.39%; vertical-align: top;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Michael Hayden, CM OBC MB ChB PhD FRCP(C) FRSC</div>
          <div>&#160;</div>
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    <td style="width: 2.05%; vertical-align: top;">&#160;</td>

    <td style="width: 49.28%; vertical-align: top;">&#160;</td>

    <td style="width: 2.22%; vertical-align: top;">&#160;</td>

    <td style="width: 16.06%; vertical-align: top;">&#160;</td>

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    <td style="width: 30.39%; vertical-align: top; border-bottom: #000000 2px solid;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">/s/ JOAN E. HERMAN</div>
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    <td style="width: 2.05%; vertical-align: top;">&#160;</td>

    <td style="width: 49.28%; vertical-align: top;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Director</div>
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    <td style="width: 2.22%; vertical-align: top;">&#160;</td>

    <td style="width: 16.06%; vertical-align: top;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">February 24, 2022</div>
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  <tr>

    <td style="width: 30.39%; vertical-align: top;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Joan E. Herman</div>
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    <td style="width: 2.05%; vertical-align: top;">&#160;</td>

    <td style="width: 49.28%; vertical-align: top;">&#160;</td>

    <td style="width: 2.22%; vertical-align: top;">&#160;</td>

    <td style="width: 16.06%; vertical-align: top;">&#160;</td>

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  <tr>

    <td style="width: 30.39%; vertical-align: top;">&#160;</td>

    <td style="width: 2.05%; vertical-align: top;">&#160;</td>

    <td style="width: 49.28%; vertical-align: top;">&#160;</td>

    <td style="width: 2.22%; vertical-align: top;">&#160;</td>

    <td style="width: 16.06%; vertical-align: top;">&#160;</td>

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          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">/s/ JOSEPH KLEIN</div>
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    <td style="width: 2.05%; vertical-align: top;">&#160;</td>

    <td style="width: 49.28%; vertical-align: top;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Director</div>
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    <td style="width: 2.22%; vertical-align: top;">&#160;</td>

    <td style="width: 16.06%; vertical-align: top;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">February 24, 2022</div>
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  <tr>

    <td style="width: 30.39%; vertical-align: top;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Joseph Klein, III</div>
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          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">/s/ FREDERICK T. MUTO</div>
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          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Director</div>
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          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">February 24, 2022</div>
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          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Frederick T. Muto, Esq.</div>
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          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">/s/ B. LYNNE PARSHALL</div>
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          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Director and Senior Strategic Advisor</div>
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          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">February 24, 2022</div>
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          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">B. Lynne Parshall, J.D.</div>
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          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">/s/ JOSEPH H. WENDER</div>
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          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Lead Independent Director</div>
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          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">February 24, 2022</div>
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          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Joseph H. Wender</div>
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  <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">IONIS PHARMACEUTICALS, INC.</div>

  <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><!--PROfilePageNumberReset%Num%1%%%--></div>

  <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">INDEX TO CONSOLIDATED FINANCIAL STATEMENTS</div>

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          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Page</div>
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          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 12pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Report of Independent Registered Public Accounting Firm
              (PCAOB ID <span style="-sec-ix-hidden:Fact_f9b9f674bc63468ab83af297625355ec">42</span>)</span></div>
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          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">F-2</div>
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          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 12pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Consolidated Balance Sheets at December 31, 2021 and 2020</span></div>
        </td>

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          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">F-4</div>
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          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 12pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Consolidated Statements of Operations for the years ended
              December 31, 2021, 2020
              and 2019</span></div>
        </td>

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          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">F-5</div>
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          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 12pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Consolidated Statements of Comprehensive Income (Loss) for
              the years ended December 31, 2021, 2020
              and 2019</span></div>
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          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">F-6</div>
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          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 12pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Consolidated Statements of Stockholders&#8217; Equity for the
              years ended December 31, 2021, 2020
              and 2019</span></div>
        </td>

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          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">F-7</div>
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          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 12pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Consolidated Statements of Cash Flows for the years ended
              December 31, 2021, 2020
              and 2019</span></div>
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          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">F-8</div>
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          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Notes to Consolidated Financial Statements</div>
        </td>

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          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">F-10</div>
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  <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">REPORT OF INDEPENDENT REGISTERED PUBLIC ACCOUNTING FIRM</div>

  <div style="text-align: center;"><br />
  </div>

  <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">To the Stockholders and Board of Directors of Ionis Pharmaceuticals, Inc.</div>

  <div><br />
  </div>

  <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Opinion on the Financial Statements</div>

  <div><br />
  </div>

  <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We have audited the accompanying consolidated balance sheets of Ionis Pharmaceuticals, Inc. (the Company) as of December 31, 2021 and 2020,
    the related consolidated statements of operations, comprehensive income (loss), stockholders&#8217; equity and cash flows for each of the three years in the period ended December 31, 2021, and the related notes (collectively referred to as the &#8220;consolidated
    financial statements&#8221;). In our opinion, the consolidated financial statements present fairly, in all material respects, the financial position of the Company at December 31, 2021 and 2020, and the results of its operations and its cash flows for each
    of the three years in the period ended December 31, 2021, in conformity with U.S. generally accepted accounting principles.</div>

  <div><br />
  </div>

  <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We also have audited, in accordance with the standards of the Public Company Accounting Oversight Board (United States) (PCAOB), the
    Company&#8217;s internal control over financial reporting as of December 31, 2021, based on criteria established in Internal Control &#8212; Integrated Framework issued by the Committee of Sponsoring Organizations of the Treadway Commission (2013 framework) and
    our report dated February 24, 2022 expressed an unqualified opinion thereon.</div>

  <div><br />
  </div>

  <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Adoption of ASU No. 2020-06</div>

  <div><br />
  </div>

  <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">As discussed in Note 1 to the consolidated financial statements, the Company changed its method of accounting for convertible instruments for
    all years presented, 2019 through 2021, due to the adoption of ASU No. 2020-06, <span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Debt&#8211;Debt with Conversion and Other Options (Subtopic 470-20) and
      Derivatives and Hedging&#8211;Contracts in Entity&#8217;s Own Equity (Subtopic 815-40): Accounting for Convertible Instruments and Contracts in an Entity&#8217;s Own Equity</span>.</div>

  <div><br />
  </div>

  <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Basis for Opinion</div>

  <div><br />
  </div>

  <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">These financial statements are the responsibility of the Company&#8217;s management. Our responsibility is to express an opinion on the Company&#8217;s
    financial statements based on our audits. We are a public accounting firm registered with the PCAOB and are required to be independent with respect to the Company in accordance with the U.S. federal securities laws and the applicable rules and
    regulations of the Securities and Exchange Commission and the PCAOB.</div>

  <div><br />
  </div>

  <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We conducted our audits in accordance with the standards of the PCAOB. Those standards require that we plan and perform the audit to obtain
    reasonable assurance about whether the financial statements are free of material misstatement, whether due to error or fraud. Our audits included performing procedures to assess the risks of material misstatement of the financial statements, whether
    due to error or fraud, and performing procedures that respond to those risks. Such procedures included examining, on a test basis, evidence regarding the amounts and disclosures in the financial statements. Our audits also included evaluating the
    accounting principles used and significant estimates made by management, as well as evaluating the overall presentation of the financial statements. We believe that our audits provide a reasonable basis for our opinion.</div>

  <div><br />
  </div>

  <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Critical Audit Matters</div>

  <div><br />
  </div>

  <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">The critical audit matters communicated below are matters arising from the current period audit of the financial statements that were
    communicated or required to be communicated to the audit committee and that: (1) relate to accounts or disclosures that are material to the financial statements and (2) involved our especially challenging, subjective or complex judgments. The
    communication of critical audit matters does not alter in any way our opinion on the consolidated financial statements, taken as a whole, and we are not, by communicating the critical audit matters below, providing a separate opinion on the critical
    audit matters or on the accounts or disclosures to which they relate.</div>

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          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic; font-weight: bold;">AstraZeneca &#8211; Eplontersen Collaboration</div>
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          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;">Description of the Matter</div>
        </td>

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    <td style="width: 81.74%; vertical-align: top;">
          <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">As discussed in Note 6 to the consolidated financial statements, the Company entered into a joint development and commercialization
            agreement with AstraZeneca AB (&#8220;AstraZeneca&#8221;), referred to as the &#8220;AstraZeneca agreement&#8221;, which resulted in the recognition of $200 million in revenue for the year ended December 31, 2021. The Company determined that there were four material
            components of the AstraZeneca agreement: (i) license granted to AstraZeneca to develop and commercialize eplontersen; (ii) the parties&#8217; co-development activities for eplontersen; (iii) the parties&#8217; co-commercialization activities for
            eplontersen; and (iv) the parties&#8217; co-medical affairs activities for eplontersen.</div>
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          <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Auditing management&#8217;s initial application of the relevant US GAAP guidance under Accounting Standards Codification (ASC) 606, Revenue
            from Contracts With Customers, and ASC 808, Collaborative Arrangements, related to the AstraZeneca Agreement was especially challenging due to the complex nature of its terms and conditions. In particular, determining the distinct performance
            obligations with a customer was highly judgmental.</div>
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          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;">How We Addressed the Matter in Our Audit</div>
        </td>

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    <td style="width: 81.74%; vertical-align: top;">
          <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We obtained an understanding, evaluated the design and tested the operating effectiveness of internal controls over management&#8217;s
            review of the terms and conditions of the AstraZeneca Agreement, identification of performance obligations, and consideration of the appropriate accounting guidance in determining the appropriate conclusions.</div>
          <div>&#160;</div>
          <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">To test management&#8217;s initial application of the accounting guidance to the AstraZeneca Agreement, we performed audit procedures that
            included, among others, reading the contractual agreement and assessing management&#8217;s application of the appropriate accounting guidance in their evaluation. Our procedures included evaluating management&#8217;s identification of distinct performance
            obligations with a customer. We also evaluated alternative views and any contrary or corroborative evidence associated with management&#8217;s evaluation, and discussed with management the underlying business objectives of the AstraZeneca Agreement.</div>
        </td>

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          <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic; font-weight: bold;">Estimated Liability for Clinical Development Costs</div>
          <div>&#160;</div>
        </td>

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          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;">Description of the Matter</div>
        </td>

    <td style="width: 2.85%; vertical-align: top;">&#160;</td>

    <td style="width: 81.74%; vertical-align: top;">
          <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">As of December 31, 2021, the Company accrued $65.7 million for accrued clinical development costs. As discussed in Note 2 to the
            consolidated financial statements, the Company records costs for clinical trial activities based upon estimates of costs incurred through the balance sheet date that have yet to be invoiced related to clinical management costs, laboratory and
            analysis costs, toxicology studies and investigator grants.</div>
          <div>&#160;</div>
          <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Auditing the Company&#8217;s accruals for clinical development costs is especially complex as the information necessary to estimate the
            accruals is accumulated from multiple sources. In addition, in certain circumstances, the determination of the nature and level of services that have been received during the reporting period requires judgment because the timing and pattern of
            vendor invoicing does not correspond to the level of services provided and there may be delays in invoicing from vendors.</div>
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          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;">How We Addressed the Matter in Our Audit</div>
        </td>

    <td style="width: 2.85%; vertical-align: top;">&#160;</td>

    <td style="width: 81.74%; vertical-align: top;">
          <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We obtained an understanding and evaluated the design and tested the operating effectiveness of controls over the accounting for
            accrued clinical development costs. This included controls over management&#8217;s assessment of the assumptions and accuracy of data underlying the accrued clinical development expenses estimate.</div>
          <div>&#160;</div>
          <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">To test the accuracy of the Company&#8217;s accrued clinical development costs, we performed audit procedures that included, among other
            procedures, obtaining supporting evidence of the research and development activities performed for significant clinical trials. We corroborated the status of significant clinical development costs through meetings with accounting and clinical
            project managers. We compared the costs for a sample of transactions against the related invoices and contracts, and examined a sample of subsequent payments to evaluate the accuracy of the accrued clinical development costs and compared the
            results to the current year accrual.</div>
        </td>

  </tr>


</table>
  <div><br />
  </div>

  <div><br />
  </div>

  <div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">/s/ <ix:nonNumeric name="dei:AuditorName" id="Fact_499e60cc06c04cbb9af98ac66184d658" contextRef="c20210101to20211231">Ernst &amp; Young LLP</ix:nonNumeric></div>

  <div><br />
  </div>

  <div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We have served as the Company&#8217;s auditor since 1989.</div>

  <div><br />
  </div>

  <div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonNumeric name="dei:AuditorLocation" id="Fact_f7f2808cf31c4a749453b2b079adfea9" contextRef="c20210101to20211231">San Diego, California</ix:nonNumeric></div>

  <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">February 24, 2022</div>

  <div><br />
  </div>

  <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" class="DSPFPageBreakArea">
    <div class="DSPFPageFooter">
      <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">F-<span class="DSPFPageNumber">3</span></div>

    </div>

    <div style="page-break-after:always;" class="DSPFPageBreak">
      <hr style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;" /></div>


  </div>

  <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">IONIS PHARMACEUTICALS, INC.</div>

  <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">CONSOLIDATED BALANCE SHEETS</div>

  <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">(In thousands, except share data)</div>

  <div><br />
  </div>

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  <tr>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">

        </td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" colspan="6">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">December 31,</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" colspan="2">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2021</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" colspan="2">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2020</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom;">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="2">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="2">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">(as revised*)</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom;">
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        </td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="2">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="2">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom;">
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        </td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="2">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="2">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 76%; background-color: #CCEEFF;">
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    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:CashAndCashEquivalentsAtCarryingValue" id="Fact_7d7f77575df24801aeb6d430b5e2aea9" contextRef="c20201231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">397,664</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 76%;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 18pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Short-term investments</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:AvailableForSaleSecuritiesDebtSecuritiesCurrent" id="Fact_f2286909ac5641e29bb72849f613afb8" contextRef="c20211231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">1,245,782</ix:nonFraction></div>
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 76%; background-color: #CCEEFF;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 18pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Contracts receivable</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 76%;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 18pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Inventories</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 76%; padding-bottom: 2px; background-color: #CCEEFF;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 18pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Other current assets</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:OtherAssetsCurrent" id="Fact_ea0ef4e752a74ed2b3d6cfb2d9a33c46" contextRef="c20211231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">143,374</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 76%;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 27pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Total current assets</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 76%; background-color: #CCEEFF;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Property, plant and equipment, net</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 76%;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Patents, net</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 76%; padding-bottom: 2px; background-color: #CCEEFF;">
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    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 76%; padding-bottom: 4px;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Total assets</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 76%; background-color: #CCEEFF;">
          <div style="text-align: center; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">LIABILITIES
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        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 76%;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Current liabilities:</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 76%; background-color: #CCEEFF;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 18pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Accounts payable</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:AccountsPayableCurrent" id="Fact_d2f4209896534c34b236247e2f014047" contextRef="c20211231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">11,904</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:AccountsPayableCurrent" id="Fact_4a77a0a95bc24ec9879730f3c54c5767" contextRef="c20201231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">17,199</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 76%;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 18pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Accrued compensation</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:EmployeeRelatedLiabilitiesCurrent" id="Fact_6757e467d4ca4989a92e1b0146882726" contextRef="c20211231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">38,810</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:EmployeeRelatedLiabilitiesCurrent" id="Fact_e13f67f862ed4bf9b0ccd8241eabef36" contextRef="c20201231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">65,728</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 76%; background-color: #CCEEFF;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 18pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Accrued liabilities</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:AccruedLiabilitiesCurrent" id="Fact_70b781ca48864bb9b31bb2272f1c75fd" contextRef="c20211231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">88,560</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:AccruedLiabilitiesCurrent" id="Fact_969294300c9b472f89e106ba0b60bd69" contextRef="c20201231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">90,161</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 76%;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 18pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Income taxes payable</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:AccruedIncomeTaxesCurrent" id="Fact_0ac97222f6364543b31753077f08b8f9" contextRef="c20211231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">36</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:AccruedIncomeTaxesCurrent" id="Fact_924182cca560478288901c6e2b93dbec" contextRef="c20201231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">1,324</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 76%; background-color: #CCEEFF;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 18pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="text-indent: 0pt;"><ix:nonFraction name="us-gaap:DebtInstrumentInterestRateStatedPercentage" id="Fact_39d5a3a53e5248cc80afe777746fa9c2" contextRef="c20201231_DebtInstrumentAxis_ConvertibleSeniorNotes1PercentMember" unitRef="U003" decimals="2" scale="-2" format="ixt:numdotdecimal"><ix:nonFraction name="us-gaap:DebtInstrumentInterestRateStatedPercentage" id="Fact_b46b772e4c824409a6790433f9d2595c" contextRef="c20211231_DebtInstrumentAxis_ConvertibleSeniorNotes1PercentMember" unitRef="U003" decimals="2" scale="-2" format="ixt:numdotdecimal">1</ix:nonFraction></ix:nonFraction> percent</span> convertible senior notes, net</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:ConvertibleDebtCurrent" id="Fact_a6d3c639a96b430cbd40608aaee204de" contextRef="c20211231" unitRef="U001" decimals="-3" scale="3" format="ixt:zerodash">&#8212;</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:ConvertibleDebtCurrent" id="Fact_46f8c4b40e45494fa43b881a701c30ef" contextRef="c20201231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">308,809</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 76%;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 18pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Current portion of long-term obligations</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="ions:LongTermObligationsExcludingConvertibleDebtCurrent" id="Fact_c3dd012ae5014734b3edfded476645f1" contextRef="c20211231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">3,526</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="ions:LongTermObligationsExcludingConvertibleDebtCurrent" id="Fact_b637339218424d74ba82205fd72c11a5" contextRef="c20201231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">7,301</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 76%; padding-bottom: 2px; background-color: #CCEEFF;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 18pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Current portion of deferred contract revenue</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:ContractWithCustomerLiabilityCurrent" id="Fact_dde59dcefdfc41a5aece21fc7e36d234" contextRef="c20211231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">97,714</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:ContractWithCustomerLiabilityCurrent" id="Fact_b5c48cb25c964d7c97633d915cafdb42" contextRef="c20201231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">108,376</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 76%;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 27pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Total current liabilities</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 76%; background-color: #CCEEFF;">
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    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 76%;">
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        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 76%; background-color: #CCEEFF;">
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        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 76%;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Long-term obligations, less current portion</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 76%; padding-bottom: 2px; background-color: #CCEEFF;">
          <div style="text-align: left; text-indent: -36pt; margin-left: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Long-term mortgage debt</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:LongTermLoansFromBank" id="Fact_d0bdde965a494bd1967c669121c18b69" contextRef="c20211231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">59,713</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:LongTermLoansFromBank" id="Fact_b1093c295a3e4d8980c112cd144aa095" contextRef="c20201231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">59,984</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 76%;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Total liabilities</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:Liabilities" id="Fact_72e72fa97a344884ae45c7d1457d4c58" contextRef="c20211231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">1,839,953</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:Liabilities" id="Fact_e80cd271efab4a4c8c3d5beb70de894b" contextRef="c20201231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">1,646,473</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 76%; background-color: #CCEEFF;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Stockholders&#8217; equity:</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 76%;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 18pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Common stock, $<span style="text-indent: 0pt;"><ix:nonFraction name="us-gaap:CommonStockParOrStatedValuePerShare" id="Fact_633d3f736e2247d291880fed08c8de60" contextRef="c20201231" unitRef="U004" decimals="3" scale="0" format="ixt:numdotdecimal"><ix:nonFraction name="us-gaap:CommonStockParOrStatedValuePerShare" id="Fact_3582d99df2904a4ab26bce510bf362eb" contextRef="c20211231" unitRef="U004" decimals="3" scale="0" format="ixt:numdotdecimal">0.001</ix:nonFraction></ix:nonFraction></span> par value; <span style="text-indent: 0pt;"><ix:nonFraction name="us-gaap:CommonStockSharesAuthorized" id="Fact_9a0912d45871495e9d5ffb48117b86ac" contextRef="c20201231" unitRef="U002" decimals="0" scale="0" format="ixt:numdotdecimal"><ix:nonFraction name="us-gaap:CommonStockSharesAuthorized" id="Fact_7cf23bc0b3da4da3818fa69653f089c6" contextRef="c20211231" unitRef="U002" decimals="0" scale="0" format="ixt:numdotdecimal">300,000,000</ix:nonFraction></ix:nonFraction></span> shares authorized, <span style="text-indent: 0pt;"><ix:nonFraction name="us-gaap:CommonStockSharesOutstanding" id="Fact_6b03136461bc406ab4ea599c454895bc" contextRef="c20211231" unitRef="U002" decimals="0" scale="0" format="ixt:numdotdecimal"><ix:nonFraction name="us-gaap:CommonStockSharesIssued" id="Fact_83959e73ecef45b7bf3b111575f95c72" contextRef="c20211231" unitRef="U002" decimals="0" scale="0" format="ixt:numdotdecimal">141,210,015</ix:nonFraction></ix:nonFraction></span> and <span style="text-indent: 0pt;"><ix:nonFraction name="us-gaap:CommonStockSharesOutstanding" id="Fact_ae85ba7613de4a38acdf354791b136fa" contextRef="c20201231" unitRef="U002" decimals="0" scale="0" format="ixt:numdotdecimal"><ix:nonFraction name="us-gaap:CommonStockSharesIssued" id="Fact_2e7ea39c8d104a0ca5cf2a5f9cdbc016" contextRef="c20201231" unitRef="U002" decimals="0" scale="0" format="ixt:numdotdecimal">140,365,594</ix:nonFraction></ix:nonFraction></span>
            shares issued and outstanding at December 31, <span style="text-indent: 0pt;">2021</span> and December 31, <span style="text-indent: 0pt;">2020</span>, respectively</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:CommonStockValue" id="Fact_5f48063ae846417a85a50e82db398716" contextRef="c20211231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">141</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:CommonStockValue" id="Fact_942a957fd1a642b4a9846b941b383984" contextRef="c20201231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">140</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 76%; background-color: #CCEEFF;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 18pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Additional paid-in capital</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:AdditionalPaidInCapitalCommonStock" id="Fact_3f85039492a3477ba262bbaf1e3a9940" contextRef="c20211231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">1,964,167</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:AdditionalPaidInCapitalCommonStock" id="Fact_a0bd160ae16c4b96869235d0b1952ae3" contextRef="c20201231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">1,895,519</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 76%;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 18pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Accumulated other comprehensive loss</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:AccumulatedOtherComprehensiveIncomeLossNetOfTax" id="Fact_7f6094dad8014d18a90ab96ded5f7902" contextRef="c20211231" unitRef="U001" decimals="-3" scale="3" sign="-" format="ixt:numdotdecimal">32,668</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">
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        </td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 76%; padding-bottom: 2px; background-color: #CCEEFF;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 18pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Accumulated deficit</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 76%; padding-bottom: 2px;">
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        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 76%; padding-bottom: 4px; background-color: #CCEEFF;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Total liabilities and stockholders&#8217; equity</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:LiabilitiesAndStockholdersEquity" id="Fact_52b3ab3e91024ab988399c759f32bda8" contextRef="c20201231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">2,389,755</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>


</table>
  <div><br />
  </div>

  <div><br />
  </div>

  <table cellspacing="0" cellpadding="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">


  <tr>

    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">*</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We revised our 2020 amounts to reflect the simplified convertible instruments accounting guidance, which we adopted retrospectively. Refer to Note 1, <span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Organization and Significant Accounting Policies</span>, for further information.</div>
        </td>

  </tr>


</table>
  <div><br />
  </div>

  <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">See accompanying notes.</div>

  <div><br />
  </div>

  <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" class="DSPFPageBreakArea">
    <div class="DSPFPageFooter">
      <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">F-<span class="DSPFPageNumber">4</span></div>

    </div>

    <div style="page-break-after:always;" class="DSPFPageBreak">
      <hr style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;" /></div>


  </div>

  <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">IONIS PHARMACEUTICALS, INC.</div>

  <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">CONSOLIDATED STATEMENTS OF OPERATIONS</div>

  <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">(In thousands, except for per share amounts)</div>

  <div><br />
  </div>

  <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;" class="cfttable">


  <tr>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">

        </td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" colspan="10">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Year Ended December 31,</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" colspan="2">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2021</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" colspan="2">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2020</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" colspan="2">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2019</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom;">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="2">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="2">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">(as revised*)</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="2">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">(as revised*)</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Revenue:</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="2">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="2">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="2">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 18pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Commercial revenue:</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="2">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="2">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="2">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;">
          <div style="text-align: left; text-indent: 8.85pt; margin-left: 18pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">SPINRAZA royalties</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:RevenueFromContractWithCustomerExcludingAssessedTax" id="Fact_fdaf4e7de3e14bc88036b45f358b0bc2" contextRef="c20210101to20211231_ProductOrServiceAxis_SpinrazaRoyaltiesMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">267,776</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:RevenueFromContractWithCustomerExcludingAssessedTax" id="Fact_7043d15f95394ffe96f0662fa9fad2fa" contextRef="c20200101to20201231_ProductOrServiceAxis_SpinrazaRoyaltiesMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">286,583</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:RevenueFromContractWithCustomerExcludingAssessedTax" id="Fact_ac6e240eca5848d5badb78f0ca60c1a3" contextRef="c20190101to20191231_ProductOrServiceAxis_SpinrazaRoyaltiesMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">292,992</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 64%;">
          <div style="text-align: left; text-indent: 8.85pt; margin-left: 18pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">TEGSEDI and WAYLIVRA revenue, net</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:RevenueFromContractWithCustomerExcludingAssessedTax" id="Fact_e82af709616c487887988783c2c8d9c7" contextRef="c20210101to20211231_ProductOrServiceAxis_ProductMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">55,500</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:RevenueFromContractWithCustomerExcludingAssessedTax" id="Fact_a83fa126a57b41d599f30e7cad218b6c" contextRef="c20200101to20201231_ProductOrServiceAxis_ProductMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">69,999</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:RevenueFromContractWithCustomerExcludingAssessedTax" id="Fact_ad9a698af9f24b05865de462af852631" contextRef="c20190101to20191231_ProductOrServiceAxis_ProductMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">42,253</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #CCEEFF;">
          <div style="text-align: left; text-indent: 8.85pt; margin-left: 18pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Licensing and other royalty revenue</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:RevenueFromContractWithCustomerExcludingAssessedTax" id="Fact_573e884a4bdb425aa0b05fe6b144961b" contextRef="c20210101to20211231_ProductOrServiceAxis_LicensingAndOtherRoyaltiesMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">19,119</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 64%;">
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    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #CCEEFF;">
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    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 2px;">
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    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" colspan="1">
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" colspan="1">
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" colspan="1">
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 64%;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Expenses:</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 18pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Cost of sales</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:CostOfGoodsAndServicesSold" id="Fact_284d13f3b0c542e2be15e9d709d0fa47" contextRef="c20210101to20211231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">10,842</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 64%;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 18pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Research, development and patent</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #CCEEFF;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 18pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Selling, general and administrative</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:SellingGeneralAndAdministrativeExpense" id="Fact_45acc2391f3d437c94c32375af3fd727" contextRef="c20210101to20211231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">186,347</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:SellingGeneralAndAdministrativeExpense" id="Fact_4b516d97f3e644e3bebe35a3e962a2d3" contextRef="c20200101to20201231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">354,322</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 2px;">
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    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" colspan="1">
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" colspan="1">
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" colspan="1">
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

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  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 64%;">
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        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 64%;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Other income (expense):</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 18pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Investment income</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 64%;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 18pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Interest expense</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:InterestExpense" id="Fact_47eb0551e96b4a789a0b721ce64eef0f" contextRef="c20210101to20211231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">9,349</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 18pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Gain on investments</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 64%;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 18pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Loss on early retirement of debt</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #CCEEFF;">
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        </td>

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          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

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          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
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    <td valign="bottom" style="vertical-align: bottom; width: 64%;">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

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  <tr>

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    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
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    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
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    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

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  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 64%;">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #CCEEFF;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Income tax benefit (expense)</div>
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    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
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    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:IncomeTaxExpenseBenefit" id="Fact_4e00bc85f9de44bc9fae3e310059dd54" contextRef="c20190101to20191231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">51,507</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
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  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 64%;">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Net income (loss)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:ProfitLoss" id="Fact_eed2832b2f23443a8a7b6a11b3b5c8be" contextRef="c20210101to20211231" unitRef="U001" decimals="-3" scale="3" sign="-" format="ixt:numdotdecimal">28,597</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:ProfitLoss" id="Fact_17fba83bb5c645feab5192b45331713f" contextRef="c20200101to20201231" unitRef="U001" decimals="-3" scale="3" sign="-" format="ixt:numdotdecimal">479,743</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:ProfitLoss" id="Fact_1b16a95e7fa948b78f84194e8da4f693" contextRef="c20190101to20191231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">287,259</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 64%;">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #CCEEFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Net (income) loss attributable to noncontrolling interest in Akcea Therapeutics, Inc.</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:NetIncomeLossAttributableToNoncontrollingInterest" id="Fact_39c266b37a4b4b75807a14eb73538310" contextRef="c20210101to20211231" unitRef="U001" decimals="-3" scale="3" format="ixt:zerodash">&#8212;</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:NetIncomeLossAttributableToNoncontrollingInterest" id="Fact_498b97278bb645e598fad5c547449f5f" contextRef="c20200101to20201231" unitRef="U001" decimals="-3" scale="3" sign="-" format="ixt:numdotdecimal">35,480</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 64%;">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

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  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 4px; background-color: #CCEEFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Net income (loss) attributable to Ionis Pharmaceuticals, Inc. common stockholders</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:NetIncomeLoss" id="Fact_d67d140ccc41433e809a30cd81e184e2" contextRef="c20210101to20211231" unitRef="U001" decimals="-3" scale="3" sign="-" format="ixt:numdotdecimal">28,597</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:NetIncomeLoss" id="Fact_41f8afe988ab4add8c88a8e7caefd925" contextRef="c20200101to20201231" unitRef="U001" decimals="-3" scale="3" sign="-" format="ixt:numdotdecimal">444,263</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:NetIncomeLoss" id="Fact_bb9a33cf051a47359fe47c04a4566435" contextRef="c20190101to20191231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">278,143</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 4px;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Basic net income (loss) per share</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:EarningsPerShareBasic" id="Fact_ad4c690aa177438c98b7e63bbcd61da7" contextRef="c20210101to20211231" unitRef="U004" decimals="2" sign="-" scale="0" format="ixt:numdotdecimal">0.20</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:EarningsPerShareBasic" id="Fact_2c847af7934d4aee8d1e75c8c45eaaed" contextRef="c20200101to20201231" unitRef="U004" decimals="2" sign="-" scale="0" format="ixt:numdotdecimal">3.18</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:EarningsPerShareBasic" id="Fact_dc69ad9fdaac456cb95135c896add9e4" contextRef="c20190101to20191231" unitRef="U004" decimals="2" scale="0" format="ixt:numdotdecimal">2.00</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 4px; background-color: #CCEEFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Shares used in computing basic net income (loss) per share</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:WeightedAverageNumberOfSharesOutstandingBasic" id="Fact_974483869c87424686f8a9d8ad9407f8" contextRef="c20210101to20211231" unitRef="U002" decimals="-3" scale="3" format="ixt:numdotdecimal">141,021</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:WeightedAverageNumberOfSharesOutstandingBasic" id="Fact_57a007ce704b4b8e9d16bf5187758b1a" contextRef="c20200101to20201231" unitRef="U002" decimals="-3" scale="3" format="ixt:numdotdecimal">139,612</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:WeightedAverageNumberOfSharesOutstandingBasic" id="Fact_24585fd306204e04ac047eefaae344a7" contextRef="c20190101to20191231" unitRef="U002" decimals="-3" scale="3" format="ixt:numdotdecimal">139,998</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 4px;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Diluted net income (loss) per share</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:EarningsPerShareDiluted" id="Fact_7912333792fd463c8e34f1de8bd9f9e6" contextRef="c20210101to20211231" unitRef="U004" decimals="2" sign="-" scale="0" format="ixt:numdotdecimal">0.20</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:EarningsPerShareDiluted" id="Fact_be3545ea33e8465ea31dcf5f8cde1413" contextRef="c20200101to20201231" unitRef="U004" decimals="2" sign="-" scale="0" format="ixt:numdotdecimal">3.18</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:EarningsPerShareDiluted" id="Fact_1c75266fa9c242d78bbf9c06298d1fe8" contextRef="c20190101to20191231" unitRef="U004" decimals="2" scale="0" format="ixt:numdotdecimal">1.90</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 4px; background-color: #CCEEFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Shares used in computing diluted net income (loss) per share</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:WeightedAverageNumberOfDilutedSharesOutstanding" id="Fact_2e175ab1f4b4430c94110075de726551" contextRef="c20210101to20211231" unitRef="U002" decimals="-3" scale="3" format="ixt:numdotdecimal">141,021</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:WeightedAverageNumberOfDilutedSharesOutstanding" id="Fact_2bfa48d5ab3a400f9f083d57c473a574" contextRef="c20200101to20201231" unitRef="U002" decimals="-3" scale="3" format="ixt:numdotdecimal">139,612</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:WeightedAverageNumberOfDilutedSharesOutstanding" id="Fact_5a8e2e89a8854d18b716d51e6be5e33a" contextRef="c20190101to20191231" unitRef="U002" decimals="-3" scale="3" format="ixt:numdotdecimal">153,164</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>


</table>
  <div><br />
  </div>

  <div><br />
  </div>

  <table cellspacing="0" cellpadding="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">


  <tr>

    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">*</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We revised our 2020 and 2019 amounts to reflect the simplified convertible instruments accounting guidance, which we adopted retrospectively. Refer to
            Note 1, <span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Organization and Significant Accounting Policies</span>, for further information.</div>
        </td>

  </tr>


</table>
  <div><br />
  </div>

  <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">See accompanying notes.</div>

  <div><br />
  </div>

  <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" class="DSPFPageBreakArea">
    <div class="DSPFPageFooter">
      <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">F-<span class="DSPFPageNumber">5</span></div>

    </div>

    <div style="page-break-after:always;" class="DSPFPageBreak">
      <hr style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;" /></div>


  </div>

  <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">IONIS PHARMACEUTICALS, INC.</div>

  <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">CONSOLIDATED STATEMENTS OF COMPREHENSIVE INCOME (LOSS)</div>

  <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">(In thousands)</div>

  <div><br />
  </div>

  <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;" class="cfttable">


  <tr>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">

        </td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" colspan="10">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Year Ended December 31,</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" colspan="2">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2021</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" colspan="2">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2020</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" colspan="2">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2019</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom;">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="2">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="2">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">(as revised*)</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="2">
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    <td valign="bottom" style="vertical-align: bottom;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="2">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="2">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="2">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; white-space: nowrap;" colspan="1">&#160;</td>

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    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">
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    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">
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    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
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    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">
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    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

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  <tr>

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    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">
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    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

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  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;">
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    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:OtherComprehensiveIncomeForeignCurrencyTransactionAndTranslationGainLossArisingDuringPeriodNetOfTax" id="Fact_0118d01a0fc0483d942b9e51407b4717" contextRef="c20210101to20211231" unitRef="U001" decimals="-3" scale="3" sign="-" format="ixt:numdotdecimal">111</ix:nonFraction></div>
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
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    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:OtherComprehensiveIncomeForeignCurrencyTransactionAndTranslationGainLossArisingDuringPeriodNetOfTax" id="Fact_e0cf23c629544136a3b19d99634a49a6" contextRef="c20200101to20201231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">617</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:OtherComprehensiveIncomeForeignCurrencyTransactionAndTranslationGainLossArisingDuringPeriodNetOfTax" id="Fact_107faab7668f4901940b3c076c0c0ec6" contextRef="c20190101to20191231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">93</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 2px;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 18pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Adjustments to other comprehensive loss from purchase of noncontrolling interest of Akcea
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    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="ions:OtherComprehensiveIncomeLossAdjustmentsFromPurchaseOfNoncontrollingInterestOfSubsidiary" id="Fact_841879a515ca4d0d9d8d3706c43e9260" contextRef="c20210101to20211231" unitRef="U001" decimals="-3" scale="3" format="ixt:zerodash">&#8212;</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="ions:OtherComprehensiveIncomeLossAdjustmentsFromPurchaseOfNoncontrollingInterestOfSubsidiary" id="Fact_ced0ce9e26744592ad27d150c4780638" contextRef="c20200101to20201231" unitRef="U001" decimals="-3" scale="3" sign="-" format="ixt:numdotdecimal">127</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="ions:OtherComprehensiveIncomeLossAdjustmentsFromPurchaseOfNoncontrollingInterestOfSubsidiary" id="Fact_8dde645333454befac18a987f4b4ffbb" contextRef="c20190101to20191231" unitRef="U001" decimals="-3" scale="3" format="ixt:zerodash">&#8212;</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Comprehensive income (loss)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:ComprehensiveIncomeNetOfTaxIncludingPortionAttributableToNoncontrollingInterest" id="Fact_88990aa910f44465b514db16de1b6797" contextRef="c20210101to20211231" unitRef="U001" decimals="-3" scale="3" sign="-" format="ixt:numdotdecimal">40,194</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:ComprehensiveIncomeNetOfTaxIncludingPortionAttributableToNoncontrollingInterest" id="Fact_a94a014398884db3aad264a9afa0f0b9" contextRef="c20200101to20201231" unitRef="U001" decimals="-3" scale="3" sign="-" format="ixt:numdotdecimal">475,524</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:ComprehensiveIncomeNetOfTaxIncludingPortionAttributableToNoncontrollingInterest" id="Fact_952a61bbba0241e4b821f51c3f0cbaf0" contextRef="c20190101to20191231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">293,985</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 2px;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Comprehensive income (loss) attributable to noncontrolling interest in Akcea Therapeutics, Inc.</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:ComprehensiveIncomeNetOfTaxAttributableToNoncontrollingInterest" id="Fact_0a2ffbf7523a40bfb67425a2f824fdda" contextRef="c20210101to20211231" unitRef="U001" decimals="-3" scale="3" format="ixt:zerodash">&#8212;</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:ComprehensiveIncomeNetOfTaxAttributableToNoncontrollingInterest" id="Fact_835fc2d29a554273b86faf6556c423be" contextRef="c20200101to20201231" unitRef="U001" decimals="-3" scale="3" sign="-" format="ixt:numdotdecimal">35,480</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:ComprehensiveIncomeNetOfTaxAttributableToNoncontrollingInterest" id="Fact_7354d55541b84356989b29706bcadb0e" contextRef="c20190101to20191231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">9,116</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 4px; background-color: #CCEEFF;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Comprehensive income (loss) attributable to Ionis Pharmaceuticals, Inc. common stockholders</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:ComprehensiveIncomeNetOfTax" id="Fact_c084b014906646ef8b8e0d1564259a56" contextRef="c20210101to20211231" unitRef="U001" decimals="-3" scale="3" sign="-" format="ixt:numdotdecimal">40,194</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:ComprehensiveIncomeNetOfTax" id="Fact_a5f2d997e0854eb2bac6beedf43dbdc0" contextRef="c20200101to20201231" unitRef="U001" decimals="-3" scale="3" sign="-" format="ixt:numdotdecimal">440,044</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>


</table>
  <div><br />
  </div>

  <div><br />
  </div>

  <table cellspacing="0" cellpadding="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">


  <tr>

    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">*</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We revised our 2020 and 2019 amounts to reflect the simplified convertible instruments accounting guidance, which we adopted retrospectively. Refer to
            Note 1, <span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Organization and Significant Accounting Policies</span>, for further information.</div>
        </td>

  </tr>


</table>
  <div><br />
  </div>

  <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">See accompanying notes.</div>

  <div><br />
  </div>

  <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" class="DSPFPageBreakArea">
    <div class="DSPFPageFooter">
      <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">F-<span class="DSPFPageNumber">6</span></div>

    </div>

    <div style="page-break-after:always;" class="DSPFPageBreak">
      <hr style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;" /></div>


  </div>

  <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">IONIS PHARMACEUTICALS, INC.</div>

  <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">CONSOLIDATED STATEMENTS OF STOCKHOLDERS</span>&#8217;<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"> EQUITY</span></div>

  <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Years Ended December 31, 2021,
    2020 and 2019</div>

  <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">(In thousands)</div>

  <div><br />
  </div>

  <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;" class="cfttable">


  <tr>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">

        </td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" colspan="6">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Common Stock</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; white-space: nowrap;" colspan="2">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Additional</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; white-space: nowrap;" colspan="2">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Accumulated Other</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; white-space: nowrap;" colspan="2">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Accumulated</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; white-space: nowrap;" colspan="2">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Total Ionis</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Stockholders</span>&#8217;</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; white-space: nowrap;" colspan="2">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Noncontrolling</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Interest in Akcea</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; white-space: nowrap;" colspan="2">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Total</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Stockholders</span>&#8217;</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Description</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" colspan="2">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Shares</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" colspan="2">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Amount</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px; white-space: nowrap;" colspan="2">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Paid in Capital</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px; white-space: nowrap;" colspan="2">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Comprehensive Loss</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px; white-space: nowrap;" colspan="2">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Deficit</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px; white-space: nowrap;" colspan="2">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Equity</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px; white-space: nowrap;" colspan="2">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Therapeutics, Inc.</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px; white-space: nowrap;" colspan="2">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Equity</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 20%; background-color: #CCEEFF;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Balance at December 31, <span style="text-indent: 0pt;">2018</span> (as revised*)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:SharesIssued" id="Fact_e117c0623dcf44afaffde41830ff31f2" contextRef="c20181231_StatementEquityComponentsAxis_CommonStockMember" unitRef="U002" decimals="-3" scale="3" format="ixt:numdotdecimal">137,929</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:StockholdersEquityIncludingPortionAttributableToNoncontrollingInterest" id="Fact_c2ee42f06fe64835a05ef7841d2d5bee" contextRef="c20181231_StatementEquityComponentsAxis_CommonStockMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">138</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:StockholdersEquityIncludingPortionAttributableToNoncontrollingInterest" id="Fact_61b12d938cc04bbd933859666c726023" contextRef="c20181231_StatementEquityComponentsAxis_AdditionalPaidInCapitalMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">1,833,668</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:StockholdersEquityIncludingPortionAttributableToNoncontrollingInterest" id="Fact_761affc8eaf842578c2a954083f3e28b" contextRef="c20181231_StatementEquityComponentsAxis_AccumulatedOtherComprehensiveIncomeMember" unitRef="U001" decimals="-3" scale="3" sign="-" format="ixt:numdotdecimal">32,016</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:StockholdersEquityIncludingPortionAttributableToNoncontrollingInterest" id="Fact_7ce172fc43e84fe9a84cda9a4771f340" contextRef="c20181231_StatementEquityComponentsAxis_RetainedEarningsMember" unitRef="U001" decimals="-3" scale="3" sign="-" format="ixt:numdotdecimal">840,251</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:StockholdersEquityIncludingPortionAttributableToNoncontrollingInterest" id="Fact_d7625d3c6da54d3c8303ca9e6db6c22e" contextRef="c20181231_StatementEquityComponentsAxis_ParentMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">961,539</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:StockholdersEquityIncludingPortionAttributableToNoncontrollingInterest" id="Fact_e263af9230d74dc0984e6063677dc5d2" contextRef="c20181231_StatementEquityComponentsAxis_NoncontrollingInterestMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">139,084</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:StockholdersEquityIncludingPortionAttributableToNoncontrollingInterest" id="Fact_8a8a123d035043aebb0000237fdd6e28" contextRef="c20181231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">1,100,623</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 20%;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Net income</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#8212;</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:NetIncomeLoss" id="Fact_b699b94c66764330a7a4dd60cfe07928" contextRef="c20190101to20191231_StatementEquityComponentsAxis_CommonStockMember" unitRef="U001" decimals="-3" scale="3" format="ixt:zerodash">&#8212;</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%;" colspan="1">
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%;" colspan="1">
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%;" colspan="1">
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%;" colspan="1">
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 20%; background-color: #CCEEFF;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Change in unrealized losses, net of tax</div>
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    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#8212;</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #CCEEFF;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #CCEEFF;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #CCEEFF;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:OtherComprehensiveIncomeAvailableforsaleSecuritiesAdjustmentNetOfTaxPortionAttributableToParent" id="Fact_1b81d231e08446d5be7fc2b7840d9fee" contextRef="c20190101to20191231_StatementEquityComponentsAxis_RetainedEarningsMember" unitRef="U001" decimals="-3" scale="3" format="ixt:zerodash">&#8212;</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #CCEEFF;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #CCEEFF;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #CCEEFF;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 20%;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Foreign currency translation</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#8212;</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:OtherComprehensiveIncomeForeignCurrencyTransactionAndTranslationGainLossArisingDuringPeriodNetOfTax" id="Fact_50a37a75aedf40108038ac8776d5bc2a" contextRef="c20190101to20191231_StatementEquityComponentsAxis_CommonStockMember" unitRef="U001" decimals="-3" scale="3" format="ixt:zerodash">&#8212;</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:OtherComprehensiveIncomeForeignCurrencyTransactionAndTranslationGainLossArisingDuringPeriodNetOfTax" id="Fact_60d6221293b84c1ea84609e2a699912c" contextRef="c20190101to20191231_StatementEquityComponentsAxis_RetainedEarningsMember" unitRef="U001" decimals="-3" scale="3" format="ixt:zerodash">&#8212;</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:OtherComprehensiveIncomeForeignCurrencyTransactionAndTranslationGainLossArisingDuringPeriodNetOfTax" id="Fact_569648b85807448bbb2acc6eb5277fac" contextRef="c20190101to20191231_StatementEquityComponentsAxis_NoncontrollingInterestMember" unitRef="U001" decimals="-3" scale="3" format="ixt:zerodash">&#8212;</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 20%; background-color: #CCEEFF;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Issuance of common stock in connection with employee stock plans</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #CCEEFF;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #CCEEFF;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #CCEEFF;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #CCEEFF;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #CCEEFF;" colspan="1">
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #CCEEFF;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #CCEEFF;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:StockIssuedDuringPeriodValueShareBasedCompensationGross" id="Fact_8f8c21adae7b472c9abe1ded2c9e36d0" contextRef="c20190101to20191231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">119,657</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 20%;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Issuance of warrants</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#8212;</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:AdjustmentsToAdditionalPaidInCapitalWarrantIssued" id="Fact_895757a3d13b4b37a27a604baa9f15bf" contextRef="c20190101to20191231_StatementEquityComponentsAxis_CommonStockMember" unitRef="U001" decimals="-3" scale="3" format="ixt:zerodash">&#8212;</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:AdjustmentsToAdditionalPaidInCapitalWarrantIssued" id="Fact_d78cbae13f7f44d39ae9484c1f286bad" contextRef="c20190101to20191231_StatementEquityComponentsAxis_AccumulatedOtherComprehensiveIncomeMember" unitRef="U001" decimals="-3" scale="3" format="ixt:zerodash">&#8212;</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:AdjustmentsToAdditionalPaidInCapitalWarrantIssued" id="Fact_fe44dedf438244c5b0d5a9b942bf0775" contextRef="c20190101to20191231_StatementEquityComponentsAxis_RetainedEarningsMember" unitRef="U001" decimals="-3" scale="3" format="ixt:zerodash">&#8212;</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:AdjustmentsToAdditionalPaidInCapitalWarrantIssued" id="Fact_f7faa4f039de4cd882c18917c63a6370" contextRef="c20190101to20191231_StatementEquityComponentsAxis_ParentMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">56,110</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:AdjustmentsToAdditionalPaidInCapitalWarrantIssued" id="Fact_757b7e68cc864f8fa6701fc4bc654480" contextRef="c20190101to20191231_StatementEquityComponentsAxis_NoncontrollingInterestMember" unitRef="U001" decimals="-3" scale="3" format="ixt:zerodash">&#8212;</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:AdjustmentsToAdditionalPaidInCapitalWarrantIssued" id="Fact_f8a8b15a87e24d3680f6ac593a7b0f26" contextRef="c20190101to20191231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">56,110</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 20%; background-color: #CCEEFF;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Purchase of note hedges, net of tax</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#8212;</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:AdjustmentsToAdditionalPaidInCapitalOther" id="Fact_94785181bb2d453e8b504c5a5c2f4157" contextRef="c20190101to20191231_StatementEquityComponentsAxis_CommonStockMember" unitRef="U001" decimals="-3" scale="3" format="ixt:zerodash">&#8212;</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:AdjustmentsToAdditionalPaidInCapitalOther" id="Fact_1907f28a56034a7791cbea4ce65d14d4" contextRef="c20190101to20191231_StatementEquityComponentsAxis_AdditionalPaidInCapitalMember" unitRef="U001" decimals="-3" scale="3" sign="-" format="ixt:numdotdecimal">85,860</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:AdjustmentsToAdditionalPaidInCapitalOther" id="Fact_4d79c890b91f416597cff381a5930811" contextRef="c20190101to20191231_StatementEquityComponentsAxis_AccumulatedOtherComprehensiveIncomeMember" unitRef="U001" decimals="-3" scale="3" format="ixt:zerodash">&#8212;</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:AdjustmentsToAdditionalPaidInCapitalOther" id="Fact_200032451959416f96a44c06facafd30" contextRef="c20190101to20191231_StatementEquityComponentsAxis_RetainedEarningsMember" unitRef="U001" decimals="-3" scale="3" format="ixt:zerodash">&#8212;</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:AdjustmentsToAdditionalPaidInCapitalOther" id="Fact_0618918863eb41b68c4b126db3836dce" contextRef="c20190101to20191231_StatementEquityComponentsAxis_ParentMember" unitRef="U001" decimals="-3" scale="3" sign="-" format="ixt:numdotdecimal">85,860</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:AdjustmentsToAdditionalPaidInCapitalOther" id="Fact_7430d448fd79410bbe88b3df1486faf1" contextRef="c20190101to20191231_StatementEquityComponentsAxis_NoncontrollingInterestMember" unitRef="U001" decimals="-3" scale="3" format="ixt:zerodash">&#8212;</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:AdjustmentsToAdditionalPaidInCapitalOther" id="Fact_136d6f57e1e94f5d902abdac293d2f96" contextRef="c20190101to20191231" unitRef="U001" decimals="-3" scale="3" sign="-" format="ixt:numdotdecimal">85,860</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 20%;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Repurchases and retirements of common stock</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:StockRepurchasedAndRetiredDuringPeriodShares" id="Fact_8b781b88a705461caf117a3965349799" contextRef="c20190101to20191231_StatementEquityComponentsAxis_CommonStockMember" unitRef="U002" decimals="-3" scale="3" format="ixt:numdotdecimal">535</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:StockRepurchasedAndRetiredDuringPeriodValue" id="Fact_5e0b148649054330bcf49db82f62eec1" contextRef="c20190101to20191231_StatementEquityComponentsAxis_CommonStockMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">1</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:StockRepurchasedAndRetiredDuringPeriodValue" id="Fact_56c235a17f074ef081eee1087de0a1dc" contextRef="c20190101to20191231_StatementEquityComponentsAxis_AdditionalPaidInCapitalMember" unitRef="U001" decimals="-3" scale="3" format="ixt:zerodash">&#8212;</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:StockRepurchasedAndRetiredDuringPeriodValue" id="Fact_d09fde4be46d440184968e4303d9fb91" contextRef="c20190101to20191231_StatementEquityComponentsAxis_AccumulatedOtherComprehensiveIncomeMember" unitRef="U001" decimals="-3" scale="3" format="ixt:zerodash">&#8212;</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:StockRepurchasedAndRetiredDuringPeriodValue" id="Fact_82eb5e45291e424eae71a0fd70b37565" contextRef="c20190101to20191231_StatementEquityComponentsAxis_RetainedEarningsMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">34,387</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%;" colspan="1">
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        </td>

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    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%;" colspan="1">
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%;" colspan="1">
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">
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  <tr>

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    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #CCEEFF;" colspan="1">
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #CCEEFF;" colspan="1">
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #CCEEFF;" colspan="1">
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #CCEEFF;" colspan="1">
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #CCEEFF;" colspan="1">
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #CCEEFF;" colspan="1">
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #CCEEFF;" colspan="1">
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #CCEEFF;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 20%;">
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    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:AdjustmentsRelatedToTaxWithholdingForShareBasedCompensation" id="Fact_f50b55d8ef9e493a980de223ce83bd7e" contextRef="c20190101to20191231_StatementEquityComponentsAxis_CommonStockMember" unitRef="U001" decimals="-3" scale="3" format="ixt:zerodash">&#8212;</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:AdjustmentsRelatedToTaxWithholdingForShareBasedCompensation" id="Fact_b40696a2aa1a463aa588302783bc1c6e" contextRef="c20190101to20191231_StatementEquityComponentsAxis_AdditionalPaidInCapitalMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">19,242</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:AdjustmentsRelatedToTaxWithholdingForShareBasedCompensation" id="Fact_aa8b717f16a8434fa7369d0393962f2b" contextRef="c20190101to20191231_StatementEquityComponentsAxis_AccumulatedOtherComprehensiveIncomeMember" unitRef="U001" decimals="-3" scale="3" format="ixt:zerodash">&#8212;</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:AdjustmentsRelatedToTaxWithholdingForShareBasedCompensation" id="Fact_2a82343fb6bd448db961d1d4323f0b11" contextRef="c20190101to20191231_StatementEquityComponentsAxis_RetainedEarningsMember" unitRef="U001" decimals="-3" scale="3" format="ixt:zerodash">&#8212;</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:AdjustmentsRelatedToTaxWithholdingForShareBasedCompensation" id="Fact_fcc84a575d9e4bd697d6f06df79559df" contextRef="c20190101to20191231_StatementEquityComponentsAxis_ParentMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">19,242</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:AdjustmentsRelatedToTaxWithholdingForShareBasedCompensation" id="Fact_51293d9f257e4602b7af460271faa719" contextRef="c20190101to20191231_StatementEquityComponentsAxis_NoncontrollingInterestMember" unitRef="U001" decimals="-3" scale="3" format="ixt:zerodash">&#8212;</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:AdjustmentsRelatedToTaxWithholdingForShareBasedCompensation" id="Fact_97ba090799d14a2ab9c043c2f8d04050" contextRef="c20190101to20191231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">19,242</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 20%; padding-bottom: 2px; background-color: #CCEEFF;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Noncontrolling interest in Akcea Therapeutics, Inc.</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#8212;</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:MinorityInterestPeriodIncreaseDecrease" id="Fact_da77c49a05994c55800439832b1dd327" contextRef="c20190101to20191231_StatementEquityComponentsAxis_CommonStockMember" unitRef="U001" decimals="-3" scale="3" format="ixt:zerodash">&#8212;</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:MinorityInterestPeriodIncreaseDecrease" id="Fact_2be302b465d142d487a688a4c7a9c374" contextRef="c20190101to20191231_StatementEquityComponentsAxis_AdditionalPaidInCapitalMember" unitRef="U001" decimals="-3" scale="3" sign="-" format="ixt:numdotdecimal">65,254</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:MinorityInterestPeriodIncreaseDecrease" id="Fact_f7ee89b02127471ab58454724cfba372" contextRef="c20190101to20191231_StatementEquityComponentsAxis_AccumulatedOtherComprehensiveIncomeMember" unitRef="U001" decimals="-3" scale="3" format="ixt:zerodash">&#8212;</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:MinorityInterestPeriodIncreaseDecrease" id="Fact_dd0aed634d0641b0b8ac10cadf9a8ea3" contextRef="c20190101to20191231_StatementEquityComponentsAxis_RetainedEarningsMember" unitRef="U001" decimals="-3" scale="3" format="ixt:zerodash">&#8212;</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
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    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 20%; padding-bottom: 4px;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Balance at December 31, <span style="text-indent: 0pt;">2019</span> (as revised*)</div>
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    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%; border-bottom: #000000 double 4px;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:SharesIssued" id="Fact_60e0ac539c624466a7e961a5cda44d3a" contextRef="c20191231_StatementEquityComponentsAxis_CommonStockMember" unitRef="U002" decimals="-3" scale="3" format="ixt:numdotdecimal">140,340</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%; border-bottom: #000000 double 4px;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:StockholdersEquityIncludingPortionAttributableToNoncontrollingInterest" id="Fact_4b39284014b0418f90e000374da7580f" contextRef="c20191231_StatementEquityComponentsAxis_CommonStockMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">140</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%; border-bottom: #000000 double 4px;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:StockholdersEquityIncludingPortionAttributableToNoncontrollingInterest" id="Fact_6585fe6638524b79b937ab63b9db5d75" contextRef="c20191231_StatementEquityComponentsAxis_AdditionalPaidInCapitalMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">1,985,650</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%; border-bottom: #000000 double 4px;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:StockholdersEquityIncludingPortionAttributableToNoncontrollingInterest" id="Fact_d286f9a454bc438c8afed1012262b3ab" contextRef="c20191231_StatementEquityComponentsAxis_AccumulatedOtherComprehensiveIncomeMember" unitRef="U001" decimals="-3" scale="3" sign="-" format="ixt:numdotdecimal">25,290</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%; border-bottom: #000000 double 4px;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:StockholdersEquityIncludingPortionAttributableToNoncontrollingInterest" id="Fact_2ff016c0f0f747c19ebd4bac48864260" contextRef="c20191231_StatementEquityComponentsAxis_RetainedEarningsMember" unitRef="U001" decimals="-3" scale="3" sign="-" format="ixt:numdotdecimal">596,495</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%; border-bottom: #000000 double 4px;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:StockholdersEquityIncludingPortionAttributableToNoncontrollingInterest" id="Fact_5fa68cfcb9f54851a4ae9660cdc60d85" contextRef="c20191231_StatementEquityComponentsAxis_ParentMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">1,364,005</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%; border-bottom: #000000 double 4px;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:StockholdersEquityIncludingPortionAttributableToNoncontrollingInterest" id="Fact_7adb69797e0542af967701b5578982ac" contextRef="c20191231_StatementEquityComponentsAxis_NoncontrollingInterestMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">213,454</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%; border-bottom: #000000 double 4px;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:StockholdersEquityIncludingPortionAttributableToNoncontrollingInterest" id="Fact_61512a893ff14270a3f4c0015b93fa30" contextRef="c20191231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">1,577,459</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 20%; background-color: #CCEEFF;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Net loss</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#8212;</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:NetIncomeLoss" id="Fact_48bf356e63ad4d97b55fa3ddcc9213c8" contextRef="c20200101to20201231_StatementEquityComponentsAxis_CommonStockMember" unitRef="U001" decimals="-3" scale="3" format="ixt:zerodash">&#8212;</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:NetIncomeLoss" id="Fact_e8dd2525dbd042a1bcdc939a738cde79" contextRef="c20200101to20201231_StatementEquityComponentsAxis_AdditionalPaidInCapitalMember" unitRef="U001" decimals="-3" scale="3" format="ixt:zerodash">&#8212;</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:NetIncomeLoss" id="Fact_9afeaa7611344fda84c4bfc3dcdc8188" contextRef="c20200101to20201231_StatementEquityComponentsAxis_AccumulatedOtherComprehensiveIncomeMember" unitRef="U001" decimals="-3" scale="3" format="ixt:zerodash">&#8212;</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:NetIncomeLoss" id="Fact_338f9e0b9ece40f2b5a46dd2eb3bc945" contextRef="c20200101to20201231_StatementEquityComponentsAxis_RetainedEarningsMember" unitRef="U001" decimals="-3" scale="3" sign="-" format="ixt:numdotdecimal">444,263</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:NetIncomeLoss" id="Fact_1726fa2840cb4086b6f7cf5c3e66cd1f" contextRef="c20200101to20201231_StatementEquityComponentsAxis_ParentMember" unitRef="U001" decimals="-3" scale="3" sign="-" format="ixt:numdotdecimal">444,263</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:NetIncomeLoss" id="Fact_5f64a422578244348f047cc3f91c1184" contextRef="c20200101to20201231_StatementEquityComponentsAxis_NoncontrollingInterestMember" unitRef="U001" decimals="-3" scale="3" format="ixt:zerodash">&#8212;</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:NetIncomeLoss" id="Fact_755544668a704c22979858000bfde38a" contextRef="c20200101to20201231" unitRef="U001" decimals="-3" scale="3" sign="-" format="ixt:numdotdecimal">444,263</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 20%;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Change in unrealized gain, net of tax</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#8212;</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:OtherComprehensiveIncomeAvailableforsaleSecuritiesAdjustmentNetOfTaxPortionAttributableToParent" id="Fact_5b6feeff0a314136a4fe63dbb89869e6" contextRef="c20200101to20201231_StatementEquityComponentsAxis_CommonStockMember" unitRef="U001" decimals="-3" scale="3" format="ixt:zerodash">&#8212;</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:OtherComprehensiveIncomeAvailableforsaleSecuritiesAdjustmentNetOfTaxPortionAttributableToParent" id="Fact_f70df17298104bb29ef7861c6b585f0e" contextRef="c20200101to20201231_StatementEquityComponentsAxis_AdditionalPaidInCapitalMember" unitRef="U001" decimals="-3" scale="3" format="ixt:zerodash">&#8212;</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:OtherComprehensiveIncomeAvailableforsaleSecuritiesAdjustmentNetOfTaxPortionAttributableToParent" id="Fact_fdb4ab077b324877bfe3b9a67020fb1a" contextRef="c20200101to20201231_StatementEquityComponentsAxis_AccumulatedOtherComprehensiveIncomeMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">3,729</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:OtherComprehensiveIncomeAvailableforsaleSecuritiesAdjustmentNetOfTaxPortionAttributableToParent" id="Fact_6fb19bacbb7d415481e528316894c7ee" contextRef="c20200101to20201231_StatementEquityComponentsAxis_RetainedEarningsMember" unitRef="U001" decimals="-3" scale="3" format="ixt:zerodash">&#8212;</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

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    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

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    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #CCEEFF;" colspan="1">
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    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #CCEEFF;" colspan="1">
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    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #CCEEFF;" colspan="1">
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #CCEEFF;" colspan="1">
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #CCEEFF;" colspan="1">
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #CCEEFF;" colspan="1">
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #CCEEFF;" colspan="1">
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #CCEEFF;" colspan="1">
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 20%;">
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    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%;" colspan="1">
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%;" colspan="1">
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%;" colspan="1">
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%;" colspan="1">
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%;" colspan="1">
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%;" colspan="1">
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%;" colspan="1">
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%;" colspan="1">
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

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  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 20%; background-color: #CCEEFF;">
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        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#8212;</div>
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #CCEEFF;" colspan="1">
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #CCEEFF;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
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    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #CCEEFF;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:MinorityInterestDecreaseFromRedemptions" id="Fact_6a8b69eca9aa4c22b0fe55404f441ed2" contextRef="c20200101to20201231_StatementEquityComponentsAxis_RetainedEarningsMember" unitRef="U001" decimals="-3" scale="3" format="ixt:zerodash">&#8212;</ix:nonFraction></div>
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:MinorityInterestDecreaseFromRedemptions" id="Fact_c1903ae0f0d946a1b18b2158425b726e" contextRef="c20200101to20201231_StatementEquityComponentsAxis_ParentMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">323,721</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #CCEEFF;" colspan="1">
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #CCEEFF;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 20%;">
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    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:StockRepurchasedAndRetiredDuringPeriodValue" id="Fact_071eed4e54f640dc9e608970c5c5fe5f" contextRef="c20200101to20201231_StatementEquityComponentsAxis_AccumulatedOtherComprehensiveIncomeMember" unitRef="U001" decimals="-3" scale="3" format="ixt:zerodash">&#8212;</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:StockRepurchasedAndRetiredDuringPeriodValue" id="Fact_5f59687fe7b44826944c0f5f8ef41516" contextRef="c20200101to20201231_StatementEquityComponentsAxis_RetainedEarningsMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">90,548</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:StockRepurchasedAndRetiredDuringPeriodValue" id="Fact_5071207261694808ac322cb9cbba656d" contextRef="c20200101to20201231_StatementEquityComponentsAxis_ParentMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">90,549</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:StockRepurchasedAndRetiredDuringPeriodValue" id="Fact_9d74c89575b44505979360a1da6ad89c" contextRef="c20200101to20201231_StatementEquityComponentsAxis_NoncontrollingInterestMember" unitRef="U001" decimals="-3" scale="3" format="ixt:zerodash">&#8212;</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:StockRepurchasedAndRetiredDuringPeriodValue" id="Fact_a39130c76124444fabf019b22011151e" contextRef="c20200101to20201231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">90,549</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 20%; background-color: #CCEEFF;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Stock-based compensation expense</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#8212;</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:AdjustmentsToAdditionalPaidInCapitalSharebasedCompensationRequisiteServicePeriodRecognitionValue" id="Fact_4769b7f8ea594366a73ab91db2a60fa9" contextRef="c20200101to20201231_StatementEquityComponentsAxis_CommonStockMember" unitRef="U001" decimals="-3" scale="3" format="ixt:zerodash">&#8212;</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:AdjustmentsToAdditionalPaidInCapitalSharebasedCompensationRequisiteServicePeriodRecognitionValue" id="Fact_29f9f2041bff44918a0cfddfa16cbc02" contextRef="c20200101to20201231_StatementEquityComponentsAxis_AdditionalPaidInCapitalMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">230,117</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:AdjustmentsToAdditionalPaidInCapitalSharebasedCompensationRequisiteServicePeriodRecognitionValue" id="Fact_3719dc6e9f1b486dae7106b08772f201" contextRef="c20200101to20201231_StatementEquityComponentsAxis_AccumulatedOtherComprehensiveIncomeMember" unitRef="U001" decimals="-3" scale="3" format="ixt:zerodash">&#8212;</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:AdjustmentsToAdditionalPaidInCapitalSharebasedCompensationRequisiteServicePeriodRecognitionValue" id="Fact_49a44ab58d2d49f8b1053aca4e966011" contextRef="c20200101to20201231_StatementEquityComponentsAxis_RetainedEarningsMember" unitRef="U001" decimals="-3" scale="3" format="ixt:zerodash">&#8212;</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:AdjustmentsToAdditionalPaidInCapitalSharebasedCompensationRequisiteServicePeriodRecognitionValue" id="Fact_dc61a61ec6984fbb83f9646ef7ebb30f" contextRef="c20200101to20201231_StatementEquityComponentsAxis_ParentMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">230,117</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:AdjustmentsToAdditionalPaidInCapitalSharebasedCompensationRequisiteServicePeriodRecognitionValue" id="Fact_1bfc73073b1042a18e0eb1fb3c034797" contextRef="c20200101to20201231_StatementEquityComponentsAxis_NoncontrollingInterestMember" unitRef="U001" decimals="-3" scale="3" format="ixt:zerodash">&#8212;</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:AdjustmentsToAdditionalPaidInCapitalSharebasedCompensationRequisiteServicePeriodRecognitionValue" id="Fact_c9e019303e9b4ff1b01e682eefe65def" contextRef="c20200101to20201231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">230,117</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 20%;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Payments of tax withholdings related to vesting of employee stock awards and exercise of employee
            stock options</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:SharesPaidForTaxWithholdingForShareBasedCompensation" id="Fact_4ae64fbea2b243829db015f863e1a525" contextRef="c20200101to20201231_StatementEquityComponentsAxis_CommonStockMember" unitRef="U002" decimals="-3" scale="3" format="ixt:numdotdecimal">217</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:AdjustmentsRelatedToTaxWithholdingForShareBasedCompensation" id="Fact_bb0a6cb28ba64220b97554fd600a837f" contextRef="c20200101to20201231_StatementEquityComponentsAxis_CommonStockMember" unitRef="U001" decimals="-3" scale="3" format="ixt:zerodash">&#8212;</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:AdjustmentsRelatedToTaxWithholdingForShareBasedCompensation" id="Fact_b049e26291e240409287825db6851635" contextRef="c20200101to20201231_StatementEquityComponentsAxis_AdditionalPaidInCapitalMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">13,410</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:AdjustmentsRelatedToTaxWithholdingForShareBasedCompensation" id="Fact_69a5b77d2ba2483884724f7deb4c0ae6" contextRef="c20200101to20201231_StatementEquityComponentsAxis_AccumulatedOtherComprehensiveIncomeMember" unitRef="U001" decimals="-3" scale="3" format="ixt:zerodash">&#8212;</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:AdjustmentsRelatedToTaxWithholdingForShareBasedCompensation" id="Fact_cbfd3f29efe544d8b18e1d3d119b4122" contextRef="c20200101to20201231_StatementEquityComponentsAxis_RetainedEarningsMember" unitRef="U001" decimals="-3" scale="3" format="ixt:zerodash">&#8212;</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:AdjustmentsRelatedToTaxWithholdingForShareBasedCompensation" id="Fact_06512793fca04aafad083ac0b4088b51" contextRef="c20200101to20201231_StatementEquityComponentsAxis_ParentMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">13,410</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%;" colspan="1">
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    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #CCEEFF;" colspan="1">
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    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #CCEEFF;" colspan="1">
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    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #CCEEFF;" colspan="1">
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #CCEEFF;" colspan="1">
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #CCEEFF;" colspan="1">
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #CCEEFF;" colspan="1">
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="ions:AdjustmentsToAdditionalPaidInCapitalDeferredTaxLiabilityAdjustment" id="Fact_36fd54e843c2434faf8fb8b01b20b67d" contextRef="c20200101to20201231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">7,714</ix:nonFraction></div>
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 20%; padding-bottom: 2px;">
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    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%; border-bottom: #000000 solid 2px;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#8212;</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%; border-bottom: #000000 solid 2px;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:MinorityInterestPeriodIncreaseDecrease" id="Fact_a883d07d575d4901a317e303780c4f98" contextRef="c20200101to20201231_StatementEquityComponentsAxis_CommonStockMember" unitRef="U001" decimals="-3" scale="3" format="ixt:zerodash">&#8212;</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%; border-bottom: #000000 solid 2px;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:MinorityInterestPeriodIncreaseDecrease" id="Fact_716f2233e5494f64ae831cbf14b94fe0" contextRef="c20200101to20201231_StatementEquityComponentsAxis_AdditionalPaidInCapitalMember" unitRef="U001" decimals="-3" scale="3" sign="-" format="ixt:numdotdecimal">42,563</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
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    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%; border-bottom: #000000 solid 2px;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:MinorityInterestPeriodIncreaseDecrease" id="Fact_39cbc2136c3f443cad8f05bb437a797f" contextRef="c20200101to20201231_StatementEquityComponentsAxis_AccumulatedOtherComprehensiveIncomeMember" unitRef="U001" decimals="-3" scale="3" sign="-" format="ixt:numdotdecimal">428</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%; border-bottom: #000000 solid 2px;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:MinorityInterestPeriodIncreaseDecrease" id="Fact_3611e225cac442aba33adda6d89990fd" contextRef="c20200101to20201231_StatementEquityComponentsAxis_RetainedEarningsMember" unitRef="U001" decimals="-3" scale="3" format="ixt:zerodash">&#8212;</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%; border-bottom: #000000 solid 2px;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:MinorityInterestPeriodIncreaseDecrease" id="Fact_64905d9dbd8a46a0a5161e39860f52ee" contextRef="c20200101to20201231_StatementEquityComponentsAxis_ParentMember" unitRef="U001" decimals="-3" scale="3" sign="-" format="ixt:numdotdecimal">42,991</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%; border-bottom: #000000 solid 2px;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:MinorityInterestPeriodIncreaseDecrease" id="Fact_77e6d511b528401fb0992448dc8b6668" contextRef="c20200101to20201231_StatementEquityComponentsAxis_NoncontrollingInterestMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">7,511</ix:nonFraction></div>
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%; border-bottom: #000000 solid 2px;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:MinorityInterestPeriodIncreaseDecrease" id="Fact_5e90027fb447413a9b81af7dfcbb2fec" contextRef="c20200101to20201231" unitRef="U001" decimals="-3" scale="3" sign="-" format="ixt:numdotdecimal">35,480</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 20%; padding-bottom: 4px; background-color: #CCEEFF;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Balance at December 31, <span style="text-indent: 0pt;">2020</span> (as revised*)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:SharesIssued" id="Fact_dcb079e20cba446096baf2d275d36dd5" contextRef="c20201231_StatementEquityComponentsAxis_CommonStockMember" unitRef="U002" decimals="-3" scale="3" format="ixt:numdotdecimal">140,366</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:StockholdersEquityIncludingPortionAttributableToNoncontrollingInterest" id="Fact_d01227787819409c840436d67e7d48a3" contextRef="c20201231_StatementEquityComponentsAxis_CommonStockMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">140</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:StockholdersEquityIncludingPortionAttributableToNoncontrollingInterest" id="Fact_acc570beab1c44b1b82a54a05d599805" contextRef="c20201231_StatementEquityComponentsAxis_AdditionalPaidInCapitalMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">1,895,519</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:StockholdersEquityIncludingPortionAttributableToNoncontrollingInterest" id="Fact_23b29f4e087c4f1ca664c32300610294" contextRef="c20201231_StatementEquityComponentsAxis_AccumulatedOtherComprehensiveIncomeMember" unitRef="U001" decimals="-3" scale="3" sign="-" format="ixt:numdotdecimal">21,071</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:StockholdersEquityIncludingPortionAttributableToNoncontrollingInterest" id="Fact_71c821501e124dbfa12ced3159be86a4" contextRef="c20201231_StatementEquityComponentsAxis_RetainedEarningsMember" unitRef="U001" decimals="-3" scale="3" sign="-" format="ixt:numdotdecimal">1,131,306</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:StockholdersEquityIncludingPortionAttributableToNoncontrollingInterest" id="Fact_2efb06adbdd5486db43852bff651ab65" contextRef="c20201231_StatementEquityComponentsAxis_NoncontrollingInterestMember" unitRef="U001" decimals="-3" scale="3" format="ixt:zerodash">&#8212;</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:StockholdersEquityIncludingPortionAttributableToNoncontrollingInterest" id="Fact_e7271e8b196b47b3bbe7e15968a86b6b" contextRef="c20201231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">743,282</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 20%;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Net loss</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#8212;</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:NetIncomeLoss" id="Fact_2c0f61fe913a4e9c87a2ecd4f94a7897" contextRef="c20210101to20211231_StatementEquityComponentsAxis_AccumulatedOtherComprehensiveIncomeMember" unitRef="U001" decimals="-3" scale="3" format="ixt:zerodash">&#8212;</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:NetIncomeLoss" id="Fact_3178904620f649fd815c50c1e7ed399f" contextRef="c20210101to20211231_StatementEquityComponentsAxis_RetainedEarningsMember" unitRef="U001" decimals="-3" scale="3" sign="-" format="ixt:numdotdecimal">28,597</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:NetIncomeLoss" id="Fact_f243d5703018413db94848f32ca2937c" contextRef="c20210101to20211231_StatementEquityComponentsAxis_ParentMember" unitRef="U001" decimals="-3" scale="3" sign="-" format="ixt:numdotdecimal">28,597</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:NetIncomeLoss" id="Fact_1594a599ee844816944f74aef5e5ce6b" contextRef="c20210101to20211231_StatementEquityComponentsAxis_NoncontrollingInterestMember" unitRef="U001" decimals="-3" scale="3" format="ixt:zerodash">&#8212;</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:NetIncomeLoss" id="Fact_a25515ec6f7446728b15a5adbf23f4bf" contextRef="c20210101to20211231" unitRef="U001" decimals="-3" scale="3" sign="-" format="ixt:numdotdecimal">28,597</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 20%; background-color: #CCEEFF;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Change in unrealized gains, net of tax</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#8212;</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:OtherComprehensiveIncomeAvailableforsaleSecuritiesAdjustmentNetOfTaxPortionAttributableToParent" id="Fact_1d4ee35e2c024559a37a84c8318f1601" contextRef="c20210101to20211231_StatementEquityComponentsAxis_CommonStockMember" unitRef="U001" decimals="-3" scale="3" format="ixt:zerodash">&#8212;</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:OtherComprehensiveIncomeAvailableforsaleSecuritiesAdjustmentNetOfTaxPortionAttributableToParent" id="Fact_7d3cc28a8d714c2892f946fd7d69085f" contextRef="c20210101to20211231_StatementEquityComponentsAxis_AdditionalPaidInCapitalMember" unitRef="U001" decimals="-3" scale="3" format="ixt:zerodash">&#8212;</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:OtherComprehensiveIncomeAvailableforsaleSecuritiesAdjustmentNetOfTaxPortionAttributableToParent" id="Fact_5b13464fcc914218a22621cadb3f01cf" contextRef="c20210101to20211231_StatementEquityComponentsAxis_AccumulatedOtherComprehensiveIncomeMember" unitRef="U001" decimals="-3" scale="3" sign="-" format="ixt:numdotdecimal">11,486</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:OtherComprehensiveIncomeAvailableforsaleSecuritiesAdjustmentNetOfTaxPortionAttributableToParent" id="Fact_9612b70e89ab4a65902c6735833f3cf2" contextRef="c20210101to20211231_StatementEquityComponentsAxis_RetainedEarningsMember" unitRef="U001" decimals="-3" scale="3" format="ixt:zerodash">&#8212;</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:OtherComprehensiveIncomeAvailableforsaleSecuritiesAdjustmentNetOfTaxPortionAttributableToParent" id="Fact_2efba56ab30f4a1787e7e7083c0cea31" contextRef="c20210101to20211231_StatementEquityComponentsAxis_ParentMember" unitRef="U001" decimals="-3" scale="3" sign="-" format="ixt:numdotdecimal">11,486</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:OtherComprehensiveIncomeAvailableforsaleSecuritiesAdjustmentNetOfTaxPortionAttributableToParent" id="Fact_30984b5d00c64ee78163e3107fdca05d" contextRef="c20210101to20211231_StatementEquityComponentsAxis_NoncontrollingInterestMember" unitRef="U001" decimals="-3" scale="3" format="ixt:zerodash">&#8212;</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:OtherComprehensiveIncomeAvailableforsaleSecuritiesAdjustmentNetOfTaxPortionAttributableToParent" id="Fact_48167af9646f4982bdfaad59e0abcc5e" contextRef="c20210101to20211231" unitRef="U001" decimals="-3" scale="3" sign="-" format="ixt:numdotdecimal">11,486</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 20%;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Foreign currency translation</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#8212;</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:OtherComprehensiveIncomeForeignCurrencyTransactionAndTranslationGainLossArisingDuringPeriodNetOfTax" id="Fact_ce16072ab9b244a89d48f9a6da9f2ec7" contextRef="c20210101to20211231_StatementEquityComponentsAxis_CommonStockMember" unitRef="U001" decimals="-3" scale="3" format="ixt:zerodash">&#8212;</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:OtherComprehensiveIncomeForeignCurrencyTransactionAndTranslationGainLossArisingDuringPeriodNetOfTax" id="Fact_f3399875cb2a4718beaa89abf3740adb" contextRef="c20210101to20211231_StatementEquityComponentsAxis_AdditionalPaidInCapitalMember" unitRef="U001" decimals="-3" scale="3" format="ixt:zerodash">&#8212;</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:OtherComprehensiveIncomeForeignCurrencyTransactionAndTranslationGainLossArisingDuringPeriodNetOfTax" id="Fact_5e4f250c628941c5ab8f2733d1fe80b1" contextRef="c20210101to20211231_StatementEquityComponentsAxis_AccumulatedOtherComprehensiveIncomeMember" unitRef="U001" decimals="-3" scale="3" sign="-" format="ixt:numdotdecimal">111</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:OtherComprehensiveIncomeForeignCurrencyTransactionAndTranslationGainLossArisingDuringPeriodNetOfTax" id="Fact_9fd03cd0f21e43968c5091b9a0144faa" contextRef="c20210101to20211231_StatementEquityComponentsAxis_RetainedEarningsMember" unitRef="U001" decimals="-3" scale="3" format="ixt:zerodash">&#8212;</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:OtherComprehensiveIncomeForeignCurrencyTransactionAndTranslationGainLossArisingDuringPeriodNetOfTax" id="Fact_d7f12853e21647d092a6acdeb0554051" contextRef="c20210101to20211231_StatementEquityComponentsAxis_ParentMember" unitRef="U001" decimals="-3" scale="3" sign="-" format="ixt:numdotdecimal">111</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%;" colspan="1">
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%;" colspan="1">
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">
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        </td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 20%; background-color: #CCEEFF;">
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        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #CCEEFF;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #CCEEFF;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #CCEEFF;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #CCEEFF;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #CCEEFF;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #CCEEFF;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:StockIssuedDuringPeriodValueShareBasedCompensationGross" id="Fact_d2915794d3524068818ebf5287d8cb34" contextRef="c20210101to20211231_StatementEquityComponentsAxis_NoncontrollingInterestMember" unitRef="U001" decimals="-3" scale="3" format="ixt:zerodash">&#8212;</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:StockIssuedDuringPeriodValueShareBasedCompensationGross" id="Fact_16eddf25382740f89ca0946d88b1d303" contextRef="c20210101to20211231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">11,564</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 20%;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Issuance of warrants</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#8212;</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:AdjustmentsToAdditionalPaidInCapitalWarrantIssued" id="Fact_8978cd6f0b6c41fd91af0d0631212004" contextRef="c20210101to20211231_StatementEquityComponentsAxis_CommonStockMember" unitRef="U001" decimals="-3" scale="3" format="ixt:zerodash">&#8212;</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:AdjustmentsToAdditionalPaidInCapitalWarrantIssued" id="Fact_9bea72690cec41a685ef1c664eed2deb" contextRef="c20210101to20211231_StatementEquityComponentsAxis_AdditionalPaidInCapitalMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">89,752</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:AdjustmentsToAdditionalPaidInCapitalWarrantIssued" id="Fact_f0e473ce342e4a1f8f850cd92326c7fc" contextRef="c20210101to20211231_StatementEquityComponentsAxis_AccumulatedOtherComprehensiveIncomeMember" unitRef="U001" decimals="-3" scale="3" format="ixt:zerodash">&#8212;</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:AdjustmentsToAdditionalPaidInCapitalWarrantIssued" id="Fact_fa9a36f8a5634f14a7cea219d8a890bf" contextRef="c20210101to20211231_StatementEquityComponentsAxis_RetainedEarningsMember" unitRef="U001" decimals="-3" scale="3" format="ixt:zerodash">&#8212;</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:AdjustmentsToAdditionalPaidInCapitalWarrantIssued" id="Fact_49d8b8460e684b5e8864799c0abdde75" contextRef="c20210101to20211231_StatementEquityComponentsAxis_ParentMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">89,752</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:AdjustmentsToAdditionalPaidInCapitalWarrantIssued" id="Fact_882a028e866e41e28838575efd2ebd78" contextRef="c20210101to20211231_StatementEquityComponentsAxis_NoncontrollingInterestMember" unitRef="U001" decimals="-3" scale="3" format="ixt:zerodash">&#8212;</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:AdjustmentsToAdditionalPaidInCapitalWarrantIssued" id="Fact_f8f79b04c8fa484ca538d0e17602dd70" contextRef="c20210101to20211231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">89,752</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 20%; background-color: #CCEEFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Purchases of note hedges</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#8212;</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:AdjustmentsToAdditionalPaidInCapitalOther" id="Fact_633a39449db8432e82611fc5ce0ed1b7" contextRef="c20210101to20211231_StatementEquityComponentsAxis_CommonStockMember" unitRef="U001" decimals="-3" scale="3" format="ixt:zerodash">&#8212;</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:AdjustmentsToAdditionalPaidInCapitalOther" id="Fact_ace3af22303646f6a534986c2b45f43c" contextRef="c20210101to20211231_StatementEquityComponentsAxis_AdditionalPaidInCapitalMember" unitRef="U001" decimals="-3" scale="3" sign="-" format="ixt:numdotdecimal">136,620</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:AdjustmentsToAdditionalPaidInCapitalOther" id="Fact_3f71ee33398947bca9d7da2795e6ffbe" contextRef="c20210101to20211231_StatementEquityComponentsAxis_AccumulatedOtherComprehensiveIncomeMember" unitRef="U001" decimals="-3" scale="3" format="ixt:zerodash">&#8212;</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:AdjustmentsToAdditionalPaidInCapitalOther" id="Fact_2db606cecb0240709e49a684ebaecfdc" contextRef="c20210101to20211231_StatementEquityComponentsAxis_RetainedEarningsMember" unitRef="U001" decimals="-3" scale="3" format="ixt:zerodash">&#8212;</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:AdjustmentsToAdditionalPaidInCapitalOther" id="Fact_5c3e6547d9c74e17bd5e1346323f87b4" contextRef="c20210101to20211231_StatementEquityComponentsAxis_ParentMember" unitRef="U001" decimals="-3" scale="3" sign="-" format="ixt:numdotdecimal">136,620</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:AdjustmentsToAdditionalPaidInCapitalOther" id="Fact_50826e063fef49c7893ebef0ece20ddb" contextRef="c20210101to20211231_StatementEquityComponentsAxis_NoncontrollingInterestMember" unitRef="U001" decimals="-3" scale="3" format="ixt:zerodash">&#8212;</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #CCEEFF;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
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  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 20%;">
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        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#8212;</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:AdjustmentsToAdditionalPaidInCapitalSharebasedCompensationRequisiteServicePeriodRecognitionValue" id="Fact_3984b222032b4f89a6067a1a1115ba11" contextRef="c20210101to20211231_StatementEquityComponentsAxis_CommonStockMember" unitRef="U001" decimals="-3" scale="3" format="ixt:zerodash">&#8212;</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:AdjustmentsToAdditionalPaidInCapitalSharebasedCompensationRequisiteServicePeriodRecognitionValue" id="Fact_56cd8c22ed5544bbb6a31360f46ba604" contextRef="c20210101to20211231_StatementEquityComponentsAxis_AccumulatedOtherComprehensiveIncomeMember" unitRef="U001" decimals="-3" scale="3" format="ixt:zerodash">&#8212;</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:AdjustmentsToAdditionalPaidInCapitalSharebasedCompensationRequisiteServicePeriodRecognitionValue" id="Fact_3058a5ae36ca41e8bec4bc5d2b8cd05a" contextRef="c20210101to20211231_StatementEquityComponentsAxis_RetainedEarningsMember" unitRef="U001" decimals="-3" scale="3" format="ixt:zerodash">&#8212;</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:AdjustmentsToAdditionalPaidInCapitalSharebasedCompensationRequisiteServicePeriodRecognitionValue" id="Fact_3ae1822c76c04a1992dde0883ff4a37c" contextRef="c20210101to20211231_StatementEquityComponentsAxis_ParentMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">120,678</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:AdjustmentsToAdditionalPaidInCapitalSharebasedCompensationRequisiteServicePeriodRecognitionValue" id="Fact_a248bf7583bf4355a4573ce2eac838af" contextRef="c20210101to20211231_StatementEquityComponentsAxis_NoncontrollingInterestMember" unitRef="U001" decimals="-3" scale="3" format="ixt:zerodash">&#8212;</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:AdjustmentsToAdditionalPaidInCapitalSharebasedCompensationRequisiteServicePeriodRecognitionValue" id="Fact_1d5e95fbc00e4e7180ca1c989b620568" contextRef="c20210101to20211231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">120,678</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 20%; padding-bottom: 2px; background-color: #CCEEFF;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Payments of tax withholdings related to vesting of employee stock awards and exercise of employee
            stock options</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:SharesPaidForTaxWithholdingForShareBasedCompensation" id="Fact_bb9a0a3c8c0f460d8907df35ba024998" contextRef="c20210101to20211231_StatementEquityComponentsAxis_CommonStockMember" unitRef="U002" decimals="-3" scale="3" format="ixt:numdotdecimal">288</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:AdjustmentsRelatedToTaxWithholdingForShareBasedCompensation" id="Fact_89851b9aadd54cb785b1306c44008fb2" contextRef="c20210101to20211231_StatementEquityComponentsAxis_CommonStockMember" unitRef="U001" decimals="-3" scale="3" format="ixt:zerodash">&#8212;</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:AdjustmentsRelatedToTaxWithholdingForShareBasedCompensation" id="Fact_1c7c759f6400434fbbc88dcf198244d3" contextRef="c20210101to20211231_StatementEquityComponentsAxis_AdditionalPaidInCapitalMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">16,725</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:AdjustmentsRelatedToTaxWithholdingForShareBasedCompensation" id="Fact_d0ee55a07bf34b8e8d13580401c7c54f" contextRef="c20210101to20211231_StatementEquityComponentsAxis_AccumulatedOtherComprehensiveIncomeMember" unitRef="U001" decimals="-3" scale="3" format="ixt:zerodash">&#8212;</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:AdjustmentsRelatedToTaxWithholdingForShareBasedCompensation" id="Fact_e3a3359a6199474d974e8f7baa127a45" contextRef="c20210101to20211231_StatementEquityComponentsAxis_RetainedEarningsMember" unitRef="U001" decimals="-3" scale="3" format="ixt:zerodash">&#8212;</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:AdjustmentsRelatedToTaxWithholdingForShareBasedCompensation" id="Fact_2980774b43c54434b88a59ac547cddbb" contextRef="c20210101to20211231_StatementEquityComponentsAxis_ParentMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">16,725</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:AdjustmentsRelatedToTaxWithholdingForShareBasedCompensation" id="Fact_d14b5866235c4ab1aeb47f1c1c6ca402" contextRef="c20210101to20211231_StatementEquityComponentsAxis_NoncontrollingInterestMember" unitRef="U001" decimals="-3" scale="3" format="ixt:zerodash">&#8212;</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:AdjustmentsRelatedToTaxWithholdingForShareBasedCompensation" id="Fact_0c79c70d50d2443aa074c4fd2102d981" contextRef="c20210101to20211231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">16,725</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 20%; padding-bottom: 4px;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Balance at December 31, <span style="text-indent: 0pt;">2021</span></div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%; border-bottom: #000000 double 4px;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:SharesIssued" id="Fact_1d1f0719541143f2ae5ac80a19fb4007" contextRef="c20211231_StatementEquityComponentsAxis_CommonStockMember" unitRef="U002" decimals="-3" scale="3" format="ixt:numdotdecimal">141,210</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%; border-bottom: #000000 double 4px;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:StockholdersEquityIncludingPortionAttributableToNoncontrollingInterest" id="Fact_74064f8288c1486bb2496106d6fd8aa7" contextRef="c20211231_StatementEquityComponentsAxis_CommonStockMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">141</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%; border-bottom: #000000 double 4px;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:StockholdersEquityIncludingPortionAttributableToNoncontrollingInterest" id="Fact_41e9cc98d38a41778cf6eb70280117c2" contextRef="c20211231_StatementEquityComponentsAxis_AdditionalPaidInCapitalMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">1,964,167</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%; border-bottom: #000000 double 4px;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:StockholdersEquityIncludingPortionAttributableToNoncontrollingInterest" id="Fact_aced03aa44534069aacaa219a523b4fc" contextRef="c20211231_StatementEquityComponentsAxis_AccumulatedOtherComprehensiveIncomeMember" unitRef="U001" decimals="-3" scale="3" sign="-" format="ixt:numdotdecimal">32,668</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%; border-bottom: #000000 double 4px;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:StockholdersEquityIncludingPortionAttributableToNoncontrollingInterest" id="Fact_05be694dedb54ba2866c147ae24a252c" contextRef="c20211231_StatementEquityComponentsAxis_RetainedEarningsMember" unitRef="U001" decimals="-3" scale="3" sign="-" format="ixt:numdotdecimal">1,159,903</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%; border-bottom: #000000 double 4px;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:StockholdersEquityIncludingPortionAttributableToNoncontrollingInterest" id="Fact_08847d93eb194cbc8441f04f28fab350" contextRef="c20211231_StatementEquityComponentsAxis_ParentMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">771,737</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
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    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%; border-bottom: #000000 double 4px;" colspan="1">
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 7%; border-bottom: #000000 double 4px;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>


</table>
  <div><br />
  </div>

  <div><br />
  </div>

  <table cellspacing="0" cellpadding="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">


  <tr>

    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">*</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We revised our 2018, 2019 and 2020 amounts to reflect the simplified convertible instruments accounting guidance, which we adopted retrospectively. Refer
            to Note 1, <span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Organization and Significant Accounting Policies</span>, for further information.</div>
        </td>

  </tr>


</table>
  <div><br />
  </div>

  <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">See accompanying notes.</div>

  <div><br />
  </div>

  <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" class="DSPFPageBreakArea">
    <div class="DSPFPageFooter">
      <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">F-<span class="DSPFPageNumber">7</span></div>

    </div>

    <div style="page-break-after:always;" class="DSPFPageBreak">
      <hr style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;" /></div>


  </div>

  <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">IONIS PHARMACEUTICALS, INC.</div>

  <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">CONSOLIDATED STATEMENTS OF CASH FLOWS</div>

  <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">(In thousands)</div>

  <div><br />
  </div>

  <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;" class="cfttable">


  <tr>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">

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    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" colspan="10">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" colspan="2">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2021</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" colspan="2">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2020</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" colspan="2">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2019</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom;">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="2">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="2">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">(as revised*)</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="2">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">(as revised*)</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Operating activities:</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="2">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="2">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="2">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Net income (loss)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:ProfitLoss" id="Fact_74418700e541478eadc5aced379a124b" contextRef="c20210101to20211231" unitRef="U001" decimals="-3" scale="3" sign="-" format="ixt:numdotdecimal">28,597</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:ProfitLoss" id="Fact_3fb9b4a0ea3c4f27a1399c4165b5801f" contextRef="c20200101to20201231" unitRef="U001" decimals="-3" scale="3" sign="-" format="ixt:numdotdecimal">479,743</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:ProfitLoss" id="Fact_39b8baae321b42f7a5f4fa01fd0016cc" contextRef="c20190101to20191231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">287,259</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 64%;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 18pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Adjustments to reconcile net income (loss) to net cash provided by operating activities:</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 18pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Depreciation</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:Depreciation" id="Fact_6e647886642547db938d5dd7ac6cb6ac" contextRef="c20200101to20201231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">13,365</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 64%;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 18pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Amortization of right-of-use operating lease assets</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 18pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Amortization of patents</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:AmortizationOfIntangibleAssets" id="Fact_c4419687fb464fe5bdc6e0d2984bef36" contextRef="c20210101to20211231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">2,352</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 64%;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 18pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Amortization of premium (discount) on investments, net</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">
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  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;">
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    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 64%;">
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    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;">
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    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 64%;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 18pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Gain on investments</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 18pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Deferred income taxes, including changes in valuation allowance</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 64%;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 18pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Non-cash losses related to patents</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 18pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Changes in operating assets and liabilities:</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 64%;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 27pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Contracts receivable</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
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    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">
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  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;">
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    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:IncreaseDecreaseInInventories" id="Fact_085c28a5897b4fdc902bd3eb96b38cfe" contextRef="c20210101to20211231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">2,841</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
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    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
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    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
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        </td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 64%;">
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    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:IncreaseDecreaseInOtherOperatingAssets" id="Fact_864803efe0c94dcc8ef6304a526731c5" contextRef="c20210101to20211231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">877</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;">
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    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="ions:IncreaseDecreaseInIncomeTaxesReceivablePayable" id="Fact_f85089599ebd420ab0dfeb4f295cfc60" contextRef="c20210101to20211231" unitRef="U001" decimals="-3" scale="3" sign="-" format="ixt:numdotdecimal">1,008</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="ions:IncreaseDecreaseInIncomeTaxesReceivablePayable" id="Fact_39986573e52c4b22a4e7523064d4a2b9" contextRef="c20200101to20201231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">89</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 64%;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 27pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Accounts payable</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:IncreaseDecreaseInAccountsPayable" id="Fact_a2882fd1ebf24bd894bdd232be12bb88" contextRef="c20210101to20211231" unitRef="U001" decimals="-3" scale="3" sign="-" format="ixt:numdotdecimal">6,000</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:IncreaseDecreaseInAccountsPayable" id="Fact_19037c392df44ffaa87bb0e8fa58cb64" contextRef="c20200101to20201231" unitRef="U001" decimals="-3" scale="3" sign="-" format="ixt:numdotdecimal">2,755</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:IncreaseDecreaseInAccountsPayable" id="Fact_fdf8edb884a5467dbfa35ec370b22a73" contextRef="c20190101to20191231" unitRef="U001" decimals="-3" scale="3" sign="-" format="ixt:numdotdecimal">16,343</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 27pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Income taxes</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:IncreaseDecreaseInIncomeTaxesPayableNetOfIncomeTaxesReceivable" id="Fact_cbe5d4f72a7b47b6bbf20a734efa0ff9" contextRef="c20210101to20211231" unitRef="U001" decimals="-3" scale="3" sign="-" format="ixt:numdotdecimal">1,288</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:IncreaseDecreaseInIncomeTaxesPayableNetOfIncomeTaxesReceivable" id="Fact_928bf4ded5484066ada8046ae256e5bd" contextRef="c20200101to20201231" unitRef="U001" decimals="-3" scale="3" sign="-" format="ixt:numdotdecimal">31,190</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:IncreaseDecreaseInIncomeTaxesPayableNetOfIncomeTaxesReceivable" id="Fact_35b11d3a61584178b39dbfdaa63e5d23" contextRef="c20190101to20191231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">31,656</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 64%;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 27pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Accrued compensation</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:IncreaseDecreaseInOtherEmployeeRelatedLiabilities" id="Fact_be8c0f046cfa423dbf8943de92eacba3" contextRef="c20210101to20211231" unitRef="U001" decimals="-3" scale="3" sign="-" format="ixt:numdotdecimal">26,918</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:IncreaseDecreaseInOtherEmployeeRelatedLiabilities" id="Fact_c2e1e6792bbf4d45bb9581a0838da942" contextRef="c20200101to20201231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">28,371</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:IncreaseDecreaseInOtherEmployeeRelatedLiabilities" id="Fact_1610f4d30b0d484693cb2ccb1dd531cd" contextRef="c20190101to20191231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">8,089</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 27pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Accrued liabilities and other current liabilities</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:IncreaseDecreaseInOtherAccountsPayableAndAccruedLiabilities" id="Fact_c2d76681eaf6401eb0820fac87914240" contextRef="c20210101to20211231" unitRef="U001" decimals="-3" scale="3" sign="-" format="ixt:numdotdecimal">8,381</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:IncreaseDecreaseInOtherAccountsPayableAndAccruedLiabilities" id="Fact_46fb0027cc774970b1e33fe73a8d0134" contextRef="c20200101to20201231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">32,424</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:IncreaseDecreaseInOtherAccountsPayableAndAccruedLiabilities" id="Fact_fd2ee65b38e940ef8147608e66310a1d" contextRef="c20190101to20191231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">16,406</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 2px;">
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    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" colspan="1">
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" colspan="1">
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    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" colspan="1">
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" colspan="1">
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    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" colspan="1">
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" colspan="1">
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        </td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #CCEEFF;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Net cash provided by operating activities</div>
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    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 64%;">
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    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 27pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Purchases of short-term investments</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:PaymentsToAcquireAvailableForSaleSecuritiesDebt" id="Fact_e72b6b733f32469391537642ed9f915f" contextRef="c20210101to20211231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">1,124,193</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:PaymentsToAcquireAvailableForSaleSecuritiesDebt" id="Fact_dade26c6f20f4b60a4feec4e181794e8" contextRef="c20200101to20201231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">1,570,410</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:PaymentsToAcquireAvailableForSaleSecuritiesDebt" id="Fact_67fd6ba04f7343b8835d000a36955a72" contextRef="c20190101to20191231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">1,946,726</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 64%;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 27pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Proceeds from the sale of short-term investments</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:ProceedsFromSaleAndMaturityOfAvailableForSaleSecurities" id="Fact_4c7538b4bbdc45c8b0632c5597958d34" contextRef="c20210101to20211231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">1,344,185</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:ProceedsFromSaleAndMaturityOfAvailableForSaleSecurities" id="Fact_38e7752c94b34c97a1435e616eb5db40" contextRef="c20200101to20201231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">1,885,935</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:ProceedsFromSaleAndMaturityOfAvailableForSaleSecurities" id="Fact_80d5593638ef4ce1981649265ba744b9" contextRef="c20190101to20191231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">1,951,734</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 27pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Purchases of property, plant and equipment</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:PaymentsToAcquirePropertyPlantAndEquipment" id="Fact_af7f2fbf99644b83883250b2765bc5ae" contextRef="c20210101to20211231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">11,955</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:PaymentsToAcquirePropertyPlantAndEquipment" id="Fact_28d3f3d53dd04a84a5b65fcacb820e59" contextRef="c20200101to20201231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">35,120</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:PaymentsToAcquirePropertyPlantAndEquipment" id="Fact_77a9b1f4ce9d4712ac162eef39cf7ca1" contextRef="c20190101to20191231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">30,905</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 64%;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 27pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Acquisition of licenses and other assets, net</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:PaymentsToAcquireIntangibleAssets" id="Fact_c4ddbc47fdde42a994020ac78cea3e4d" contextRef="c20210101to20211231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">5,946</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:PaymentsToAcquireIntangibleAssets" id="Fact_dff874e0a9d440f2b2291df63ce33c1c" contextRef="c20200101to20201231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">5,928</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:PaymentsToAcquireIntangibleAssets" id="Fact_83d9fabba44a4c58856c75295f25be39" contextRef="c20190101to20191231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">5,377</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #CCEEFF;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 27pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Purchases of strategic investments</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:PaymentsToAcquireOtherInvestments" id="Fact_80fc4ad369ea4266aa819342e5a274f3" contextRef="c20210101to20211231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">7,185</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:PaymentsToAcquireOtherInvestments" id="Fact_2dd3f9b1b98e487c90386a8b5c2e7dbd" contextRef="c20200101to20201231" unitRef="U001" decimals="-3" scale="3" format="ixt:zerodash">&#8212;</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
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        </td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 2px;">
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    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" colspan="1">
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" colspan="1">
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" colspan="1">
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" colspan="1">
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        </td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;">
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        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 64%;">
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        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:ProceedsFromIssuanceOfSharesUnderIncentiveAndShareBasedCompensationPlansIncludingStockOptions" id="Fact_9766979c83c547faaf9db39fd1ec8b13" contextRef="c20210101to20211231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">11,565</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:ProceedsFromIssuanceOfSharesUnderIncentiveAndShareBasedCompensationPlansIncludingStockOptions" id="Fact_e8614ff277e9476fabd71fcec8d4876c" contextRef="c20200101to20201231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">52,036</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:ProceedsFromIssuanceOfSharesUnderIncentiveAndShareBasedCompensationPlansIncludingStockOptions" id="Fact_847a8383a3104ae19857ffdfc7350136" contextRef="c20190101to20191231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">119,657</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 27pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Payments of tax withholdings related to vesting of employee stock awards and exercise of employee
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        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:PaymentsRelatedToTaxWithholdingForShareBasedCompensation" id="Fact_d0c63549a159422d8925dbeac4505a02" contextRef="c20210101to20211231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">16,725</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:PaymentsRelatedToTaxWithholdingForShareBasedCompensation" id="Fact_4420366a0a5648d6bb96c8031145c0f8" contextRef="c20200101to20201231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">13,411</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:PaymentsRelatedToTaxWithholdingForShareBasedCompensation" id="Fact_0355270d749349ec8d585f6e041767cc" contextRef="c20190101to20191231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">19,242</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 64%;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 27pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Proceeds from the issuance of <span style="text-indent: 0pt;"><ix:nonFraction name="us-gaap:DebtInstrumentInterestRateStatedPercentage" id="Fact_1513b2e8ee8745e1a6d6ede2fdfd7366" contextRef="c20211231_DebtInstrumentAxis_ConvertibleSeniorNotes0PercentMember" unitRef="U003" decimals="2" scale="-2" format="ixt:numdotdecimal">0</ix:nonFraction> percent</span> convertible senior notes</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:ProceedsFromConvertibleDebt" id="Fact_4a615bd30cf04b2c8e3d6ef5f3655178" contextRef="c20210101to20211231_DebtInstrumentAxis_ConvertibleSeniorNotes0PercentMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">632,500</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:ProceedsFromConvertibleDebt" id="Fact_e572a2538ade494fa34b59c56be026f5" contextRef="c20200101to20201231_DebtInstrumentAxis_ConvertibleSeniorNotes0PercentMember" unitRef="U001" decimals="-3" scale="3" format="ixt:zerodash">&#8212;</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:ProceedsFromConvertibleDebt" id="Fact_03ab8d471d1e4c8daa6066ec97f4dae1" contextRef="c20190101to20191231_DebtInstrumentAxis_ConvertibleSeniorNotes0PercentMember" unitRef="U001" decimals="-3" scale="3" format="ixt:zerodash">&#8212;</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 27pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Proceeds from the issuance of <span style="text-indent: 0pt;"><ix:nonFraction name="us-gaap:DebtInstrumentInterestRateStatedPercentage" id="Fact_d059c5d1572341c7b1665fabcbd30820" contextRef="c20191231_DebtInstrumentAxis_ConvertibleSeniorNotes0125PercentMember" unitRef="U003" decimals="5" scale="-2" format="ixt:numdotdecimal">0.125</ix:nonFraction> percent</span> convertible senior notes</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:ProceedsFromConvertibleDebt" id="Fact_225e1862aa0445a6b71d0471dfa6b546" contextRef="c20210101to20211231_DebtInstrumentAxis_ConvertibleSeniorNotes0125PercentMember" unitRef="U001" decimals="-3" scale="3" format="ixt:zerodash">&#8212;</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:ProceedsFromConvertibleDebt" id="Fact_b7eedb2ae11b4edb9d5e14441f8c7798" contextRef="c20200101to20201231_DebtInstrumentAxis_ConvertibleSeniorNotes0125PercentMember" unitRef="U001" decimals="-3" scale="3" format="ixt:zerodash">&#8212;</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:ProceedsFromConvertibleDebt" id="Fact_fc4f30f07d0c493098e146a7aead7848" contextRef="c20190101to20191231_DebtInstrumentAxis_ConvertibleSeniorNotes0125PercentMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">109,500</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 64%;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 27pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="text-indent: 0pt;"><ix:nonFraction name="us-gaap:DebtInstrumentInterestRateStatedPercentage" id="Fact_cb89fb53ac9642199b9810bfb6bc7a9a" contextRef="c20211231_DebtInstrumentAxis_ConvertibleSeniorNotes0PercentMember" unitRef="U003" decimals="2" scale="-2" format="ixt:numdotdecimal">0</ix:nonFraction> percent</span> convertible senior notes issuance costs</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:PaymentsOfDebtIssuanceCosts" id="Fact_c265ed167f6849ca802177191ecfe56c" contextRef="c20210101to20211231_DebtInstrumentAxis_ConvertibleSeniorNotes0PercentMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">15,609</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:PaymentsOfDebtIssuanceCosts" id="Fact_71796689b9704e64b6e32c07bc23d966" contextRef="c20200101to20201231_DebtInstrumentAxis_ConvertibleSeniorNotes0PercentMember" unitRef="U001" decimals="-3" scale="3" format="ixt:zerodash">&#8212;</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:PaymentsOfDebtIssuanceCosts" id="Fact_373cff2ecd4749f3b5c73b03bbd03408" contextRef="c20190101to20191231_DebtInstrumentAxis_ConvertibleSeniorNotes0PercentMember" unitRef="U001" decimals="-3" scale="3" format="ixt:zerodash">&#8212;</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 27pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="text-indent: 0pt;"><ix:nonFraction name="us-gaap:DebtInstrumentInterestRateStatedPercentage" id="Fact_70f588014d3e4b30baa726f0da2418a1" contextRef="c20191231_DebtInstrumentAxis_ConvertibleSeniorNotes0125PercentMember" unitRef="U003" decimals="5" scale="-2" format="ixt:numdotdecimal">0.125</ix:nonFraction> percent</span> convertible senior notes issuance costs</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:PaymentsOfDebtIssuanceCosts" id="Fact_f313f339843849879880343bb3a88792" contextRef="c20200101to20201231_DebtInstrumentAxis_ConvertibleSeniorNotes0125PercentMember" unitRef="U001" decimals="-3" scale="3" format="ixt:zerodash">&#8212;</ix:nonFraction></div>
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
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  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 64%;">
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    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">
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    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;">
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    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
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    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:RepaymentsOfConvertibleDebt" id="Fact_e2c4d66efd61435abf43c876b223e173" contextRef="c20200101to20201231" unitRef="U001" decimals="-3" scale="3" format="ixt:zerodash">&#8212;</ix:nonFraction></div>
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:RepaymentsOfConvertibleDebt" id="Fact_dd36882e10e44acb8407f7c404b6f7bb" contextRef="c20190101to20191231" unitRef="U001" decimals="-3" scale="3" format="ixt:zerodash">&#8212;</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 64%;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 27pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Proceeds from issuance of warrants</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:ProceedsFromIssuanceOfWarrants" id="Fact_fd3083678ca946bc8c04d46f0ed04911" contextRef="c20200101to20201231" unitRef="U001" decimals="-3" scale="3" format="ixt:zerodash">&#8212;</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:ProceedsFromIssuanceOfWarrants" id="Fact_6a2730d1fb4e46bfbf665ffb2a8cec4f" contextRef="c20190101to20191231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">56,110</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 27pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Purchase of note hedges</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:PaymentsForHedgeFinancingActivities" id="Fact_93476033a0d54173bc9010c262c485d1" contextRef="c20210101to20211231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">136,620</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:PaymentsForHedgeFinancingActivities" id="Fact_f5757aa8a1b84931b13cb7b1821bd15a" contextRef="c20200101to20201231" unitRef="U001" decimals="-3" scale="3" format="ixt:zerodash">&#8212;</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:PaymentsForHedgeFinancingActivities" id="Fact_18ed7373cfed41688772a16bc1938cfc" contextRef="c20190101to20191231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">108,684</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 64%;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 27pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Repurchases and retirements of common stock</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:PaymentsForRepurchaseOfCommonStock" id="Fact_4ea9107410344f6ea56e07ac99f40f7d" contextRef="c20210101to20211231" unitRef="U001" decimals="-3" scale="3" format="ixt:zerodash">&#8212;</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:PaymentsForRepurchaseOfCommonStock" id="Fact_a877c68b655745d9b6bc70655c9025d0" contextRef="c20200101to20201231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">90,548</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:PaymentsForRepurchaseOfCommonStock" id="Fact_95cb066a3d5548738b8c9564f1c73b6c" contextRef="c20190101to20191231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">34,392</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 27pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Purchase of noncontrolling interest of Akcea Therapeutics, Inc., including c<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">ash payments for cancellation of Akcea Therapeutics, Inc. equity awards</span></div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:PaymentsToMinorityShareholders" id="Fact_b9c6d3a3d5254f63bed912805d966f1c" contextRef="c20210101to20211231" unitRef="U001" decimals="-3" scale="3" format="ixt:zerodash">&#8212;</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:PaymentsToMinorityShareholders" id="Fact_9a142918c8ac4d678b752b3c30b67418" contextRef="c20200101to20201231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">544,686</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:PaymentsToMinorityShareholders" id="Fact_05f1061adaa04d2d8d88f3adc5ec6f7b" contextRef="c20190101to20191231" unitRef="U001" decimals="-3" scale="3" format="ixt:zerodash">&#8212;</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 64%;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 27pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Principal payments on line of credit</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:RepaymentsOfLongTermLinesOfCredit" id="Fact_557667a97fa84b1f8a6a354d828e462f" contextRef="c20210101to20211231" unitRef="U001" decimals="-3" scale="3" format="ixt:zerodash">&#8212;</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">
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  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;">
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    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
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    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 64%;">
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        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Net increase (decrease) in cash and cash equivalents</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:CashCashEquivalentsRestrictedCashAndRestrictedCashEquivalentsPeriodIncreaseDecreaseIncludingExchangeRateEffect" id="Fact_323a2b839be44267a57618d86a42c961" contextRef="c20200101to20201231" unitRef="U001" decimals="-3" scale="3" sign="-" format="ixt:numdotdecimal">285,623</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 2px;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 27pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Cash and cash equivalents at beginning of year</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:CashCashEquivalentsRestrictedCashAndRestrictedCashEquivalents" id="Fact_07f0dd136aab4f3da006f1b408361fc2" contextRef="c20201231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">397,664</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:CashCashEquivalentsRestrictedCashAndRestrictedCashEquivalents" id="Fact_2593d613c153433fa9848ecd8821eae6" contextRef="c20191231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">683,287</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:CashCashEquivalentsRestrictedCashAndRestrictedCashEquivalents" id="Fact_ad3a4e4b42454d7f972b7be959dc74c6" contextRef="c20181231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">278,820</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 4px; background-color: #CCEEFF;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 27pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Cash and cash equivalents at end of year</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:CashCashEquivalentsRestrictedCashAndRestrictedCashEquivalents" id="Fact_3dde4ee002f342ccb3133c6d89c8a4d4" contextRef="c20211231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">869,191</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:CashCashEquivalentsRestrictedCashAndRestrictedCashEquivalents" id="Fact_033a33f533a14ef7ad9a34a1466c774e" contextRef="c20191231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">683,287</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>


</table>
  <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" class="DSPFPageBreakArea">
    <div class="DSPFPageFooter">
      <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">F-<span class="DSPFPageNumber">8</span></div>

    </div>

    <div style="page-break-after:always;" class="DSPFPageBreak">
      <hr style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;" /></div>


  </div>

  <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">IONIS PHARMACEUTICALS, INC.</div>

  <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">CONSOLIDATED STATEMENTS OF CASH FLOWS</div>

  <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">(In thousands)</div>

  <div><br />
  </div>

  <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;" class="cfttable">


  <tr>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">

        </td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" colspan="10">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Year Ended December 31,</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" colspan="2">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2021</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" colspan="2">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2020</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" colspan="2">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2019</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Supplemental disclosures of cash flow information:</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="2">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="2">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="2">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 18pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Interest paid</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:InterestPaidNet" id="Fact_6419ea93d02441d486308749fc3a69a2" contextRef="c20210101to20211231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">4,778</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
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    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

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  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 64%;">
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    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
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    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
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    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

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  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;">
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    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 64%;">
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    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 18pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Amounts accrued for capital and patent expenditures</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="ions:NonCashCapitalAndPatentExpenditures" id="Fact_7a2dfc2a1d1a4605b0263f1b76478acd" contextRef="c20210101to20211231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">705</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="ions:NonCashCapitalAndPatentExpenditures" id="Fact_f73d104fa14b4c6da9e22f41979ab811" contextRef="c20200101to20201231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">4,059</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="ions:NonCashCapitalAndPatentExpenditures" id="Fact_2e89ce6cc7c74c4aafae3dbbf97500c4" contextRef="c20190101to20191231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">3,126</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 64%;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 18pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="text-indent: 0pt;"><ix:nonFraction name="us-gaap:DebtInstrumentInterestRateStatedPercentage" id="Fact_85b2c604ea1643578611fc5d1efde99f" contextRef="c20191231_DebtInstrumentAxis_ConvertibleSeniorNotes0125PercentMember" unitRef="U003" decimals="5" scale="-2" format="ixt:numdotdecimal">0.125</ix:nonFraction> percent</span> convertible senior notes principal issued related to our December 2019 debt exchange/issuance</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:NotesIssued1" id="Fact_e452c9110d204db286b4d7a4585eafa6" contextRef="c20210101to20211231" unitRef="U001" decimals="-3" scale="3" format="ixt:zerodash">&#8212;</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:NotesIssued1" id="Fact_d0dbcfc39d7c47a1af1ba3c03948fda2" contextRef="c20200101to20201231" unitRef="U001" decimals="-3" scale="3" format="ixt:zerodash">&#8212;</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:NotesIssued1" id="Fact_2ee6ccbbced34fb287910e9ecbf356a1" contextRef="c20190101to20191231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">439,326</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 18pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="text-indent: 0pt;"><ix:nonFraction name="us-gaap:DebtInstrumentInterestRateStatedPercentage" id="Fact_0fb7afd855e24e069c48f8df5ed96d3d" contextRef="c20211231_DebtInstrumentAxis_ConvertibleSeniorNotes1PercentMember" unitRef="U003" decimals="2" scale="-2" format="ixt:numdotdecimal">1</ix:nonFraction> percent</span> convertible senior notes principal extinguished related to our December 2019 debt exchange</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:NotesReduction" id="Fact_bc295cc1c33c406fad19e7e492f2d1f4" contextRef="c20210101to20211231" unitRef="U001" decimals="-3" scale="3" format="ixt:zerodash">&#8212;</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:NotesReduction" id="Fact_46271695a609453fa312be945545847b" contextRef="c20200101to20201231" unitRef="U001" decimals="-3" scale="3" format="ixt:zerodash">&#8212;</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:NotesReduction" id="Fact_7b6bb05322ef48118b8b67bcc80bfb25" contextRef="c20190101to20191231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">375,590</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>


</table>
  <div><br />
  </div>

  <div><br />
  </div>

  <table cellspacing="0" cellpadding="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">


  <tr>

    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">*</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We revised our 2020 and 2019 amounts to reflect the simplified convertible instruments accounting guidance, which we adopted retrospectively. Refer to
            Note 1, <span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Organization and Significant Accounting Policies</span>, for further information.</div>
        </td>

  </tr>


</table>
  <div><br />
  </div>

  <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">See accompanying notes.</div>

  <div><br />
  </div>

  <div><br />
  </div>

  <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" class="DSPFPageBreakArea">
    <div class="DSPFPageFooter">
      <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">F-<span class="DSPFPageNumber">9</span></div>

    </div>

    <div style="page-break-after:always;" class="DSPFPageBreak">
      <hr style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;" /></div>


  </div>

  <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">IONIS PHARMACEUTICALS, INC.</div>

  <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">NOTES TO CONSOLIDATED FINANCIAL STATEMENTS</div>

  <div><br />
  </div>
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<div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">1. Organization and Significant Accounting Policies</div>
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<div><br />
  </div>
</ix:continuation>
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<div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Basis of Presentation</div>
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<div><br />
  </div>
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<div style="display:none;"><br /></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">In our consolidated financial statements we included the accounts of Ionis Pharmaceuticals, Inc. and the consolidated
    results of our subsidiary, Akcea Therapeutics, Inc. and its wholly owned subsidiaries (&#8220;we&#8221;, &#8220;us&#8221; or &#8220;our&#8221;). We formed Akcea in December 2014. In July 2017, Akcea completed an initial public offering, or IPO, which reduced our ownership of Akcea&#8217;s
    common stock below <ix:nonFraction name="us-gaap:MinorityInterestOwnershipPercentageByParent" id="Fact_a88597664460426696b9ccf265c067d6" contextRef="c20170630_OwnershipAxis_AkceaTherapeuticsIncMember_RangeAxis_MaximumMember" unitRef="U003" decimals="2" scale="-2" format="ixt:numdotdecimal">100</ix:nonFraction> percent. In October 2020, we completed a merger transaction with Akcea such that following the completion of the merger,
    Akcea became our wholly owned subsidiary. We will refer to this transaction as the Akcea Merger throughout the remainder of this document. We reflected changes in our ownership percentage in our financial statements as an adjustment to noncontrolling
    interest in the period the changes occurred<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">.</span></div>
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<div><br />
  </div>
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<div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Organization and Business Activity</div>
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<div style="display:none;"><br /></div>
<div style="text-align: justify; text-indent: 36pt;"><br />
  </div>
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<div style="display:none;"><br /></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We incorporated in California on January 10, 1989. In conjunction with our IPO, we reorganized as a Delaware corporation
    in April 1991. We were organized principally to develop human therapeutic medicines using antisense technology. In December 2015, we changed our name from Isis Pharmaceuticals, Inc. to Ionis Pharmaceuticals, Inc.</div>
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<div><br />
  </div>
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  <ix:continuation id="Text_ba6a171da9294812a4a91832efce6f8c10" continuedAt="Text_ba6a171da9294812a4a91832efce6f8c11"><ix:nonNumeric name="us-gaap:EarningsPerSharePolicyTextBlock" id="Text_47e97970a2d74b528c3d5e13d3b65bad" contextRef="c20210101to20211231" escape="true" continuedAt="Text_2006c403e53d492d92213d456f5da9261">
<div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Basic and Diluted Net Income (Loss) per Share</div>
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<div><br />
  </div>
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  <ix:continuation id="Text_ba6a171da9294812a4a91832efce6f8c12" continuedAt="Text_ba6a171da9294812a4a91832efce6f8c13"><ix:continuation id="Text_2006c403e53d492d92213d456f5da9262" continuedAt="Text_2006c403e53d492d92213d456f5da9263">
<div style="display:none;"><br /></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;">Basic net income (loss) per share</div>
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  <ix:continuation id="Text_ba6a171da9294812a4a91832efce6f8c13" continuedAt="Text_ba6a171da9294812a4a91832efce6f8c14"><ix:continuation id="Text_2006c403e53d492d92213d456f5da9263" continuedAt="Text_2006c403e53d492d92213d456f5da9264">
<div><br />
  </div>
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  <ix:continuation id="Text_ba6a171da9294812a4a91832efce6f8c14" continuedAt="Text_ba6a171da9294812a4a91832efce6f8c15"><ix:continuation id="Text_2006c403e53d492d92213d456f5da9264" continuedAt="Text_2006c403e53d492d92213d456f5da9265">
<div style="display:none;"><br /></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We compute basic net income (loss) per share by dividing the total net income (loss) attributable to our common
    stockholders by our weighted-average number of common shares outstanding during the period. For the year ended December 31, 2021, we did not have to consider Akcea results separately in our calculation because we owned <ix:nonFraction name="us-gaap:MinorityInterestOwnershipPercentageByParent" id="Fact_f65a71d42ef046458f851b185dab48a4" contextRef="c20211231_OwnershipAxis_AkceaTherapeuticsIncMember" unitRef="U003" decimals="2" scale="-2" format="ixt:numdotdecimal">100</ix:nonFraction> percent of Akcea for the entire period. Our basic net loss per share for the year ended December 31, 2021 was $<ix:nonFraction name="us-gaap:EarningsPerShareBasic" id="Fact_a97fd98180da49a2889ec6c1d1bbecdb" contextRef="c20210101to20211231" unitRef="U004" decimals="2" sign="-" scale="0" format="ixt:numdotdecimal">0.20</ix:nonFraction>.</div>
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<div><br />
  </div>
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  <ix:continuation id="Text_ba6a171da9294812a4a91832efce6f8c16" continuedAt="Text_ba6a171da9294812a4a91832efce6f8c17"><ix:continuation id="Text_2006c403e53d492d92213d456f5da9266" continuedAt="Text_2006c403e53d492d92213d456f5da9267">
<div style="display:none;"><br /></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">For the years ended December 31, 2020 and 2019, we calculated total net income (loss) attributable to our common
    stockholders for each year using our net income (loss) for Ionis on a stand-alone basis plus our share of Akcea&#8217;s net income (loss) for the period. To calculate the portion of Akcea&#8217;s net income (loss) attributable to our ownership for each year, we
    multiplied Akcea&#8217;s income (loss) per share by the weighted average shares we owned in Akcea during the period. As a result of this calculation, our total net income (loss) available to Ionis common stockholders for the calculation of net income (loss)
    per share is different than net income (loss) attributable to Ionis Pharmaceuticals, Inc. common stockholders in our consolidated statements of operations for each year.</div>
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<div><br />
  </div>
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  <ix:continuation id="Text_ba6a171da9294812a4a91832efce6f8c18" continuedAt="Text_ba6a171da9294812a4a91832efce6f8c19"><ix:continuation id="Text_2006c403e53d492d92213d456f5da9268" continuedAt="Text_2006c403e53d492d92213d456f5da9269"><ix:nonNumeric name="us-gaap:ScheduleOfEarningsPerShareBasicByCommonClassTextBlock" id="Text_6255ce3fc5024406b256c4e5a5be9dd3" contextRef="c20210101to20211231" escape="true" continuedAt="Text_86b296ab44ac4ec5a463f2e07a7953861">
<div style="display:none;"><br /></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We calculated our basic net loss per share for the year ended December 31, 2020 as follows (in thousands, except
    per share amounts):</div>
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<div><br />
  </div>
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<table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;" class="cfttable">


  <tr>

    <td valign="bottom" style="vertical-align: bottom; border-bottom: #000000 2px solid; white-space: nowrap;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Year Ended December 31, 2020</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px; white-space: nowrap;" colspan="2">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Weighted</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Average Shares</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Owned in Akcea</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px; white-space: nowrap;" colspan="2">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Akcea</span>&#8217;<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">s</span></div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Net Loss</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Per Share</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px; white-space: nowrap;" colspan="2">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Basic Net Loss</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Per Share</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Calculation</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: top; width: 64%; background-color: #CCEEFF; white-space: nowrap;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Akcea&#8217;s net loss in the pre-merger period attributable to our ownership</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="ions:WeightedAverageNumberOfSharesOwnedInSubsidiary" id="Fact_940b4a03fe6f4389949b2cdbec92c4e0" contextRef="c20200101to20201031_ConsolidatedEntitiesAxis_AkceaTherapeuticsIncMember" unitRef="U002" decimals="-3" scale="3" format="ixt:numdotdecimal">77,095</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:EarningsPerShareBasic" id="Fact_0332420a922344dbb39388360df6e41d" contextRef="c20200101to20201031_ConsolidatedEntitiesAxis_AkceaTherapeuticsIncMember" unitRef="U004" decimals="2" sign="-" scale="0" format="ixt:numdotdecimal">1.45</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:NetIncomeLoss" id="Fact_16fac149fc8a42eb8215243e61e0851d" contextRef="c20200101to20201031_ConsolidatedEntitiesAxis_AkceaTherapeuticsIncMember" unitRef="U001" decimals="-3" scale="3" sign="-" format="ixt:numdotdecimal">111,775</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: top; width: 64%; white-space: nowrap;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Akcea&#8217;s net loss in the post-merger period attributable to our ownership</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:NetIncomeLoss" id="Fact_c035d9c85824473ea4e130a96121b5ae" contextRef="c20201101to20201231_ConsolidatedEntitiesAxis_AkceaTherapeuticsIncMember" unitRef="U001" decimals="-3" scale="3" sign="-" format="ixt:numdotdecimal">85,987</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: top; width: 64%; background-color: #CCEEFF; white-space: nowrap;">
          <div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Akcea&#8217;s total net loss attributable to our ownership</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:NetIncomeLoss" id="Fact_3ee347bdde47445b90efca086e479676" contextRef="c20200101to20201231_ConsolidatedEntitiesAxis_AkceaTherapeuticsIncMember" unitRef="U001" decimals="-3" scale="3" sign="-" format="ixt:numdotdecimal">197,762</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: top; width: 64%; padding-bottom: 2px; white-space: nowrap;">
          <div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Ionis&#8217; stand-alone net loss</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:NetIncomeLoss" id="Fact_d92a3bd3b0bd4931871d87361205f80c" contextRef="c20200101to20201231_StatementBusinessSegmentsAxis_IonisCoreMember" unitRef="U001" decimals="-3" scale="3" sign="-" format="ixt:numdotdecimal">246,702</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: top; width: 64%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;">
          <div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Net loss available to Ionis common stockholders</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:NetIncomeLossAvailableToCommonStockholdersBasic" id="Fact_2ef73fb1e82242eb8c0ebddbf002f166" contextRef="c20200101to20201231" unitRef="U001" decimals="-3" scale="3" sign="-" format="ixt:numdotdecimal">444,464</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: top; width: 64%; padding-bottom: 2px; white-space: nowrap;">
          <div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Weighted average shares outstanding</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:WeightedAverageNumberOfSharesOutstandingBasic" id="Fact_72d06fd52aa94bd7bd4f7c81bc9ffc0d" contextRef="c20200101to20201231" unitRef="U002" decimals="-3" scale="3" format="ixt:numdotdecimal">139,612</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: top; width: 64%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;">
          <div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Basic net loss per share</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:EarningsPerShareBasic" id="Fact_eef24608fab149c7aeb01a9ecbd22706" contextRef="c20200101to20201231" unitRef="U004" decimals="2" sign="-" scale="0" format="ixt:numdotdecimal">3.18</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

  </tr>


</table>
</ix:continuation></ix:continuation></ix:continuation>
  <ix:continuation id="Text_ba6a171da9294812a4a91832efce6f8c21" continuedAt="Text_ba6a171da9294812a4a91832efce6f8c22"><ix:continuation id="Text_2006c403e53d492d92213d456f5da92611" continuedAt="Text_2006c403e53d492d92213d456f5da92612"><ix:continuation id="Text_86b296ab44ac4ec5a463f2e07a7953863" continuedAt="Text_86b296ab44ac4ec5a463f2e07a7953864">
<div><br />
  </div>
</ix:continuation></ix:continuation></ix:continuation></div>

  <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" class="DSPFPageBreakArea">
    <div class="DSPFPageFooter">
      <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">F-<span class="DSPFPageNumber">10</span></div>

    </div>

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      <hr style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;" /></div>


  </div>
<div><ix:continuation id="Text_ba6a171da9294812a4a91832efce6f8c22" continuedAt="Text_ba6a171da9294812a4a91832efce6f8c23"><ix:continuation id="Text_2006c403e53d492d92213d456f5da92612" continuedAt="Text_2006c403e53d492d92213d456f5da92613"><ix:continuation id="Text_86b296ab44ac4ec5a463f2e07a7953864" continuedAt="Text_86b296ab44ac4ec5a463f2e07a7953865">
<div style="display:none;"><br /></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We calculated our basic net income per share for the year ended December 31, 2019 as follows (in thousands, except per share amounts):</div>
</ix:continuation></ix:continuation></ix:continuation>

  <ix:continuation id="Text_ba6a171da9294812a4a91832efce6f8c23" continuedAt="Text_ba6a171da9294812a4a91832efce6f8c24"><ix:continuation id="Text_2006c403e53d492d92213d456f5da92613" continuedAt="Text_2006c403e53d492d92213d456f5da92614"><ix:continuation id="Text_86b296ab44ac4ec5a463f2e07a7953865" continuedAt="Text_86b296ab44ac4ec5a463f2e07a7953866">
<div><br />
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</ix:continuation></ix:continuation></ix:continuation>
  <ix:continuation id="Text_ba6a171da9294812a4a91832efce6f8c24" continuedAt="Text_ba6a171da9294812a4a91832efce6f8c25"><ix:continuation id="Text_2006c403e53d492d92213d456f5da92614" continuedAt="Text_2006c403e53d492d92213d456f5da92615"><ix:continuation id="Text_86b296ab44ac4ec5a463f2e07a7953866">
<table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;" class="cfttable">


  <tr>

    <td valign="bottom" style="vertical-align: bottom; border-bottom: #000000 2px solid; white-space: nowrap;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Year Ended December 31, 2019</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px; white-space: nowrap;" colspan="2">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Weighted</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Average Shares</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Owned in Akcea</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px; white-space: nowrap;" colspan="2">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Akcea</span>&#8217;<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">s</span></div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Net Income</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Per Share</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px; white-space: nowrap;" colspan="2">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Basic Net Income</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Per Share</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Calculation</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: top; width: 64%; background-color: #CCEEFF; white-space: nowrap;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Common shares</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="ions:WeightedAverageNumberOfSharesOwnedInSubsidiary" id="Fact_7f3e78d8ab30451e8241ca0e38eee153" contextRef="c20190101to20191231_ConsolidatedEntitiesAxis_AkceaTherapeuticsIncMember" unitRef="U002" decimals="-3" scale="3" format="ixt:numdotdecimal">70,100</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:EarningsPerShareBasic" id="Fact_c8212e5603a14371bc8cfbb9954ade3f" contextRef="c20190101to20191231_ConsolidatedEntitiesAxis_AkceaTherapeuticsIncMember" unitRef="U004" decimals="2" scale="0" format="ixt:numdotdecimal">0.49</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:NetIncomeLoss" id="Fact_f558eef64fe94b50b7701b347d41b454" contextRef="c20190101to20191231_ConsolidatedEntitiesAxis_AkceaTherapeuticsIncMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">34,073</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: top; width: 64%; white-space: nowrap;">
          <div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Akcea&#8217;s net income attributable to our ownership</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:NetIncomeLoss" id="Fact_2ce538bf55324fddb82784f3b5823d97" contextRef="c20190101to20191231_ConsolidatedEntitiesAxis_AkceaTherapeuticsIncMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">34,073</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: top; width: 64%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;">
          <div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Ionis&#8217; stand-alone net income</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: top; width: 64%; padding-bottom: 2px; white-space: nowrap;">
          <div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Net income available to Ionis common stockholders</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; white-space: nowrap;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: top; width: 64%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;">
          <div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Weighted average shares outstanding</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:WeightedAverageNumberOfSharesOutstandingBasic" id="Fact_6e20b5dc98e74ce0ad6e1a482f420ece" contextRef="c20190101to20191231" unitRef="U002" decimals="-3" scale="3" format="ixt:numdotdecimal">139,998</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: top; width: 64%; padding-bottom: 4px; white-space: nowrap;">
          <div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Basic net income per share</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:EarningsPerShareBasic" id="Fact_ad6c2e5e6ed344dcb0ba160dc5450ebd" contextRef="c20190101to20191231" unitRef="U004" decimals="2" scale="0" format="ixt:numdotdecimal">2.00</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>


</table>
</ix:continuation></ix:continuation></ix:continuation>
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<div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 12pt;"><br />
  </div>
</ix:continuation></ix:continuation>
  <ix:continuation id="Text_ba6a171da9294812a4a91832efce6f8c26" continuedAt="Text_ba6a171da9294812a4a91832efce6f8c27"><ix:continuation id="Text_2006c403e53d492d92213d456f5da92616" continuedAt="Text_2006c403e53d492d92213d456f5da92617">
<div style="display:none;"><br /></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;">Diluted net income (loss) per share</div>
</ix:continuation></ix:continuation>
  <ix:continuation id="Text_ba6a171da9294812a4a91832efce6f8c27" continuedAt="Text_ba6a171da9294812a4a91832efce6f8c28"><ix:continuation id="Text_2006c403e53d492d92213d456f5da92617" continuedAt="Text_2006c403e53d492d92213d456f5da92618">
<div><br />
  </div>
</ix:continuation></ix:continuation>
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<div style="display:none;"><br /></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">For the years ended December 31, 2021 and 2020, we incurred a net loss; therefore, we did not include dilutive common
    equivalent shares in the computation of diluted net loss per share because the effect would have been anti-dilutive. Common stock underlying the following would have had an anti-dilutive effect on net loss per share:</div>
</ix:continuation></ix:continuation>
  <ix:continuation id="Text_ba6a171da9294812a4a91832efce6f8c29" continuedAt="Text_ba6a171da9294812a4a91832efce6f8c30"><ix:continuation id="Text_2006c403e53d492d92213d456f5da92619" continuedAt="Text_2006c403e53d492d92213d456f5da92620">
<div><br />
  </div>
</ix:continuation></ix:continuation>
  <ix:continuation id="Text_ba6a171da9294812a4a91832efce6f8c30" continuedAt="Text_ba6a171da9294812a4a91832efce6f8c31"><ix:continuation id="Text_2006c403e53d492d92213d456f5da92620" continuedAt="Text_2006c403e53d492d92213d456f5da92621">
<table cellspacing="0" cellpadding="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">


  <tr>

    <td style="width: 36pt;"></td>

    <td style="width: 18pt; vertical-align: top; align: right; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:DebtInstrumentInterestRateStatedPercentage" id="Fact_2458a3845ed24510a9f7ee91849cccfd" contextRef="c20201231_DebtInstrumentAxis_ConvertibleSeniorNotes0125PercentMember" unitRef="U003" decimals="5" scale="-2" format="ixt:numdotdecimal"><ix:nonFraction name="us-gaap:DebtInstrumentInterestRateStatedPercentage" id="Fact_eb796a9cff164893992d0656c18cb133" contextRef="c20211231_DebtInstrumentAxis_ConvertibleSeniorNotes0125PercentMember" unitRef="U003" decimals="5" scale="-2" format="ixt:numdotdecimal">0.125</ix:nonFraction></ix:nonFraction> percent<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> convertible senior notes, or </span><ix:nonFraction name="us-gaap:DebtInstrumentInterestRateStatedPercentage" id="Fact_bcce470fa324421c93178604ee9e5a13" contextRef="c20211231_DebtInstrumentAxis_ConvertibleSeniorNotes0125PercentMember" unitRef="U003" decimals="5" scale="-2" format="ixt:numdotdecimal">0.125</ix:nonFraction>%<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> Notes;</span></div>
        </td>

  </tr>


</table>
</ix:continuation></ix:continuation>
  <ix:continuation id="Text_ba6a171da9294812a4a91832efce6f8c31" continuedAt="Text_ba6a171da9294812a4a91832efce6f8c32"><ix:continuation id="Text_2006c403e53d492d92213d456f5da92621" continuedAt="Text_2006c403e53d492d92213d456f5da92622">
<table cellspacing="0" cellpadding="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">


  <tr>

    <td style="width: 36pt;"></td>

    <td style="width: 18pt; vertical-align: top; align: right; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">Note hedges related to the </span><ix:nonFraction name="us-gaap:DebtInstrumentInterestRateStatedPercentage" id="Fact_dc44402204c4448692e653ec341d99d2" contextRef="c20201231_DebtInstrumentAxis_ConvertibleSeniorNotes0125PercentMember" unitRef="U003" decimals="5" scale="-2" format="ixt:numdotdecimal"><ix:nonFraction name="us-gaap:DebtInstrumentInterestRateStatedPercentage" id="Fact_7fd315721b164ea29e1410fd930ca260" contextRef="c20211231_DebtInstrumentAxis_ConvertibleSeniorNotes0125PercentMember" unitRef="U003" decimals="5" scale="-2" format="ixt:numdotdecimal">0.125</ix:nonFraction></ix:nonFraction>%<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> Notes;</span></div>
        </td>

  </tr>


</table>
</ix:continuation></ix:continuation>
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<table cellspacing="0" cellpadding="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">


  <tr>

    <td style="width: 36pt;"></td>

    <td style="width: 18pt; vertical-align: top; align: right; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:DebtInstrumentInterestRateStatedPercentage" id="Fact_e1e4ce6d99304ee2869dcb8f7128390e" contextRef="c20201231_DebtInstrumentAxis_ConvertibleSeniorNotes1PercentMember" unitRef="U003" decimals="2" scale="-2" format="ixt:numdotdecimal"><ix:nonFraction name="us-gaap:DebtInstrumentInterestRateStatedPercentage" id="Fact_249642bbc67c4af8aee0dce96615e1db" contextRef="c20211231_DebtInstrumentAxis_ConvertibleSeniorNotes1PercentMember" unitRef="U003" decimals="2" scale="-2" format="ixt:numdotdecimal">1</ix:nonFraction></ix:nonFraction> percent<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> convertible senior notes, or </span><ix:nonFraction name="us-gaap:DebtInstrumentInterestRateStatedPercentage" id="Fact_b251b8c781014f68a165a1d7e6caafb9" contextRef="c20211231_DebtInstrumentAxis_ConvertibleSeniorNotes1PercentMember" unitRef="U003" decimals="2" scale="-2" format="ixt:numdotdecimal">1</ix:nonFraction>%<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> Notes;</span></div>
        </td>

  </tr>


</table>
</ix:continuation></ix:continuation>
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<table cellspacing="0" cellpadding="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">


  <tr>

    <td style="width: 36pt;"></td>

    <td style="width: 18pt; vertical-align: top; align: right; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Dilutive stock options;</div>
        </td>

  </tr>


</table>
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  <ix:continuation id="Text_ba6a171da9294812a4a91832efce6f8c34" continuedAt="Text_ba6a171da9294812a4a91832efce6f8c35"><ix:continuation id="Text_2006c403e53d492d92213d456f5da92624" continuedAt="Text_2006c403e53d492d92213d456f5da92625">
<table cellspacing="0" cellpadding="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">


  <tr>

    <td style="width: 36pt;"></td>

    <td style="width: 18pt; vertical-align: top; align: right; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Unvested restricted stock units, or RSUs;</div>
        </td>

  </tr>


</table>
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  <ix:continuation id="Text_ba6a171da9294812a4a91832efce6f8c35" continuedAt="Text_ba6a171da9294812a4a91832efce6f8c36"><ix:continuation id="Text_2006c403e53d492d92213d456f5da92625" continuedAt="Text_2006c403e53d492d92213d456f5da92626">
<table cellspacing="0" cellpadding="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">


  <tr>

    <td style="width: 36pt;"></td>

    <td style="width: 18pt; vertical-align: top; align: right; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Unvested performance restricted stock units, or PRSUs; and</div>
        </td>

  </tr>


</table>
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  <ix:continuation id="Text_ba6a171da9294812a4a91832efce6f8c36" continuedAt="Text_ba6a171da9294812a4a91832efce6f8c37"><ix:continuation id="Text_2006c403e53d492d92213d456f5da92626" continuedAt="Text_2006c403e53d492d92213d456f5da92627">
<table cellspacing="0" cellpadding="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">


  <tr>

    <td style="width: 36pt;"></td>

    <td style="width: 18pt; vertical-align: top; align: right; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Employee Stock Purchase Plan, or ESPP.</div>
        </td>

  </tr>


</table>
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<div><br />
  </div>
</ix:continuation></ix:continuation>
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<div style="display:none;"><br /></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">For the year ended December 31, 2021, common stock underlying the following would also have had an anti-dilutive effect on
    net loss per share:</div>
</ix:continuation></ix:continuation>
  <ix:continuation id="Text_ba6a171da9294812a4a91832efce6f8c39" continuedAt="Text_ba6a171da9294812a4a91832efce6f8c40"><ix:continuation id="Text_2006c403e53d492d92213d456f5da92629" continuedAt="Text_2006c403e53d492d92213d456f5da92630">
<div><br />
  </div>
</ix:continuation></ix:continuation>
  <ix:continuation id="Text_ba6a171da9294812a4a91832efce6f8c40" continuedAt="Text_ba6a171da9294812a4a91832efce6f8c41"><ix:continuation id="Text_2006c403e53d492d92213d456f5da92630" continuedAt="Text_2006c403e53d492d92213d456f5da92631">
<table cellspacing="0" cellpadding="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">


  <tr>

    <td style="width: 36pt;"></td>

    <td style="width: 18pt; vertical-align: top; align: right; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
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  </tr>


</table>
</ix:continuation></ix:continuation>
  <ix:continuation id="Text_ba6a171da9294812a4a91832efce6f8c41" continuedAt="Text_ba6a171da9294812a4a91832efce6f8c42"><ix:continuation id="Text_2006c403e53d492d92213d456f5da92631" continuedAt="Text_2006c403e53d492d92213d456f5da92632">
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  <tr>

    <td style="width: 36pt;"></td>

    <td style="width: 18pt; vertical-align: top; align: right; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
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        </td>

  </tr>


</table>
</ix:continuation></ix:continuation>
  <ix:continuation id="Text_ba6a171da9294812a4a91832efce6f8c42" continuedAt="Text_ba6a171da9294812a4a91832efce6f8c43"><ix:continuation id="Text_2006c403e53d492d92213d456f5da92632" continuedAt="Text_2006c403e53d492d92213d456f5da92633">
<div><br />
  </div>
</ix:continuation></ix:continuation>
  <ix:continuation id="Text_ba6a171da9294812a4a91832efce6f8c43" continuedAt="Text_ba6a171da9294812a4a91832efce6f8c44"><ix:continuation id="Text_2006c403e53d492d92213d456f5da92633" continuedAt="Text_2006c403e53d492d92213d456f5da92634">
<div style="display:none;"><br /></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Additionally as of December 31, 2021, we had warrants related to our <ix:nonFraction name="us-gaap:DebtInstrumentInterestRateStatedPercentage" id="Fact_5e58b95589c84ac9b547f68765b4e7c6" contextRef="c20211231_DebtInstrumentAxis_ConvertibleSeniorNotes0PercentMember" unitRef="U003" decimals="2" scale="-2" format="ixt:numdotdecimal">0</ix:nonFraction> percent and <ix:nonFraction name="us-gaap:DebtInstrumentInterestRateStatedPercentage" id="Fact_3ff6581e719f484fa5f31e462a6f100e" contextRef="c20211231_DebtInstrumentAxis_ConvertibleSeniorNotes0125PercentMember" unitRef="U003" decimals="5" scale="-2" format="ixt:numdotdecimal">0.125</ix:nonFraction> percent Notes outstanding. We will include the shares issuable
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</ix:continuation></ix:continuation>
  <ix:continuation id="Text_ba6a171da9294812a4a91832efce6f8c44" continuedAt="Text_ba6a171da9294812a4a91832efce6f8c45"><ix:continuation id="Text_2006c403e53d492d92213d456f5da92634" continuedAt="Text_2006c403e53d492d92213d456f5da92635">
<div><br />
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</ix:continuation></ix:continuation>
  <ix:continuation id="Text_ba6a171da9294812a4a91832efce6f8c45" continuedAt="Text_ba6a171da9294812a4a91832efce6f8c46"><ix:continuation id="Text_2006c403e53d492d92213d456f5da92635" continuedAt="Text_2006c403e53d492d92213d456f5da92636"><ix:nonNumeric name="us-gaap:ScheduleOfEarningsPerShareBasicAndDilutedTableTextBlock" id="Text_f50931b8ca754a76923abe397ae6ad17" contextRef="c20210101to20211231" escape="true" continuedAt="Text_ffd297e1744241d2b22f4c36ddaaa4f11">
<div style="display:none;"><br /></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">For the
      year ended December 31, 2019, we reported net income available to Ionis common stockholders. As a result, we computed diluted net income per share using the weighted-average number of common shares and dilutive common equivalent shares outstanding
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</ix:nonNumeric></ix:continuation></ix:continuation>
  <ix:continuation id="Text_ba6a171da9294812a4a91832efce6f8c46" continuedAt="Text_ba6a171da9294812a4a91832efce6f8c47"><ix:continuation id="Text_2006c403e53d492d92213d456f5da92636" continuedAt="Text_2006c403e53d492d92213d456f5da92637"><ix:continuation id="Text_ffd297e1744241d2b22f4c36ddaaa4f11" continuedAt="Text_ffd297e1744241d2b22f4c36ddaaa4f12">
<div><br />
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</ix:continuation></ix:continuation></ix:continuation>
  <ix:continuation id="Text_ba6a171da9294812a4a91832efce6f8c47" continuedAt="Text_ba6a171da9294812a4a91832efce6f8c48"><ix:continuation id="Text_2006c403e53d492d92213d456f5da92637"><ix:continuation id="Text_ffd297e1744241d2b22f4c36ddaaa4f12">
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  <tr>

    <td valign="bottom" style="vertical-align: bottom; border-bottom: #000000 2px solid;">
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        </td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

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    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" colspan="2">
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" colspan="2">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: top; width: 64%; padding-bottom: 4px; background-color: #CCEEFF;">
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        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" colspan="1">
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        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px; background-color: #CCEEFF;" colspan="1">
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px; background-color: #CCEEFF;" colspan="1">
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" colspan="1">
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    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: top; width: 64%;">
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        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: top; width: 64%; background-color: #CCEEFF;">
          <div style="text-align: left; text-indent: -8.9pt; margin-left: 18pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Shares issuable upon exercise of stock options</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#8212;</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: top; width: 64%;">
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        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#8212;</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: top; width: 64%; background-color: #CCEEFF;">
          <div style="text-align: left; text-indent: 9.1pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Shares issuable related to our ESPP</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#8212;</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: top; width: 64%;">
          <div style="text-align: left; text-indent: 9.1pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">Shares issuable related to our </span>0.125<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> percent convertible notes</span></div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
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    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

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          <div style="text-align: left; text-indent: 9.1pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Shares issuable related to our 1 percent convertible notes</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

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    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: top; width: 64%; padding-bottom: 4px;">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:NetIncomeLossAvailableToCommonStockholdersDiluted" id="Fact_f82cfb848ace4686aec051c3fdf525f3" contextRef="c20190101to20191231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">290,947</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" colspan="1">&#160;</td>

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<div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Revenue Recognition</div>
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<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="text-decoration: underline;">Our Revenue Sources</span></div>
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<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We generally recognize revenue when we have satisfied all contractual obligations and are reasonably assured of collecting
    the resulting receivable. We are often entitled to bill our customers and receive payment from our customers in advance of recognizing the revenue. In the instances in which we have received payment from our customers in advance of recognizing revenue,
    we include the amounts in deferred revenue on our consolidated balance sheet.</div>
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<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">At contract inception, we analyze our collaboration arrangements to assess whether such arrangements involve joint
    operating activities performed by parties that are both active participants in the activities and exposed to significant risks and rewards dependent on the commercial success of such activities and therefore within the scope of ASC Topic 808,
    Collaborative Arrangements (ASC 808).&#160; For collaboration arrangements within the scope of ASC 808 that contain multiple elements, we first determine which elements of the collaboration reflect a vendor-customer relationship and therefore within the
    scope of ASC 606. When we determine elements of a collaboration do not reflect a vendor-customer relationship, we consistently apply the reasonable and rational policy election we made by analogizing to authoritative accounting literature.</div>
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<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We evaluate the income statement classification for presentation of amounts due from or owed to other participants
    associated with multiple activities in a collaboration arrangement based on the nature of each separate activity. For example, in our eplontersen collaboration with AstraZeneca, we recognize funding received from AstraZeneca for co-development
    activities as revenue. While, we recognize cost sharing payments to and from AstraZeneca associated with co-commercialization activities and co-medical affairs activities as SG&amp;A expense and research and development expense, respectively.</div>
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<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;">Commercial Revenue: SPINRAZA royalties and Licensing and other royalty revenue</div>
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<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We earn commercial revenue primarily in the form of royalty payments on net sales of SPINRAZA. We will also recognize as
    commercial revenue sales milestone payments and royalties we earn under our other partnerships.</div>
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<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;">Commercial Revenue: TEGSEDI and WAYLIVRA revenue, net</div>
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<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We began commercializing TEGSEDI and WAYLIVRA in Europe in January 2021 and TEGSEDI in North America in April 2021 through distribution
    agreements with Swedish Orphan Biovitrum AB, or Sobi. Under our agreements, we are responsible for supplying finished goods inventory to Sobi and Sobi is responsible for selling each medicine to the end customer. As a result of these agreements, we
    earn a distribution fee on net sales from Sobi for each medicine.</div>
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<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Prior to the second quarter of 2021 in North America, we sold TEGSEDI through exclusive distribution agreements with third-party logistics
    companies, or 3PLs, that took title to TEGSEDI. The 3PLs then distributed TEGSEDI to a specialty pharmacy and a specialty distributor, which we collectively refer to as wholesalers, who then distributed TEGSEDI to health care providers and patients. In
    the United States, or U.S., we had a single 3PL as our sole customer and in Canada we also had a single 3PL as our sole customer. Prior to 2021 in Europe, we sold TEGSEDI and WAYLIVRA to hospitals and pharmacies, which were our customers, using 3PLs as
    distributors.</div>
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<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">Under our collaboration agreement with PTC
      Therapeutics International Limited, or PTC, PTC is responsible for commercializing TEGSEDI and WAYLIVRA in Latin America and Caribbean countries. In the third quarter of 2021, we earned a </span>$<ix:nonFraction name="us-gaap:RevenueFromContractWithCustomerExcludingAssessedTax" id="Fact_149cd590044543a08025ed12d7e1b880" contextRef="c20210701to20210930_ProductOrServiceAxis_ProductMember_TypeOfArrangementAxis_PtcTherapeuticsCollaborationMember" unitRef="U001" decimals="-6" scale="6" format="ixt:numdotdecimal">4</ix:nonFraction> million milestone payment from PTC when WAYLIVRA was approved in Brazil, which we included in TEGSEDI and WAYLIVRA revenue in our consolidated statement of operations. Under our agreement, we
    started receiving royalties from PTC for TEGSEDI sales beginning in December 2021.</div>
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<div style="text-align: left; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;">Research and development revenue under collaborative agreements</div>
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<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We often enter into collaboration agreements to license and sell our technology on an exclusive or non-exclusive basis.
    Our collaboration agreements typically contain multiple elements, or performance obligations, including technology licenses or options to obtain technology licenses, research and development, or R&amp;D, services, and manufacturing services.</div>
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<div style="display:none;"><br /></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We provide details about our collaboration agreements in Note 6, <span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Collaborative Arrangements and Licensing Agreements.</span><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">&#160;</span>For each collaboration, we discuss our specific revenue
    recognition conclusions, including our significant performance obligations under each collaboration.</div>
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<div style="text-align: left; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="text-decoration: underline;">Steps to Recognize Revenue</span></div>
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<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We use a five-step process to determine the amount of revenue we should recognize and when we should recognize it. The
    five step process is as follows:</div>
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    <td style="width: 18pt; vertical-align: top; align: right; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic; font-weight: bold;">1.</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic; font-weight: bold;">Identify the contract</div>
        </td>

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<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Accounting rules require us to first determine if we have a contract with our partner, including confirming that we have met each of the
    following criteria:</div>
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<div><br />
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    <td style="width: 18pt; vertical-align: top; align: right; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We and our partner approved the contract and we are both committed to perform our obligations;</div>
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    <td style="width: 18pt; vertical-align: top; align: right; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We have identified our rights, our partner&#8217;s rights and the payment terms;</div>
        </td>

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    <td style="width: 18pt; vertical-align: top; align: right; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We have concluded that the contract has commercial substance, meaning that the risk, timing, or amount of our future cash flows is expected to change as a result of the
            contract; and</div>
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    <td style="width: 18pt; vertical-align: top; align: right; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We believe collectability of the consideration is probable.</div>
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    <td style="width: 18pt; vertical-align: top; align: right;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold; font-style: italic;">2.</span></td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic; font-weight: bold;">Identify the performance obligations</div>
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<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We next identify our performance obligations, which represent the distinct goods and services we are required to provide under the
    contract.</div>
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<div style="display:none;"><br /></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">Often we enter into a collaboration agreement
      in which we provide our partner with an option to license a medicine in the future. We may also provide our partner with an option to request that we provide additional goods or services in the future, such as active pharmaceutical ingredient, or
      API. We evaluate whether these options are material rights at the inception of the agreement. If we determine an option is a material right, we will consider the option a separate performance obligation. Historically, we have concluded that the
      options we grant to license a medicine in the future or to provide additional goods and services as requested by our partner are not material rights because these items are contingent upon future events that may not occur and are not priced at a
      significant discount. When a partner exercises its option to license a medicine or requests additional goods or services, then we identify a new performance obligation for that item</span>.</div>
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<div style="display:none;"><br /></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">In some cases, we deliver a license at the start of an agreement. If we determine that our partner has full use of the license and we do
    not have any additional material performance obligations related to the license after delivery, then we consider the license to be a separate performance obligation. For example, in the fourth quarter of 2021, we received a $<ix:nonFraction name="us-gaap:RevenueFromContractWithCustomerExcludingAssessedTax" id="Fact_bbede8f332e443e6b71660aa38e37fa3" contextRef="c20211001to20211231_ProductOrServiceAxis_EplontersenMember_TypeOfArrangementAxis_AstrazenecaCollaborationEplontersenMember" unitRef="U001" decimals="-6" scale="6" format="ixt:numdotdecimal">200</ix:nonFraction> million upfront payment when we entered into an agreement with AstraZeneca to jointly develop and commercialize eplontersen. We recognized the upfront
    payment in full in the fourth quarter of 2021 because we did not have any remaining performance obligations after we delivered the license to AstraZeneca.</div>
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    <td style="width: 18pt; vertical-align: top; align: right; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic; font-weight: bold;">3.</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic; font-weight: bold;">Determine the transaction price</div>
        </td>

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  </div>
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  <div>
    <ix:continuation id="Text_ba6a171da9294812a4a91832efce6f8c100" continuedAt="Text_ba6a171da9294812a4a91832efce6f8c101"><ix:continuation id="Text_b1241e53de0f474cbd49eab8f51e9c8251" continuedAt="Text_b1241e53de0f474cbd49eab8f51e9c8252">
<div style="display:none;"><br /></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We then determine the transaction price by reviewing the amount of consideration we are eligible to earn under the
        collaboration agreement, including any variable consideration. Under our collaboration agreements, consideration typically includes fixed consideration in the form of an upfront payment and variable consideration in the form of potential milestone
        payments, license fees and royalties. At the start of an agreement, our transaction price usually consists of only the upfront payment. We do not typically include any payments we may receive in the future in our initial transaction price because
        the payments are not probable and are contingent on certain future events. We reassess the total transaction price at each reporting period to determine if we should include additional payments in the transaction price.</div>
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  <div>
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<div><br />
    </div>
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  </div>
<div><ix:continuation id="Text_ba6a171da9294812a4a91832efce6f8c102" continuedAt="Text_ba6a171da9294812a4a91832efce6f8c103"><ix:continuation id="Text_b1241e53de0f474cbd49eab8f51e9c8253" continuedAt="Text_b1241e53de0f474cbd49eab8f51e9c8254">
<div style="display:none;"><br /></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">Milestone payments are our most common type
      of variable consideration. We recognize milestone payments using the most likely amount method because we will either receive the milestone payment or we will not, which makes the potential milestone payment a binary event. The most likely amount
      method requires us to determine the likelihood of earning the milestone payment. We include a milestone payment in the transaction price once it is probable we will achieve the milestone event. Most often, we do not consider our milestone payments
      probable until we or our partner achieve the milestone event because the majority of our milestone payments are contingent upon events that are not within our control and/ or are usually based on scientific progress which is inherently uncertain. For
      example, in the fourth quarter of 2021, we earned</span> a $<ix:nonFraction name="us-gaap:RevenueFromContractWithCustomerExcludingAssessedTax" id="Fact_c1c41f960a754a9f9617c952a530c029" contextRef="c20211001to20211231_TypeOfArrangementAxis_AstrazenecaCollaborationCardiovascularRenalAndMetabolicDiseasesMember" unitRef="U001" decimals="-6" scale="6" format="ixt:numdotdecimal">10</ix:nonFraction> million <span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">milestone payment from AstraZeneca when AstraZeneca advanced a target for a metabolic disease. We did not consider the milestone payment probable until AstraZeneca achieved the milestone event because advancing the target was
      contingent on AstraZeneca initiating a Phase 1 study and was not within our control. We recognized the milestone payment in full in the period the milestone event was achieved because we did not have any remaining performance obligations related to
      the milestone payment</span>.</div>
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<div><br />
  </div>
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    <div class="DSPFPageFooter">
      <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">F-<span class="DSPFPageNumber">13</span></div>

    </div>

    <div style="page-break-after:always;" class="DSPFPageBreak">
      <hr style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;" /></div>


  </div>
<div><ix:continuation id="Text_ba6a171da9294812a4a91832efce6f8c104" continuedAt="Text_ba6a171da9294812a4a91832efce6f8c105"><ix:continuation id="Text_b1241e53de0f474cbd49eab8f51e9c8255" continuedAt="Text_b1241e53de0f474cbd49eab8f51e9c8256">
<table cellspacing="0" cellpadding="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">


  <tr>

    <td style="width: 36pt;"></td>

    <td style="width: 18pt; vertical-align: top; align: right; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic; font-weight: bold;">4.</td>

    <td style="width: auto; vertical-align: top; text-align: left;">
          <div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic; font-weight: bold;">Allocate the transaction price</div>
        </td>

  </tr>


</table>
</ix:continuation></ix:continuation>

  <ix:continuation id="Text_ba6a171da9294812a4a91832efce6f8c105" continuedAt="Text_ba6a171da9294812a4a91832efce6f8c106"><ix:continuation id="Text_b1241e53de0f474cbd49eab8f51e9c8256" continuedAt="Text_b1241e53de0f474cbd49eab8f51e9c8257">
<div><br />
  </div>
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  <div>
    <ix:continuation id="Text_ba6a171da9294812a4a91832efce6f8c106" continuedAt="Text_ba6a171da9294812a4a91832efce6f8c107"><ix:continuation id="Text_b1241e53de0f474cbd49eab8f51e9c8257" continuedAt="Text_b1241e53de0f474cbd49eab8f51e9c8258">
<div style="display:none;"><br /></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Next, we allocate the transaction price to
        each of our performance obligations. When we have to allocate the transaction price to more than </span>one<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> performance obligation, we make estimates of the relative
        stand-alone selling price of each performance obligation because we do not typically sell our goods or services on a stand-alone basis. We then allocate the transaction price to each performance obligation based on the relative stand-alone selling
        price. We do not reallocate the transaction price after the start of an agreement to reflect subsequent changes in stand-alone selling prices.</span></div>
</ix:continuation></ix:continuation>
  </div>

  <div>
    <ix:continuation id="Text_ba6a171da9294812a4a91832efce6f8c107" continuedAt="Text_ba6a171da9294812a4a91832efce6f8c108"><ix:continuation id="Text_b1241e53de0f474cbd49eab8f51e9c8258" continuedAt="Text_b1241e53de0f474cbd49eab8f51e9c8259">
<div><br />
    </div>
</ix:continuation></ix:continuation>
  </div>
<div><ix:continuation id="Text_ba6a171da9294812a4a91832efce6f8c108" continuedAt="Text_ba6a171da9294812a4a91832efce6f8c109"><ix:continuation id="Text_b1241e53de0f474cbd49eab8f51e9c8259" continuedAt="Text_b1241e53de0f474cbd49eab8f51e9c8260">
<div style="display:none;"><br /></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We may engage a </span>third<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> party, independent valuation specialist to assist us with determining a stand-alone selling price for collaborations in which we deliver a license at the start of an agreement.
      We estimate the stand-alone selling price of these licenses using valuation methodologies, such as the relief from royalty method. Under this method, we estimate the amount of income, net of taxes, for the license. We then discount the projected
      income to present value. The significant inputs we use to determine the projected income of a license could include</span>:</div>
</ix:continuation></ix:continuation>

  <ix:continuation id="Text_ba6a171da9294812a4a91832efce6f8c109" continuedAt="Text_ba6a171da9294812a4a91832efce6f8c110"><ix:continuation id="Text_b1241e53de0f474cbd49eab8f51e9c8260" continuedAt="Text_b1241e53de0f474cbd49eab8f51e9c8261">
<div><br />
  </div>
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  <ix:continuation id="Text_ba6a171da9294812a4a91832efce6f8c110" continuedAt="Text_ba6a171da9294812a4a91832efce6f8c111"><ix:continuation id="Text_b1241e53de0f474cbd49eab8f51e9c8261" continuedAt="Text_b1241e53de0f474cbd49eab8f51e9c8262">
<table cellspacing="0" cellpadding="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">


  <tr>

    <td style="width: 36pt;"></td>

    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Estimated future product sales;</div>
        </td>

  </tr>


</table>
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  <ix:continuation id="Text_ba6a171da9294812a4a91832efce6f8c111" continuedAt="Text_ba6a171da9294812a4a91832efce6f8c112"><ix:continuation id="Text_b1241e53de0f474cbd49eab8f51e9c8262" continuedAt="Text_b1241e53de0f474cbd49eab8f51e9c8263">
<table cellspacing="0" cellpadding="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">


  <tr>

    <td style="width: 36pt;"></td>

    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Estimated royalties we may receive from future product sales;</div>
        </td>

  </tr>


</table>
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  <ix:continuation id="Text_ba6a171da9294812a4a91832efce6f8c112" continuedAt="Text_ba6a171da9294812a4a91832efce6f8c113"><ix:continuation id="Text_b1241e53de0f474cbd49eab8f51e9c8263" continuedAt="Text_b1241e53de0f474cbd49eab8f51e9c8264">
<table cellspacing="0" cellpadding="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">


  <tr>

    <td style="width: 36pt;"></td>

    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Estimated contractual milestone payments we may receive;</div>
        </td>

  </tr>


</table>
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  <ix:continuation id="Text_ba6a171da9294812a4a91832efce6f8c113" continuedAt="Text_ba6a171da9294812a4a91832efce6f8c114"><ix:continuation id="Text_b1241e53de0f474cbd49eab8f51e9c8264" continuedAt="Text_b1241e53de0f474cbd49eab8f51e9c8265">
<table cellspacing="0" cellpadding="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">


  <tr>

    <td style="width: 36pt;"></td>

    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Expenses we expect to incur;</div>
        </td>

  </tr>


</table>
</ix:continuation></ix:continuation>
  <ix:continuation id="Text_ba6a171da9294812a4a91832efce6f8c114" continuedAt="Text_ba6a171da9294812a4a91832efce6f8c115"><ix:continuation id="Text_b1241e53de0f474cbd49eab8f51e9c8265" continuedAt="Text_b1241e53de0f474cbd49eab8f51e9c8266">
<table cellspacing="0" cellpadding="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">


  <tr>

    <td style="width: 36pt;"></td>

    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Estimated income taxes; and</div>
        </td>

  </tr>


</table>
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  <ix:continuation id="Text_ba6a171da9294812a4a91832efce6f8c115" continuedAt="Text_ba6a171da9294812a4a91832efce6f8c116"><ix:continuation id="Text_b1241e53de0f474cbd49eab8f51e9c8266" continuedAt="Text_b1241e53de0f474cbd49eab8f51e9c8267">
<table cellspacing="0" cellpadding="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">


  <tr>

    <td style="width: 36pt;"></td>

    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">A discount rate.</div>
        </td>

  </tr>


</table>
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  <ix:continuation id="Text_ba6a171da9294812a4a91832efce6f8c116" continuedAt="Text_ba6a171da9294812a4a91832efce6f8c117"><ix:continuation id="Text_b1241e53de0f474cbd49eab8f51e9c8267" continuedAt="Text_b1241e53de0f474cbd49eab8f51e9c8268">
<div><br />
  </div>
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  <ix:continuation id="Text_ba6a171da9294812a4a91832efce6f8c117" continuedAt="Text_ba6a171da9294812a4a91832efce6f8c118"><ix:continuation id="Text_b1241e53de0f474cbd49eab8f51e9c8268" continuedAt="Text_b1241e53de0f474cbd49eab8f51e9c8269">
<div style="display:none;"><br /></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We typically estimate the selling price of R&amp;D services by using our internal estimates of the cost to perform the
    specific services. The significant inputs we use to determine the selling price of our R&amp;D services include:</div>
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<div><br />
  </div>
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  <ix:continuation id="Text_ba6a171da9294812a4a91832efce6f8c119" continuedAt="Text_ba6a171da9294812a4a91832efce6f8c120"><ix:continuation id="Text_b1241e53de0f474cbd49eab8f51e9c8270" continuedAt="Text_b1241e53de0f474cbd49eab8f51e9c8271">
<table cellspacing="0" cellpadding="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">


  <tr>

    <td style="width: 36pt;"></td>

    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">The number of internal hours we estimate we will spend performing these services;</div>
        </td>

  </tr>


</table>
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  <ix:continuation id="Text_ba6a171da9294812a4a91832efce6f8c120" continuedAt="Text_ba6a171da9294812a4a91832efce6f8c121"><ix:continuation id="Text_b1241e53de0f474cbd49eab8f51e9c8271" continuedAt="Text_b1241e53de0f474cbd49eab8f51e9c8272">
<table cellspacing="0" cellpadding="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">


  <tr>

    <td style="width: 36pt;"></td>

    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">The estimated cost of work we will perform;</div>
        </td>

  </tr>


</table>
</ix:continuation></ix:continuation>
  <ix:continuation id="Text_ba6a171da9294812a4a91832efce6f8c121" continuedAt="Text_ba6a171da9294812a4a91832efce6f8c122"><ix:continuation id="Text_b1241e53de0f474cbd49eab8f51e9c8272" continuedAt="Text_b1241e53de0f474cbd49eab8f51e9c8273">
<table cellspacing="0" cellpadding="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">


  <tr>

    <td style="width: 36pt;"></td>

    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">The estimated cost of work that we will contract with third parties to perform; and</div>
        </td>

  </tr>


</table>
</ix:continuation></ix:continuation>
  <ix:continuation id="Text_ba6a171da9294812a4a91832efce6f8c122" continuedAt="Text_ba6a171da9294812a4a91832efce6f8c123"><ix:continuation id="Text_b1241e53de0f474cbd49eab8f51e9c8273" continuedAt="Text_b1241e53de0f474cbd49eab8f51e9c8274">
<table cellspacing="0" cellpadding="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">


  <tr>

    <td style="width: 36pt;"></td>

    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">The estimated cost of API we will use.</div>
        </td>

  </tr>


</table>
</ix:continuation></ix:continuation>
  <ix:continuation id="Text_ba6a171da9294812a4a91832efce6f8c123" continuedAt="Text_ba6a171da9294812a4a91832efce6f8c124"><ix:continuation id="Text_b1241e53de0f474cbd49eab8f51e9c8274" continuedAt="Text_b1241e53de0f474cbd49eab8f51e9c8275">
<div><br />
  </div>
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  <ix:continuation id="Text_ba6a171da9294812a4a91832efce6f8c124" continuedAt="Text_ba6a171da9294812a4a91832efce6f8c125"><ix:continuation id="Text_b1241e53de0f474cbd49eab8f51e9c8275" continuedAt="Text_b1241e53de0f474cbd49eab8f51e9c8276">
<div style="display:none;"><br /></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">For purposes of determining the stand-alone selling price of the R&amp;D services we perform and the API we will deliver,
    accounting guidance requires us to include a markup for a reasonable profit margin.</div>
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  <ix:continuation id="Text_ba6a171da9294812a4a91832efce6f8c125" continuedAt="Text_ba6a171da9294812a4a91832efce6f8c126"><ix:continuation id="Text_b1241e53de0f474cbd49eab8f51e9c8276" continuedAt="Text_b1241e53de0f474cbd49eab8f51e9c8277">
<div><br />
  </div>
</ix:continuation></ix:continuation>
  <ix:continuation id="Text_ba6a171da9294812a4a91832efce6f8c126" continuedAt="Text_ba6a171da9294812a4a91832efce6f8c127"><ix:continuation id="Text_b1241e53de0f474cbd49eab8f51e9c8277" continuedAt="Text_b1241e53de0f474cbd49eab8f51e9c8278">
<table cellspacing="0" cellpadding="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">


  <tr>

    <td style="width: 36pt;"></td>

    <td style="width: 18pt; vertical-align: top; align: right; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic; font-weight: bold;">5.</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic; font-weight: bold;">Recognize revenue</div>
        </td>

  </tr>


</table>
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  <ix:continuation id="Text_ba6a171da9294812a4a91832efce6f8c127" continuedAt="Text_ba6a171da9294812a4a91832efce6f8c128"><ix:continuation id="Text_b1241e53de0f474cbd49eab8f51e9c8278" continuedAt="Text_b1241e53de0f474cbd49eab8f51e9c8279">
<div><br />
  </div>
</ix:continuation></ix:continuation></div>

  <div>
    <ix:continuation id="Text_ba6a171da9294812a4a91832efce6f8c128" continuedAt="Text_ba6a171da9294812a4a91832efce6f8c129"><ix:continuation id="Text_b1241e53de0f474cbd49eab8f51e9c8279" continuedAt="Text_b1241e53de0f474cbd49eab8f51e9c8280">
<div style="display:none;"><br /></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We recognize revenue in </span>one<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> of </span>two<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> ways, over time or at a point in time. We recognize revenue over time when we are
        executing on our performance obligation over time and our partner receives benefit over time. For example, we recognize revenue over time when we provide R&amp;D services. We recognize revenue at a point in time when our partner receives full use
        of an item at a specific point in time. For example, we recognize revenue at a point in time when we deliver a license or API to a partner.</span></div>
</ix:continuation></ix:continuation>
  </div>

  <div>
    <ix:continuation id="Text_ba6a171da9294812a4a91832efce6f8c129" continuedAt="Text_ba6a171da9294812a4a91832efce6f8c130"><ix:continuation id="Text_b1241e53de0f474cbd49eab8f51e9c8280" continuedAt="Text_b1241e53de0f474cbd49eab8f51e9c8281">
<div><br />
    </div>
</ix:continuation></ix:continuation>
  </div>
<div><ix:continuation id="Text_ba6a171da9294812a4a91832efce6f8c130" continuedAt="Text_ba6a171da9294812a4a91832efce6f8c131"><ix:continuation id="Text_b1241e53de0f474cbd49eab8f51e9c8281" continuedAt="Text_b1241e53de0f474cbd49eab8f51e9c8282">
<div style="display:none;"><br /></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">For R&amp;D services that we recognize over
      time, we measure our progress using an input method. The input methods we use are based on the effort we expend or costs we incur toward the satisfaction of our performance obligation. We estimate the amount of effort we expend, including the time we
      estimate it will take us to complete the activities, or costs we incur in a given period, relative to the estimated total effort or costs to satisfy the performance obligation. This results in a percentage that we multiply by the transaction price to
      determine the amount of revenue we recognize each period. This approach requires us to make numerous estimates and use significant judgement. If our estimates or judgements change over the course of the collaboration, they may affect the timing and
      amount of revenue that we recognize in the current and future periods.</span> Refer to Note 6, <span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Collaborative Arrangements and Licensing Agreements</span>,
    for further discussion of the cumulative catch up adjustment we made.</div>
</ix:continuation></ix:continuation>

  <ix:continuation id="Text_ba6a171da9294812a4a91832efce6f8c131" continuedAt="Text_ba6a171da9294812a4a91832efce6f8c132"><ix:continuation id="Text_b1241e53de0f474cbd49eab8f51e9c8282" continuedAt="Text_b1241e53de0f474cbd49eab8f51e9c8283">
<div><br />
  </div>
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<div style="text-align: left; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">The following are examples of when we typically recognize revenue based on the types of payments we receive.</div>
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<div><br />
  </div>
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<div style="display:none;"><br /></div>
<div style="text-align: left; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;"><span style="text-decoration: underline;">Commercial Revenue: SPINRAZA royalties and Licensing and other royalty revenue</span></div>
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<div><br />
  </div>
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  <ix:continuation id="Text_ba6a171da9294812a4a91832efce6f8c136" continuedAt="Text_ba6a171da9294812a4a91832efce6f8c137"><ix:continuation id="Text_b1241e53de0f474cbd49eab8f51e9c8287" continuedAt="Text_b1241e53de0f474cbd49eab8f51e9c8288">
<div style="display:none;"><br /></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We recognize royalty revenue, including
      royalties from SPINRAZA sales, in the period in which the counterparty sells the related product and recognizes the related revenue, which in certain cases may require us to estimate our royalty revenue</span>.</div>
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  </div>
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  </div>
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<div style="text-align: left; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;"><span style="text-decoration: underline;">Commercial Revenue: TEGSEDI and WAYLIVRA revenue, net</span></div>
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<div><br />
  </div>
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<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Under our distribution agreements with Sobi we concluded that our performance obligation is to provide services to
      Sobi over the term of the agreement, which includes supplying finished goods inventory to Sobi and because we retained the marketing authorization for TEGSEDI and WAYLIVRA we are responsible for leading the global commercial strategy for each
      medicine. We view this performance obligation as a series of distinct activities that are substantially the same. Therefore, we recognize as revenue the price Sobi pays us for the inventory when we deliver the finished goods inventory to Sobi. We
      also recognize distribution fee revenue based on Sobi&#8217;s net sales of TEGSEDI and WAYLIVRA in the period in which the sales occurred. Under our agreements with Sobi, Sobi does not generally have a right of return.</div>
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<div><br />
  </div>
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  <ix:continuation id="Text_ba6a171da9294812a4a91832efce6f8c142" continuedAt="Text_ba6a171da9294812a4a91832efce6f8c143"><ix:continuation id="Text_b1241e53de0f474cbd49eab8f51e9c8293" continuedAt="Text_b1241e53de0f474cbd49eab8f51e9c8294">
<div style="display:none;"><br /></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">Prior to our distribution agreements with
      Sobi, we recognized TEGSEDI and WAYLIVRA commercial revenue in the period when our customer obtained control of our products, which occurred at a point in time upon transfer of title to the customer. We classified payments to customers or other
      parties in the distribution channel for services that were distinct and priced at fair value as selling, general and administrative, or SG&amp;A, expenses in our consolidated statements of operations. We classified payments to customers or other
      parties in the distribution channel that did not meet those criteria as a reduction of revenue, as discussed further below. We excluded from revenues taxes collected from customers relating to TEGSEDI and WAYLIVRA commercial revenue and remitted
      these amounts to governmental authorities</span>.</div>
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  </div>
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<div style="display:none;"><br /></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;">Reserves for TEGSEDI and WAYLIVRA commercial revenue</div>
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<div><br />
  </div>
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<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Prior to our distribution agreements with Sobi, we recorded TEGSEDI and WAYLIVRA commercial revenue at our net sales
      price, or transaction price. We included in our transaction price estimated reserves for discounts, returns, chargebacks, rebates and other allowances that we offered within contracts between us and our customers, wholesalers, distributors, health
      care providers and other indirect customers. We estimated our reserves using the amounts we have earned or we could claim on the associated sales. We classified our reserves as a reduction of accounts receivable when we were not required to make a
      payment or as a current liability when we were required to make a payment. In certain cases, our estimates included a range of possible outcomes that were probability weighted for relevant factors such as our historical experience, current
      contractual and statutory requirements, specific known market events and trends, industry data and forecasted customer buying and payment patterns. Overall, our reserves reflected our best estimates under the terms of our respective contracts. When
      calculating our reserves and related TEGSEDI and WAYLIVRA commercial revenue, we only recognized amounts to the extent that we considered it probable that we would not have to reverse a significant amount of the cumulative sales we previously
      recognized in a future period. Under our agreements with Sobi, we transferred all reserves to Sobi.</div>
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  </div>
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<div style="display:none;"><br /></div>
<div style="text-align: left; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">The following were the components of variable consideration related to TEGSEDI and WAYLIVRA product sales prior to our agreements with Sobi:</div>
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<div><br />
  </div>
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<div style="text-align: justify; margin-left: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Chargebacks: </span><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">In the U.S., we estimated obligations resulting from contractual commitments with the government and other entities to sell products to qualified healthcare
      providers at prices lower than the list prices charged to our U.S. customer. Our U.S. customer charged us for the difference between what it paid for the product and the selling price to the qualified healthcare providers. We also estimated the
      amount of chargebacks related to our estimated product remaining in the distribution channel at the end of the reporting period that we expected our customer to sell to healthcare providers in future periods. We recorded these reserves as a reduction
      to contracts receivable on our consolidated balance sheet</span>.</div>
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  </div>
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<div style="text-align: justify; margin-left: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic; color: #000000;">Government rebates</span><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">: We were subject to discount obligations under government programs, including Medicaid and Medicare programs in the U.S. and we recorded reserves for government
      rebates based on statutory discount rates and estimated utilization. We estimated Medicaid and Medicare rebates based on a range of possible outcomes that were probability weighted for the estimated payer mix. We recorded these reserves as an accrued
      liability on our consolidated balance sheet with a corresponding offset reducing our product sales in the same period we recognized the related sale. For Medicare, we also estimated the number of patients in the prescription drug coverage gap for
      whom we would owe an additional liability under the Medicare Part D program. On a quarterly basis, we updated our estimates and recorded any adjustments in the period that we identified the adjustments</span>.</div>
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  <ix:continuation id="Text_ba6a171da9294812a4a91832efce6f8c154" continuedAt="Text_ba6a171da9294812a4a91832efce6f8c155"><ix:continuation id="Text_b1241e53de0f474cbd49eab8f51e9c82105" continuedAt="Text_b1241e53de0f474cbd49eab8f51e9c82106">
<div style="text-align: justify; margin-left: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Managed care rebates: </span><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">We were subject to rebates in connection with agreements with certain contracted commercial payers. We recorded these rebates as a liability on our consolidated
      balance sheet in the same period we recognized the related revenue. We estimated our managed care rebates based on our estimated payer mix and the applicable contractual rebate rate</span>.</div>
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<div style="text-align: justify; margin-left: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Trade discounts: </span><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">We provided customary invoice discounts on product sales to our U.S. customer for prompt payment. We recorded this discount as a reduction of product sales in the
      period in which we recognized the related product revenue</span>.</div>
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  <ix:continuation id="Text_ba6a171da9294812a4a91832efce6f8c158" continuedAt="Text_ba6a171da9294812a4a91832efce6f8c159"><ix:continuation id="Text_b1241e53de0f474cbd49eab8f51e9c82109" continuedAt="Text_b1241e53de0f474cbd49eab8f51e9c82110">
<div style="text-align: justify; margin-left: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Distribution services</span>: <span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">We received and paid for various distribution services from our U.S. and European customers (prior to our agreement with Sobi) and wholesalers in the U.S. We
      classified the costs for services we received that are either not distinct from the sale of the product or for which we could not reasonably estimate the fair value as a reduction of product sales. To the extent that the services we received are
      distinct from the sale of the product, we classified the costs for such services as SG&amp;A expenses.</span></div>
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  <ix:continuation id="Text_ba6a171da9294812a4a91832efce6f8c160" continuedAt="Text_ba6a171da9294812a4a91832efce6f8c161"><ix:continuation id="Text_b1241e53de0f474cbd49eab8f51e9c82111" continuedAt="Text_b1241e53de0f474cbd49eab8f51e9c82112">
<div style="text-align: justify; margin-left: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Product returns: </span><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">Our U.S. customer had return rights and the wholesalers had limited return rights primarily related to the product&#8217;s expiration date. We estimated the amount of
      product sales that our customer may return. We recorded our return estimate as an accrued refund liability on our consolidated balance sheet with a corresponding offset reducing our product sales in the same period we recognized the related sale.
      Based on our distribution model for product sales, contractual inventory limits with our customer and wholesalers and the price of the product, we had minimal returns. Our European customers generally only took title to the product after they
      received an order and therefore they did not maintain excess inventory levels of our products. Accordingly, we had limited return risk in Europe and we did not estimate returns in Europe</span>.</div>
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  </div>
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<div style="text-align: left; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;"><span style="text-decoration: underline;">Research and development revenue under collaboration agreements:</span></div>
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<div style="text-align: left; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;"><span style="text-decoration: underline;">Upfront payments</span></div>
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  <ix:continuation id="Text_ba6a171da9294812a4a91832efce6f8c166" continuedAt="Text_ba6a171da9294812a4a91832efce6f8c167"><ix:continuation id="Text_b1241e53de0f474cbd49eab8f51e9c82117" continuedAt="Text_b1241e53de0f474cbd49eab8f51e9c82118">
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<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">When we enter into a collaboration agreement
      with an upfront payment, we typically record the entire upfront payment as deferred revenue if our only performance obligation is for R&amp;D services we will provide in the future. We amortize the upfront payment into revenue as we perform the
      R&amp;D services. For example, under our collaboration agreement with Roche to</span><span style="background-color: #FBFBFB; font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> develop IONIS-FB-L</span><sub style="color: #000000;">Rx</sub><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> for the treatment of complement-mediated diseases, we received a $</span><ix:nonFraction name="ions:UpfrontPaymentReceived" id="Fact_80c50f2105fc45ff909730144a25f529" contextRef="c20181001to20181231_TypeOfArrangementAxis_RocheCollaborationIonisFbLForComplementMediatedDiseasesMember" unitRef="U001" decimals="-6" scale="6" format="ixt:numdotdecimal">75</ix:nonFraction><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> million upfront payment in the fourth quarter of 2018. We allocated the upfront payment to our
      single performance obligation, R&amp;D services. We are amortizing the $</span><ix:nonFraction name="ions:UpfrontPaymentReceived" id="Fact_b04a5042e2c84665977aa473309829e0" contextRef="c20181001to20181231_TypeOfArrangementAxis_RocheCollaborationIonisFbLForComplementMediatedDiseasesMember" unitRef="U001" decimals="-6" scale="6" format="ixt:numdotdecimal">75</ix:nonFraction><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> million upfront payment using an input method over the estimated period of time we are providing R&amp;D services</span>.</div>
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<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;"><span style="text-decoration: underline;">Milestone payments</span></div>
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  <div>
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<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We are required to include additional consideration in the transaction price when it is probable. We typically
        include milestone payments for R&amp;D services in the transaction price when they are achieved. We include these milestone payments when they are achieved because typically there is considerable uncertainty in the research and development
        processes that trigger these payments. Similarly, we include approval milestone payments in the transaction price once the medicine is approved by the applicable regulatory agency. We will recognize sales-based milestone payments in the period in
        which we achieve the milestone under the sales-based royalty exception allowed under accounting rules.</div>
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  <ix:continuation id="Text_ba6a171da9294812a4a91832efce6f8c172" continuedAt="Text_ba6a171da9294812a4a91832efce6f8c173"><ix:continuation id="Text_b1241e53de0f474cbd49eab8f51e9c82123" continuedAt="Text_b1241e53de0f474cbd49eab8f51e9c82124">
<div style="display:none;"><br /></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">We recognize milestone payments that relate
      to an ongoing performance obligation over our period of performance. For example, in the fourth quarter of 2021, we achieved a</span> $<ix:nonFraction name="ions:RevenueFromContractWithCustomerTransactionPriceAdditions" id="Fact_0c4239a1d9d44f1fa80e4bff81074bbf" contextRef="c20211001to20211231_TypeOfArrangementAxis_BiogenCollaboration2018StrategicNeurologyMember" unitRef="U001" decimals="-5" scale="6" format="ixt:numdotdecimal">7.5</ix:nonFraction>&#160;<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">million milestone payment from Biogen when we advanced</span>&#160;<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">a </span>target
    under our 2018 strategic collaboration.<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> We added this payment to the transaction price and allocated it to our R&amp;D services performance obligation. We are
      recognizing revenue related to this milestone payment over our estimated period of performance</span>.</div>
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<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Conversely, we recognize in full those milestone payments that we earn based on our partners&#8217; activities when our partner achieves the
    milestone event and we do not have a performance obligation. For example, in the fourth quarter of 2021, we recognized $<ix:nonFraction name="us-gaap:RevenueFromContractWithCustomerExcludingAssessedTax" id="Fact_4b33a96b00a64505b77b8ee66dc4a12b" contextRef="c20211001to20211231_TypeOfArrangementAxis_BiogenCollaboration2018StrategicNeurologyMember" unitRef="U001" decimals="-6" scale="6" format="ixt:numdotdecimal">15</ix:nonFraction> million in milestone
    payments when Biogen advanced <ix:nonFraction name="ions:NumberOfNewTargetsAdvanced" id="Fact_484d78a9267f4db2b6535e59c368a2ad" contextRef="c20211001to20211231_TypeOfArrangementAxis_BiogenCollaboration2018StrategicNeurologyMember" unitRef="U005" decimals="INF" scale="0" format="ixt-sec:numwordsen">two</ix:nonFraction> targets under our 2018 strategic collaboration. <span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">We concluded that the milestone payments were not related to our R&amp;D services performance obligation. Therefore, we recognized the milestone payments in full in the fourth quarter of 2021.</span></div>
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<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;"><span style="text-decoration: underline;">License fees</span></div>
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<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">We generally recognize as revenue the total
      amount we determine to be the relative stand-alone selling price of a license when we deliver the license to our partner. This is because our partner has full use of the license and we do not have any additional performance obligations related to the
      license after delivery. For example, in the fourth quarter of 2021, we earned a</span> $<ix:nonFraction name="us-gaap:RevenueFromContractWithCustomerExcludingAssessedTax" id="Fact_11cc7b0fae0641cda1cec3b36d0f8519" contextRef="c20211001to20211231_ProductOrServiceAxis_Ion306Member_TypeOfArrangementAxis_BiogenCollaborationNewAntisenseMedicinesForTreatmentOfSmaMember" unitRef="U001" decimals="-6" scale="6" format="ixt:numdotdecimal">60</ix:nonFraction>&#160;<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">million license fee from Biogen when Biogen licensed ION306, an investigational medicine in development to treat SMA.</span></div>
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<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;"><span style="text-decoration: underline;">Sublicense fees</span></div>
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<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">We recognize sublicense fee revenue in the
      period in which a party, who has already licensed our technology, further licenses the technology to another party because we do not have any performance obligations related to the sublicense. </span>For example, in the fourth quarter of 2020, we
    earned a $<ix:nonFraction name="us-gaap:RevenueFromContractWithCustomerExcludingAssessedTax" id="Fact_9aa225f0eeb44601a1c07a22cc707fd6" contextRef="c20201001to20201231_TypeOfArrangementAxis_AlnylamCollaborationMember" unitRef="U001" decimals="-5" scale="6" format="ixt:numdotdecimal">41.2</ix:nonFraction> million sublicense fee from Alnylam Pharmaceuticals for its sublicense of our technology to Sanofi Genzyme.</div>
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<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic; font-weight: bold;">Amendments to Agreements</div>
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<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">From time to time we amend our collaboration agreements. When this occurs, we are required to assess the following items
    to determine the accounting for the amendment:</div>
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  <tr>

    <td style="width: 36pt;"></td>

    <td style="width: 18pt; vertical-align: top; align: right; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">1)</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;">If the additional goods and/or services are distinct from the other performance obligations in the original agreement; and</div>
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    <td style="width: 18pt; vertical-align: top; align: right; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">2)</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;">If the goods and/or services are at a stand-alone selling price.</div>
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  <div>
    <ix:continuation id="Text_ba6a171da9294812a4a91832efce6f8c191" continuedAt="Text_ba6a171da9294812a4a91832efce6f8c192"><ix:continuation id="Text_b1241e53de0f474cbd49eab8f51e9c82142" continuedAt="Text_b1241e53de0f474cbd49eab8f51e9c82143">
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<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">If we conclude the goods and/or services in the amendment are distinct from the performance obligations in the
        original agreement and at a stand-alone selling price, we account for the amendment as a separate agreement. If we conclude the goods and/or services are not distinct and are sold at a stand-alone selling price, we then assess whether the remaining
        goods or services are distinct from those already provided. If the goods and/or services are distinct from what we have already provided, then we allocate the remaining transaction price from the original agreement and the additional transaction
        price from the amendment to the remaining goods and/or services. If the goods and/or services are not distinct from what we have already provided, we update the transaction price for our single performance obligation and recognize any change in our
        estimated revenue as a cumulative adjustment.</div>
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<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">For example, in May 2015, we entered into an exclusive license agreement with Bayer to develop and commercialize IONIS-FXI<sub>Rx</sub>
    for the prevention of thrombosis. As part of the agreement, Bayer paid us a $<ix:nonFraction name="ions:UpfrontPaymentReceived" id="Fact_0d6056e1b6644d9c9d653098b4049ca7" contextRef="c20150501to20150531_TypeOfArrangementAxis_BayerCollaborationIonisFxiMember" unitRef="U001" decimals="-6" scale="6" format="ixt:numdotdecimal">100</ix:nonFraction> million upfront payment. At the onset of the agreement, we were
    responsible for completing a Phase 2 study of IONIS-FXI<sub>Rx</sub> in people with end-stage renal disease on hemodialysis and for providing an initial supply of API. In February 2017, we amended our agreement with Bayer to advance IONIS-FXI<sub>Rx</sub>
    and to initiate development of fesomersen, which Bayer licensed. As part of the 2017 amendment, Bayer paid us $<ix:nonFraction name="ions:UpfrontPaymentReceived" id="Fact_a9a1805954f64878a93a25b8bdc51336" contextRef="c20170201to20170228_TypeOfArrangementAxis_BayerCollaborationIonisFxiAmendmentMember" unitRef="U001" decimals="-6" scale="6" format="ixt:numdotdecimal">75</ix:nonFraction> million. We are also eligible
    to receive milestone payments and tiered royalties on gross margins of IONIS-FXI<sub>Rx</sub> and fesomersen. Under the 2017 amendment, we concluded we had a new agreement with <ix:nonFraction name="ions:RevenueFromContractWithCustomerNumberOfSeparatePerformanceObligations" id="Fact_d7f40585d07e4c20b3f340621339c834" contextRef="c20170228_TypeOfArrangementAxis_BayerCollaborationIonisFxiAmendmentMember" unitRef="U006" decimals="INF" scale="0" format="ixt-sec:numwordsen">three</ix:nonFraction> performance obligations. These performance obligations were to deliver the license of fesomersen, to provide R&amp;D services and to deliver API. We allocated the $<ix:nonFraction name="ions:RevenueFromContractWithCustomerTransactionPrice" id="Fact_b4cb5c3382b24bcaab84c7f899cd4bb0" contextRef="c20170228_TypeOfArrangementAxis_BayerCollaborationIonisFxiAmendmentMember" unitRef="U001" decimals="-6" scale="6" format="ixt:numdotdecimal">75</ix:nonFraction> million transaction price to these performance obligations. Refer to Note 6, <span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Collaborative Arrangements and Licensing Agreements</span>, for further discussion of the Bayer collaboration.</div>
</ix:continuation></ix:continuation>

  <ix:continuation id="Text_ba6a171da9294812a4a91832efce6f8c194" continuedAt="Text_ba6a171da9294812a4a91832efce6f8c195"><ix:continuation id="Text_b1241e53de0f474cbd49eab8f51e9c82145" continuedAt="Text_b1241e53de0f474cbd49eab8f51e9c82146">
<div><br />
  </div>
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<div style="display:none;"><br /></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic; font-weight: bold;">Multiple agreements</div>
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<div><br />
  </div>
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  <ix:continuation id="Text_ba6a171da9294812a4a91832efce6f8c197" continuedAt="Text_ba6a171da9294812a4a91832efce6f8c198"><ix:continuation id="Text_b1241e53de0f474cbd49eab8f51e9c82148" continuedAt="Text_b1241e53de0f474cbd49eab8f51e9c82149">
<div style="display:none;"><br /></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">From time to time, we may enter into separate agreements at or near the same time with the same partner. We evaluate such
    agreements to determine whether we should account for them individually as distinct arrangements or whether the separate agreements should be combined and accounted for together. We evaluate the following to determine the accounting for the agreements:</div>
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<div><br />
  </div>
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  <ix:continuation id="Text_ba6a171da9294812a4a91832efce6f8c199" continuedAt="Text_ba6a171da9294812a4a91832efce6f8c200"><ix:continuation id="Text_b1241e53de0f474cbd49eab8f51e9c82150" continuedAt="Text_b1241e53de0f474cbd49eab8f51e9c82151">
<table cellspacing="0" cellpadding="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">


  <tr>

    <td style="width: 36pt;"></td>

    <td style="width: 18pt; vertical-align: top; align: right; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Whether the agreements were negotiated together with a single objective;</div>
        </td>

  </tr>


</table>
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  <ix:continuation id="Text_ba6a171da9294812a4a91832efce6f8c200" continuedAt="Text_ba6a171da9294812a4a91832efce6f8c201"><ix:continuation id="Text_b1241e53de0f474cbd49eab8f51e9c82151" continuedAt="Text_b1241e53de0f474cbd49eab8f51e9c82152">
<table cellspacing="0" cellpadding="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">


  <tr>

    <td style="width: 36pt;"></td>

    <td style="width: 18pt; vertical-align: top; align: right; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Whether the amount of consideration in one contract depends on the price or performance of the other agreement; or</div>
        </td>

  </tr>


</table>
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  <ix:continuation id="Text_ba6a171da9294812a4a91832efce6f8c201" continuedAt="Text_ba6a171da9294812a4a91832efce6f8c202"><ix:continuation id="Text_b1241e53de0f474cbd49eab8f51e9c82152" continuedAt="Text_b1241e53de0f474cbd49eab8f51e9c82153">
<table cellspacing="0" cellpadding="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">


  <tr>

    <td style="width: 36pt;"></td>

    <td style="width: 18pt; vertical-align: top; align: right; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Whether the goods and/or services promised under the agreements are a single performance obligation.</div>
        </td>

  </tr>


</table>
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  <ix:continuation id="Text_ba6a171da9294812a4a91832efce6f8c202" continuedAt="Text_ba6a171da9294812a4a91832efce6f8c203"><ix:continuation id="Text_b1241e53de0f474cbd49eab8f51e9c82153" continuedAt="Text_b1241e53de0f474cbd49eab8f51e9c82154">
<div><br />
  </div>
</ix:continuation></ix:continuation>
  <ix:continuation id="Text_ba6a171da9294812a4a91832efce6f8c203" continuedAt="Text_ba6a171da9294812a4a91832efce6f8c204"><ix:continuation id="Text_b1241e53de0f474cbd49eab8f51e9c82154" continuedAt="Text_b1241e53de0f474cbd49eab8f51e9c82155">
<div style="display:none;"><br /></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Our evaluation involves significant judgment to determine whether a group of agreements might be so closely related that accounting
    guidance requires us to account for them as a combined arrangement.</div>
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  <ix:continuation id="Text_ba6a171da9294812a4a91832efce6f8c204" continuedAt="Text_ba6a171da9294812a4a91832efce6f8c205"><ix:continuation id="Text_b1241e53de0f474cbd49eab8f51e9c82155" continuedAt="Text_b1241e53de0f474cbd49eab8f51e9c82156">
<div><br />
  </div>
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<div style="display:none;"><br /></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">For example, in the second quarter of 2018, we entered into <ix:nonFraction name="ions:NumberOfAgreementsWithCollaborationPartner" id="Fact_2c7da156332f416f88550ff96ae19478" contextRef="c20180401to20180630_MajorCustomersAxis_BiogenIncMember" unitRef="U007" decimals="INF" scale="0" format="ixt-sec:numwordsen">two</ix:nonFraction> separate agreements with Biogen at the same time: <span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">a new strategic neurology collaboration
      agreement and a stock purchase agreement, or SPA. We evaluated the Biogen agreements to determine whether we should treat the agreements separately or combine them. We considered that the agreements were negotiated concurrently and in contemplation
      of one another. Based on these facts and circumstances, we concluded that we should evaluate the provisions of the agreements on a combined basis.</span></div>
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<div><br />
  </div>
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<div style="display:none;"><br /></div>
<div style="text-align: left; text-indent: -54pt; margin-left: 54pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Contracts Receivable</div>
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<div><br />
  </div>
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<div style="display:none;"><br /></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">Our contracts receivable balance represents
      the amounts we have billed our partners or customers and that are due to us unconditionally for goods we have delivered or services we have performed. When we bill our partners or customers with payment terms based on the passage of time, we consider
      the contracts receivable to be unconditional. We typically receive payment within one </span><span style="-sec-ix-hidden:Fact_e2c2673a057f412ebd5831ca8712546a">quarter</span><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> of billing our partner or customer</span>.</div>
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<div><br />
  </div>
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<div style="display:none;"><br /></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">As of December 31, 2021, approximately <ix:nonFraction name="us-gaap:ConcentrationRiskPercentage1" id="Fact_8cbaf7e8f6f14ab8b9a5bac9f1a94ee5" contextRef="c20210101to20211231_ConcentrationRiskByBenchmarkAxis_AccountsReceivableMember_ConcentrationRiskByTypeAxis_CreditConcentrationRiskMember_MajorCustomersAxis_TwoSignificantCustomersMember" unitRef="U003" decimals="3" scale="-2" format="ixt:numdotdecimal">93.8</ix:nonFraction> percent of our contracts receivables were from <ix:nonFraction name="ions:NumberOfSignificantCustomers" id="Fact_989b31e12c534c2cb51193d15fef47ac" contextRef="c20210101to20211231" unitRef="U008" decimals="INF" scale="0" format="ixt-sec:numwordsen">two</ix:nonFraction> significant customers. As of December 31, 2020, approximately <ix:nonFraction name="us-gaap:ConcentrationRiskPercentage1" id="Fact_9b60e884ea4946728c18b631acdef31b" contextRef="c20200101to20201231_ConcentrationRiskByBenchmarkAxis_AccountsReceivableMember_ConcentrationRiskByTypeAxis_CreditConcentrationRiskMember_MajorCustomersAxis_TwoSignificantCustomersMember" unitRef="U003" decimals="3" scale="-2" format="ixt:numdotdecimal">99.5</ix:nonFraction> percent of our contracts receivables were from <ix:nonFraction name="ions:NumberOfSignificantCustomers" id="Fact_5e1263191fc1438492a439c3f8e95b1d" contextRef="c20200101to20201231" unitRef="U008" decimals="INF" scale="0" format="ixt-sec:numwordsen">two</ix:nonFraction>
    significant customers.</div>
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    <div class="DSPFPageFooter">
      <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">F-<span class="DSPFPageNumber">17</span></div>

    </div>

    <div style="page-break-after:always;" class="DSPFPageBreak">
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  </div>
<div><ix:continuation id="Text_ba6a171da9294812a4a91832efce6f8c213" continuedAt="Text_ba6a171da9294812a4a91832efce6f8c214"><ix:nonNumeric name="us-gaap:TradeAndOtherAccountsReceivableUnbilledReceivablesPolicy" id="Text_11c759b68b4b4c4b94628fcf39b9e913" contextRef="c20210101to20211231" escape="true" continuedAt="Text_bd05d6ac3d104bfba5a35c2b4ca1608f1">
<div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Unbilled SPINRAZA Royalties</div>
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  <ix:continuation id="Text_ba6a171da9294812a4a91832efce6f8c214" continuedAt="Text_ba6a171da9294812a4a91832efce6f8c215"><ix:continuation id="Text_bd05d6ac3d104bfba5a35c2b4ca1608f1" continuedAt="Text_bd05d6ac3d104bfba5a35c2b4ca1608f2">
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<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Our unbilled SPINRAZA royalties represent our right to receive consideration from Biogen in advance of when we are
    eligible to bill Biogen for SPINRAZA royalties. We include these unbilled amounts in other current assets on our consolidated balance sheet.</div>
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<div><br />
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<div style="text-align: left; text-indent: -54pt; margin-left: 54pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Deferred Revenue</div>
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<div><br />
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  <ix:continuation id="Text_ba6a171da9294812a4a91832efce6f8c219" continuedAt="Text_ba6a171da9294812a4a91832efce6f8c220"><ix:continuation id="Text_affdcd79f76c43e29ef57ae00630c5542">
<div style="display:none;"><br /></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">We are often entitled to bill our customers
      and receive payment from our customers in advance of our obligation to provide services or transfer goods to our partners. In these instances, we include the amounts in deferred revenue on our consolidated balance sheet.</span> During the years ended
    December 31, 2021 and 2020, we recognized $<ix:nonFraction name="us-gaap:ContractWithCustomerLiabilityRevenueRecognized" id="Fact_7a9ec3bea8ad464ca6e12c6aa16435cd" contextRef="c20210101to20211231" unitRef="U001" decimals="-5" scale="6" format="ixt:numdotdecimal">98.1</ix:nonFraction> million and $<ix:nonFraction name="us-gaap:ContractWithCustomerLiabilityRevenueRecognized" id="Fact_ced6b030f6d146bb91eabbce81e6f413" contextRef="c20200101to20201231" unitRef="U001" decimals="-5" scale="6" format="ixt:numdotdecimal">100.4</ix:nonFraction> million of revenue from amounts that were in our beginning deferred revenue balance for each respective period. For further discussion, refer to our revenue recognition policy above.</div>
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<div><br />
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<div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Cost of Sales</div>
</ix:nonNumeric></ix:continuation>
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<div><br />
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<div style="display:none;"><br /></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Our cost of sales includes manufacturing costs, transportation and freight costs and indirect overhead costs associated with the
    manufacturing and distribution of our products. We also may include certain period costs related to manufacturing services and inventory adjustments in cost of sales. We also may include certain period costs related to manufacturing services and
    inventory adjustments in cost of sales.</div>
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<div><br />
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<div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Research, Development and Patent Expenses</div>
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<div><br />
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<div style="display:none;"><br /></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Our research and development expenses include wages, benefits, facilities, supplies, external
    services, clinical trial and manufacturing costs and other expenses that are directly related to our research and development operations. We expense research and development costs as we incur them. When we make payments for research and development
    services prior to the services being rendered, we record those amounts as prepaid assets on our consolidated balance sheet and we expense them as the services are provided. For the years ended December 31, 2021, 2020 and 2019, research and development expenses were $<ix:nonFraction name="us-gaap:ResearchAndDevelopmentExpense" id="Fact_d0c1565159a044b595630e050bb43a4e" contextRef="c20210101to20211231" unitRef="U001" decimals="-5" scale="6" format="ixt:numdotdecimal">638.2</ix:nonFraction> million, $<ix:nonFraction name="us-gaap:ResearchAndDevelopmentExpense" id="Fact_0114d1a3cfd445bbb2a6b5bc9fba079f" contextRef="c20200101to20201231" unitRef="U001" decimals="-5" scale="6" format="ixt:numdotdecimal">531.0</ix:nonFraction> million and $<ix:nonFraction name="us-gaap:ResearchAndDevelopmentExpense" id="Fact_203e9d3fa0b14eca9d0edbb437f4f325" contextRef="c20190101to20191231" unitRef="U001" decimals="-5" scale="6" format="ixt:numdotdecimal">461.5</ix:nonFraction> million, respectively. A
    portion of the costs included in research and development expenses are costs associated with our partner agreements.</div>
</ix:nonNumeric></ix:continuation>
  <ix:continuation id="Text_ba6a171da9294812a4a91832efce6f8c228" continuedAt="Text_ba6a171da9294812a4a91832efce6f8c229">
<div><br />
  </div>
</ix:continuation>
  <ix:continuation id="Text_ba6a171da9294812a4a91832efce6f8c229" continuedAt="Text_ba6a171da9294812a4a91832efce6f8c230"><ix:nonNumeric name="us-gaap:IntangibleAssetsFiniteLivedPolicy" id="Text_4ba9c595a228410fb80294db6e9e8808" contextRef="c20210101to20211231" escape="true" continuedAt="Text_b5bb00f1f9784cd5a74ba254e81781491">
<div style="display:none;"><br /></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We capitalize costs consisting principally of outside legal costs and filing fees related to obtaining
    patents. We amortize patent costs over the useful life of the patent, beginning with the date the U.S. Patent and Trademark Office, or foreign equivalent, issues the patent. The weighted average remaining amortizable life of our issued patents was <ix:nonNumeric name="us-gaap:FiniteLivedIntangibleAssetUsefulLife" id="Fact_0743de364414479fa413c5d659ce3213" contextRef="c20210101to20211231_FiniteLivedIntangibleAssetsByMajorClassAxis_PatentsMember" format="ixt-sec:duryear">10.2</ix:nonNumeric> years at December 31, 2021.</div>
</ix:nonNumeric></ix:continuation>
  <ix:continuation id="Text_ba6a171da9294812a4a91832efce6f8c230" continuedAt="Text_ba6a171da9294812a4a91832efce6f8c231"><ix:continuation id="Text_b5bb00f1f9784cd5a74ba254e81781491" continuedAt="Text_b5bb00f1f9784cd5a74ba254e81781492">
<div><br />
  </div>
</ix:continuation></ix:continuation>
  <ix:continuation id="Text_ba6a171da9294812a4a91832efce6f8c231" continuedAt="Text_ba6a171da9294812a4a91832efce6f8c232"><ix:continuation id="Text_b5bb00f1f9784cd5a74ba254e81781492" continuedAt="Text_b5bb00f1f9784cd5a74ba254e81781493">
<div style="display:none;"><br /></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">The cost of our patents capitalized on our consolidated balance sheet at December 31, 2021 and 2020 was $<ix:nonFraction name="us-gaap:FiniteLivedIntangibleAssetsGross" id="Fact_df1e6fe595054242bd56601d34e950e2" contextRef="c20211231_FiniteLivedIntangibleAssetsByMajorClassAxis_PatentsMember" unitRef="U001" decimals="-5" scale="6" format="ixt:numdotdecimal">38.4</ix:nonFraction> million and $<ix:nonFraction name="us-gaap:FiniteLivedIntangibleAssetsGross" id="Fact_421e79a98335467eb99a9cba6857377d" contextRef="c20201231_FiniteLivedIntangibleAssetsByMajorClassAxis_PatentsMember" unitRef="U001" decimals="-5" scale="6" format="ixt:numdotdecimal">37.0</ix:nonFraction> million, respectively.
    Accumulated amortization related to patents was $<ix:nonFraction name="us-gaap:FiniteLivedIntangibleAssetsAccumulatedAmortization" id="Fact_414dd9c96ebb45a28f493a17da9dec2e" contextRef="c20211231_FiniteLivedIntangibleAssetsByMajorClassAxis_PatentsMember" unitRef="U001" decimals="-5" scale="6" format="ixt:numdotdecimal">9.4</ix:nonFraction> million and $<ix:nonFraction name="us-gaap:FiniteLivedIntangibleAssetsAccumulatedAmortization" id="Fact_91380e7cfc944a1e8053aef43d6d897f" contextRef="c20201231_FiniteLivedIntangibleAssetsByMajorClassAxis_PatentsMember" unitRef="U001" decimals="-5" scale="6" format="ixt:numdotdecimal">9.1</ix:nonFraction> million at December 31, 2021 and 2020, respectively.</div>
</ix:continuation></ix:continuation>
  <ix:continuation id="Text_ba6a171da9294812a4a91832efce6f8c232" continuedAt="Text_ba6a171da9294812a4a91832efce6f8c233"><ix:continuation id="Text_b5bb00f1f9784cd5a74ba254e81781493" continuedAt="Text_b5bb00f1f9784cd5a74ba254e81781494">
<div><br />
  </div>
</ix:continuation></ix:continuation>
  <ix:continuation id="Text_ba6a171da9294812a4a91832efce6f8c233" continuedAt="Text_ba6a171da9294812a4a91832efce6f8c234"><ix:continuation id="Text_b5bb00f1f9784cd5a74ba254e81781494" continuedAt="Text_b5bb00f1f9784cd5a74ba254e81781495"><ix:nonNumeric name="us-gaap:ScheduleofFiniteLivedIntangibleAssetsFutureAmortizationExpenseTableTextBlock" id="Text_94528c9584664d73b67412f9d345feef" contextRef="c20210101to20211231" escape="true" continuedAt="Text_3ee79a1f534f4406bdaebe94645e806e1">
<div style="display:none;"><br /></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Based on our existing patents, we estimate amortization expense related to patents in each of
    the next five years to be the following:</div>
</ix:nonNumeric></ix:continuation></ix:continuation>
  <ix:continuation id="Text_ba6a171da9294812a4a91832efce6f8c234" continuedAt="Text_ba6a171da9294812a4a91832efce6f8c235"><ix:continuation id="Text_b5bb00f1f9784cd5a74ba254e81781495" continuedAt="Text_b5bb00f1f9784cd5a74ba254e81781496"><ix:continuation id="Text_3ee79a1f534f4406bdaebe94645e806e1" continuedAt="Text_3ee79a1f534f4406bdaebe94645e806e2">
<div><br />
  </div>
</ix:continuation></ix:continuation></ix:continuation>
  <ix:continuation id="Text_ba6a171da9294812a4a91832efce6f8c235" continuedAt="Text_ba6a171da9294812a4a91832efce6f8c236"><ix:continuation id="Text_b5bb00f1f9784cd5a74ba254e81781496" continuedAt="Text_b5bb00f1f9784cd5a74ba254e81781497"><ix:continuation id="Text_3ee79a1f534f4406bdaebe94645e806e2">
<table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;" class="cfttable">


  <tr>

    <td valign="bottom" style="vertical-align: bottom; border-bottom: #000000 2px solid;">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Year Ending December 31,</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" colspan="2">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Amortization</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">(in millions)</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 88%; background-color: #CCEEFF;">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="text-indent: 0pt;">2022</span></div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:FiniteLivedIntangibleAssetsAmortizationExpenseNextTwelveMonths" id="Fact_8b4595506d5b46448ab97fdee1240d0f" contextRef="c20211231_FiniteLivedIntangibleAssetsByMajorClassAxis_PatentsMember" unitRef="U001" decimals="-5" scale="6" format="ixt:numdotdecimal">2.2</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 88%;">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="text-indent: 0pt;">2023</span></div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:FiniteLivedIntangibleAssetsAmortizationExpenseYearTwo" id="Fact_e44494ea589f4fd6bf584443ca16bfcc" contextRef="c20211231_FiniteLivedIntangibleAssetsByMajorClassAxis_PatentsMember" unitRef="U001" decimals="-5" scale="6" format="ixt:numdotdecimal">2.1</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 88%; background-color: #CCEEFF;">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="text-indent: 0pt;">2024</span></div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:FiniteLivedIntangibleAssetsAmortizationExpenseYearThree" id="Fact_5f35096f0bcf43fb92b147de0bf72462" contextRef="c20211231_FiniteLivedIntangibleAssetsByMajorClassAxis_PatentsMember" unitRef="U001" decimals="-5" scale="6" format="ixt:numdotdecimal">1.9</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 88%;">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="text-indent: 0pt;">2025</span></div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:FiniteLivedIntangibleAssetsAmortizationExpenseYearFour" id="Fact_7b3245e6bc5b4426819c1fb6dc13148c" contextRef="c20211231_FiniteLivedIntangibleAssetsByMajorClassAxis_PatentsMember" unitRef="U001" decimals="-5" scale="6" format="ixt:numdotdecimal">1.8</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 88%; background-color: #CCEEFF;">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="text-indent: 0pt;">2026</span></div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:FiniteLivedIntangibleAssetsAmortizationExpenseYearFive" id="Fact_f350bd894a8d412c8d2a916536e277ef" contextRef="c20211231_FiniteLivedIntangibleAssetsByMajorClassAxis_PatentsMember" unitRef="U001" decimals="-5" scale="6" format="ixt:numdotdecimal">1.8</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>


</table>
</ix:continuation></ix:continuation></ix:continuation>
  <ix:continuation id="Text_ba6a171da9294812a4a91832efce6f8c236" continuedAt="Text_ba6a171da9294812a4a91832efce6f8c237"><ix:continuation id="Text_b5bb00f1f9784cd5a74ba254e81781497" continuedAt="Text_b5bb00f1f9784cd5a74ba254e81781498">
<div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 12pt;"><br />
  </div>
</ix:continuation></ix:continuation>
  <ix:continuation id="Text_ba6a171da9294812a4a91832efce6f8c237" continuedAt="Text_ba6a171da9294812a4a91832efce6f8c238"><ix:continuation id="Text_b5bb00f1f9784cd5a74ba254e81781498">
<div style="display:none;"><br /></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We review our capitalized patent costs regularly to ensure that they include costs for patents and patent applications
    that have future value. When we identify patents and patent applications that we are not actively pursuing, we write off any associated costs. In 2021,
    2020 and 2019, patent expenses
    were $<ix:nonFraction name="us-gaap:ResearchAndDevelopmentExpense" id="Fact_49b21994e36f479d8fb8491e6b0e2bec" contextRef="c20210101to20211231_FiniteLivedIntangibleAssetsByMajorClassAxis_PatentsMember" unitRef="U001" decimals="-5" scale="6" format="ixt:numdotdecimal">5.3</ix:nonFraction> million, $<ix:nonFraction name="us-gaap:ResearchAndDevelopmentExpense" id="Fact_9907ec92e4dd4419b5a9f4fb46f56330" contextRef="c20200101to20201231_FiniteLivedIntangibleAssetsByMajorClassAxis_PatentsMember" unitRef="U001" decimals="-5" scale="6" format="ixt:numdotdecimal">4.1</ix:nonFraction> million and $<ix:nonFraction name="us-gaap:ResearchAndDevelopmentExpense" id="Fact_3201b72effcf4c0c8e0d51523e32d64f" contextRef="c20190101to20191231_FiniteLivedIntangibleAssetsByMajorClassAxis_PatentsMember" unitRef="U001" decimals="-5" scale="6" format="ixt:numdotdecimal">4.2</ix:nonFraction> million, respectively, and included non-cash charges related to the write-down of our patent costs to their estimated net realizable values of $<ix:nonFraction name="us-gaap:ImpairmentOfIntangibleAssetsFinitelived" id="Fact_acdbb50a6f92446b87e379e817f900c3" contextRef="c20210101to20211231_FiniteLivedIntangibleAssetsByMajorClassAxis_PatentsMember" unitRef="U001" decimals="-5" scale="6" format="ixt:numdotdecimal">2.7</ix:nonFraction> million, $<ix:nonFraction name="us-gaap:ImpairmentOfIntangibleAssetsFinitelived" id="Fact_3029299725d54805be6165d35d2050b9" contextRef="c20200101to20201231_FiniteLivedIntangibleAssetsByMajorClassAxis_PatentsMember" unitRef="U001" decimals="-5" scale="6" format="ixt:numdotdecimal">1.9</ix:nonFraction> million and $<ix:nonFraction name="us-gaap:ImpairmentOfIntangibleAssetsFinitelived" id="Fact_1057b62f0867480b862004e4e8b9e9ed" contextRef="c20190101to20191231_FiniteLivedIntangibleAssetsByMajorClassAxis_PatentsMember" unitRef="U001" decimals="-5" scale="6" format="ixt:numdotdecimal">2.2</ix:nonFraction> million, respectively.</div>
</ix:continuation></ix:continuation>
  <ix:continuation id="Text_ba6a171da9294812a4a91832efce6f8c238" continuedAt="Text_ba6a171da9294812a4a91832efce6f8c239">
<div><br />
  </div>
</ix:continuation></div>

  <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" class="DSPFPageBreakArea">
    <div class="DSPFPageFooter">
      <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">F-<span class="DSPFPageNumber">18</span></div>

    </div>

    <div style="page-break-after:always;" class="DSPFPageBreak">
      <hr style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;" /></div>


  </div>
<div><ix:continuation id="Text_ba6a171da9294812a4a91832efce6f8c239" continuedAt="Text_ba6a171da9294812a4a91832efce6f8c240">
<div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Accrued Liabilities</div>
</ix:continuation>

  <ix:continuation id="Text_ba6a171da9294812a4a91832efce6f8c240" continuedAt="Text_ba6a171da9294812a4a91832efce6f8c241">
<div><br />
  </div>
</ix:continuation>
  <ix:continuation id="Text_ba6a171da9294812a4a91832efce6f8c241" continuedAt="Text_ba6a171da9294812a4a91832efce6f8c242"><ix:nonNumeric name="us-gaap:ScheduleOfAccruedLiabilitiesTableTextBlock" id="Text_dee06e4770204682af8c0b46599d481a" contextRef="c20210101to20211231" escape="true" continuedAt="Text_668daa606380488b85af2af2446eb1021">
<div style="display:none;"><br /></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Our accrued liabilities consisted of the following (in thousands):</div>
</ix:nonNumeric></ix:continuation>
  <ix:continuation id="Text_ba6a171da9294812a4a91832efce6f8c242" continuedAt="Text_ba6a171da9294812a4a91832efce6f8c243"><ix:continuation id="Text_668daa606380488b85af2af2446eb1021" continuedAt="Text_668daa606380488b85af2af2446eb1022">
<div><br />
  </div>
</ix:continuation></ix:continuation>
  <ix:continuation id="Text_ba6a171da9294812a4a91832efce6f8c243" continuedAt="Text_ba6a171da9294812a4a91832efce6f8c244"><ix:continuation id="Text_668daa606380488b85af2af2446eb1022">
<table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;" class="cfttable">


  <tr>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">

        </td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" colspan="6">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">December 31,</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" colspan="2">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2021</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" colspan="2">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2020</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 76%; background-color: #CCEEFF;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Clinical expenses</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 76%;">
          <div style="text-align: left; text-indent: -18pt; margin-left: 18pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">In-licensing expenses</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 76%; background-color: #CCEEFF;">
          <div style="text-align: left; text-indent: -18pt; margin-left: 18pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Commercial expenses</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="ions:AccruedCommercialExpensesCurrent" id="Fact_991e082179bb4e87b5afb60cdf56fada" contextRef="c20211231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">2,471</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 76%; padding-bottom: 2px;">
          <div style="text-align: left; text-indent: -18pt; margin-left: 18pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Other miscellaneous expenses</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:OtherAccruedLiabilitiesCurrent" id="Fact_36801832e43e415bbc066744d39ceba6" contextRef="c20211231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">12,315</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:OtherAccruedLiabilitiesCurrent" id="Fact_558a2514ca9d46d38ef6431a99ec3875" contextRef="c20201231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">30,861</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 76%; padding-bottom: 4px; background-color: #CCEEFF;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Total accrued liabilities</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:AccruedLiabilitiesCurrent" id="Fact_d3d4336195b54976b7bcea8d3b30b7ac" contextRef="c20211231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">88,560</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:AccruedLiabilitiesCurrent" id="Fact_e91e73e81dd74acab89c06a66144eab3" contextRef="c20201231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">90,161</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>


</table>
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  </div>
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  <ix:continuation id="Text_ba6a171da9294812a4a91832efce6f8c245" continuedAt="Text_ba6a171da9294812a4a91832efce6f8c246"><ix:nonNumeric name="ions:LiabilityForClinicalDevelopmentCostsPolicyPolicyTextBlock" id="Text_567209235aa947d8b744c77c399b99ec" contextRef="c20210101to20211231" escape="true" continuedAt="Text_a4b944ee9bf742e286bfa674090a09531">
<div style="display:none;"><br /></div>
<div style="text-align: left; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;">Estimated Liability for Clinical Development Costs</div>
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<div><br />
  </div>
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<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We have numerous medicines in preclinical studies and/or clinical trials at clinical sites throughout the world. On at least a quarterly
    basis, we estimate our liability for preclinical and clinical development costs we have incurred and services that we have received but for which we have not yet been billed and maintain an accrual to cover these costs. These costs primarily relate to
    third-party clinical management costs, laboratory and analysis costs, toxicology studies and investigator grants. We estimate our liability using assumptions about study and patient activities and the related expected expenses for those activities
    determined based on the contracted fees with our service providers. The assumptions we use represent our best estimates of the activity and expenses at the time of our accrual and involve inherent uncertainties and the application of our judgment. Upon
    settlement, these costs may differ materially from the amounts accrued in our consolidated financial statements. Our historical accrual estimates have not been materially different from our actual amounts.</div>
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<div><br />
  </div>
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  <ix:continuation id="Text_ba6a171da9294812a4a91832efce6f8c249" continuedAt="Text_ba6a171da9294812a4a91832efce6f8c250"><ix:nonNumeric name="us-gaap:ConsolidationSubsidiariesOrOtherInvestmentsConsolidatedEntitiesPolicy" id="Text_4a814361d42740b68c1dd2442d40671b" contextRef="c20210101to20211231" escape="true" continuedAt="Text_4674d33211b24e4eb4160029cc545d661">
<div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Noncontrolling Interest in Akcea Therapeutics, Inc.</div>
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  <ix:continuation id="Text_ba6a171da9294812a4a91832efce6f8c250" continuedAt="Text_ba6a171da9294812a4a91832efce6f8c251"><ix:continuation id="Text_4674d33211b24e4eb4160029cc545d661" continuedAt="Text_4674d33211b24e4eb4160029cc545d662">
<div><br />
  </div>
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  <ix:continuation id="Text_ba6a171da9294812a4a91832efce6f8c251" continuedAt="Text_ba6a171da9294812a4a91832efce6f8c252"><ix:continuation id="Text_4674d33211b24e4eb4160029cc545d662">
<div style="display:none;"><br /></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">Since Akcea&#8217;s IPO in July 2017 and prior to
      the Akcea Merger in October 2020, the shares of Akcea&#8217;s common stock third parties owned represented an interest in Akcea&#8217;s equity that we did not control. During this period our ownership ranged from </span><ix:nonFraction name="us-gaap:MinorityInterestOwnershipPercentageByParent" id="Fact_1097de361427408da42d756b10b489be" contextRef="c20201031_OwnershipAxis_AkceaTherapeuticsIncMember_RangeAxis_MinimumMember" unitRef="U003" decimals="2" scale="-2" format="ixt:numdotdecimal">68</ix:nonFraction> percent<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> to </span><ix:nonFraction name="us-gaap:MinorityInterestOwnershipPercentageByParent" id="Fact_5665dba820d74eba9e6f5307d4168e81" contextRef="c20201031_OwnershipAxis_AkceaTherapeuticsIncMember_RangeAxis_MaximumMember" unitRef="U003" decimals="2" scale="-2" format="ixt:numdotdecimal">77</ix:nonFraction> percent<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">. However, as we maintained overall control of Akcea through our voting interest, we
      reflected the assets, liabilities and results of operations of Akcea in our consolidated financial statements. Since Akcea&#8217;s IPO in July 2017 and through the closing of the Akcea Merger, we reflected the noncontrolling interest attributable to other
      owners of Akcea&#8217;s common stock on a separate line on our statement of operations and a separate line within stockholders&#8217; equity in our consolidated balance sheet. In addition, through the closing of the Akcea Merger, we recorded a noncontrolling
      interest adjustment to account for the stock options Akcea granted, which if exercised, would have diluted our ownership in Akcea. This adjustment was a reclassification within stockholders&#8217; equity from additional paid-in capital to noncontrolling
      interest in Akcea equal to the amount of stock-based compensation expense Akcea had recognized. Additionally, w</span>e reflected changes in our ownership percentage in our financial statements as an adjustment to noncontrolling interest in the
    period the change occurred.</div>
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  </div>
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<div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Concentration of Credit Risk</div>
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<div><br />
  </div>
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<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Financial instruments that potentially subject us to concentrations of credit risk consist primarily of cash equivalents,
    short-term investments and receivables. We place our cash equivalents and short-term investments with reputable financial institutions. We primarily invest our excess cash in commercial paper and debt instruments of the U.S. Treasury, financial
    institutions, corporations, and U.S. government agencies with strong credit ratings and an investment grade rating at or above A-1, P-1 or F-1 by Moody&#8217;s, Standard &amp; Poor&#8217;s, or S&amp;P, or Fitch, respectively. We have established guidelines
    relative to diversification and maturities that maintain safety and liquidity. We periodically review and modify these guidelines to maximize trends in yields and interest rates without compromising safety and liquidity.</div>
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  </div>
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<div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Cash, Cash Equivalents and Investments</div>
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<div><br />
  </div>
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<div style="display:none;"><br /></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We consider all liquid investments with maturities of three months or less when we purchase them to be cash equivalents.
    Our short-term investments have initial maturities of greater than three months from date of purchase. We classify our short-term debt investments as &#8220;available-for-sale&#8221; and carry them at fair market value based upon prices on the last day of the
    fiscal period for identical or similar items. We record unrealized gains and losses on debt securities as a separate component of comprehensive income (loss) and include net realized gains and losses in gain (loss) on investments in our consolidated
    statement of operations. We use the specific identification method to determine the cost of securities sold.</div>
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<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We also have equity investments of less than 20 percent ownership in publicly and privately held biotechnology companies
      that we received as part of a technology license or partner agreement. At December 31, 2021, we held equity investments in <ix:nonFraction name="ions:NumberOfPubliclyHeldCompaniesInWhichEntityHasEquityInvestment" id="Fact_b448547c88c7434cbc329f97a4b3ea28" contextRef="c20211231" unitRef="U009" decimals="INF" scale="0" format="ixt-sec:numwordsen">three</ix:nonFraction> publicly held companies, Antisense Therapeutics Limited, or ATL, Bicycle Therapeutics plc, or Bicycle, and ProQR Therapeutics N.V., or ProQR. We
      also held equity investments in <ix:nonFraction name="ions:NumberOfPrivatelyHeldCompaniesInWhichEntityHasEquityInvestment" id="Fact_5091e6339b9e4e85943dd42b9d332383" contextRef="c20211231" unitRef="U009" decimals="INF" scale="0" format="ixt-sec:numwordsen">seven</ix:nonFraction> privately-held companies, Aro Biotherapeutics, Atlantic Pharmaceuticals Limited, Dynacure SAS, Empirico,
      Inc., Flamingo Therapeutics BV, YourBio Health, Inc. (formerly Seventh Sense Biosystems) and Suzhou-Ribo Life Science Co, Ltd.</div>
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  </div>
<div><ix:continuation id="Text_ba6a171da9294812a4a91832efce6f8c262" continuedAt="Text_ba6a171da9294812a4a91832efce6f8c263"><ix:continuation id="Text_c51dca9cf0aa41f5868eeae7f2a09f735" continuedAt="Text_c51dca9cf0aa41f5868eeae7f2a09f736">
<div><br />
  </div>
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  <ix:continuation id="Text_ba6a171da9294812a4a91832efce6f8c263" continuedAt="Text_ba6a171da9294812a4a91832efce6f8c264"><ix:continuation id="Text_c51dca9cf0aa41f5868eeae7f2a09f736">
<div style="display:none;"><br /></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We are required to measure and record our equity investments at fair value and to recognize the changes in fair value in our consolidated
    statement of operations. We account for our equity investments in privately held companies at their cost minus impairments, plus or minus changes resulting from observable price changes in orderly transactions for the identical or similar investment of
    the same issuer. For example, d<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">uring 2020, we revalued our investments in </span><ix:nonFraction name="ions:NumberOfInvestmentsInPrivatelyHeldCompaniesThatWereRevalued" id="Fact_f7fa3e5a04194e26a2205eb8715ec05c" contextRef="c20200101to20201231" unitRef="U010" decimals="INF" scale="0" format="ixt-sec:numwordsen">three</ix:nonFraction><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> privately held companies, Dynacure, Suzhou-Ribo and Aro Biotherapeutics because the companies
      sold additional equity securities that were similar to the equity we own. As a result of these observable price changes, we recognized a $</span><ix:nonFraction name="us-gaap:GainLossOnInvestments" id="Fact_cdc5aa89677e4989aa728a9bb2e0edf9" contextRef="c20200101to20201231_FinancialInstrumentAxis_DynacureSasMember" unitRef="U001" decimals="-5" scale="6" format="ixt:numdotdecimal">6.3</ix:nonFraction><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> million gain on our investment in Dynacure, a $</span><ix:nonFraction name="us-gaap:GainLossOnInvestments" id="Fact_47b16f5d19a84a8c9a09fbbe96174527" contextRef="c20200101to20201231_FinancialInstrumentAxis_SuzhouRiboLifeScienceCoLtdMember" unitRef="U001" decimals="-5" scale="6" format="ixt:numdotdecimal">3.0</ix:nonFraction><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> million gain on our investment in Suzhou-Ribo and a $</span><ix:nonFraction name="us-gaap:GainLossOnInvestments" id="Fact_cf49d586d5334999834bf4a673cb3dfa" contextRef="c20200101to20201231_FinancialInstrumentAxis_AroBiotherapeuticsMember" unitRef="U001" decimals="-5" scale="6" format="ixt:numdotdecimal">5.5</ix:nonFraction><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> million gain on our investment in Aro Biotherapeutics in our consolidated statement of operations during 2020 because the sales were at higher prices compared to
      our recorded value.</span></div>
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<div><br />
  </div>
</ix:continuation>
  <ix:continuation id="Text_ba6a171da9294812a4a91832efce6f8c265" continuedAt="Text_ba6a171da9294812a4a91832efce6f8c266"><ix:nonNumeric name="us-gaap:InventoryPolicyTextBlock" id="Text_962b0a89596444369c91918399edde59" contextRef="c20210101to20211231" escape="true" continuedAt="Text_f9b88b22894d471aa9bb4047dfd4a1131">
<div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Inventory Valuation</div>
</ix:nonNumeric></ix:continuation>
  <ix:continuation id="Text_ba6a171da9294812a4a91832efce6f8c266" continuedAt="Text_ba6a171da9294812a4a91832efce6f8c267"><ix:continuation id="Text_f9b88b22894d471aa9bb4047dfd4a1131" continuedAt="Text_f9b88b22894d471aa9bb4047dfd4a1132">
<div><br />
  </div>
</ix:continuation></ix:continuation>
  <ix:continuation id="Text_ba6a171da9294812a4a91832efce6f8c267" continuedAt="Text_ba6a171da9294812a4a91832efce6f8c268"><ix:continuation id="Text_f9b88b22894d471aa9bb4047dfd4a1132" continuedAt="Text_f9b88b22894d471aa9bb4047dfd4a1133">
<div style="display:none;"><br /></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We reflect our inventory on our consolidated balance sheet at the lower of cost or net realizable value under the first-in, first-out
    method, or FIFO. We capitalize the costs of raw materials that we purchase for use in producing our medicines because until we use these raw materials, they have alternative future uses, which we refer to as clinical raw materials. We include in
    inventory raw material costs for medicines that we manufacture for our partners under contractual terms and that we use primarily in our clinical development activities and drug products. We can use each of our raw materials in multiple products and,
    as a result, each raw material has future economic value independent of the development status of any single medicine. For example, if one of our medicines failed, we could use the raw materials for that medicine to manufacture our other medicines. We
    expense these costs as R&amp;D expenses when we begin to manufacture API for a particular medicine if the medicine has not been approved for marketing by a regulatory agency. Our raw materials- commercial inventory includes API for our commercial
    medicines. We capitalize material, labor and overhead costs as part of our raw materials- commercial inventory.</div>
</ix:continuation></ix:continuation>
  <ix:continuation id="Text_ba6a171da9294812a4a91832efce6f8c268" continuedAt="Text_ba6a171da9294812a4a91832efce6f8c269"><ix:continuation id="Text_f9b88b22894d471aa9bb4047dfd4a1133" continuedAt="Text_f9b88b22894d471aa9bb4047dfd4a1134">
<div><br />
  </div>
</ix:continuation></ix:continuation>
  <ix:continuation id="Text_ba6a171da9294812a4a91832efce6f8c269" continuedAt="Text_ba6a171da9294812a4a91832efce6f8c270"><ix:continuation id="Text_f9b88b22894d471aa9bb4047dfd4a1134" continuedAt="Text_f9b88b22894d471aa9bb4047dfd4a1135">
<div style="display:none;"><br /></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We review our inventory periodically and reduce the carrying value of items we consider to be slow moving or obsolete to
    their estimated net realizable value based on forecasted demand compared to quantities on hand. We consider several factors in estimating the net realizable value, including shelf life of our inventory, alternative uses for our medicines in development
    and historical write-offs. We recorded an <span style="-sec-ix-hidden:Fact_df7c1770e27a4789b9f7ad5345f29256"><span style="-sec-ix-hidden:Fact_7ba6995a24424942b581829d4ed245cc">insignificant</span></span> amount of inventory write-offs during the years ended December 31, 2021 and 2020.</div>
</ix:continuation></ix:continuation>
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<div><br />
  </div>
</ix:continuation></ix:continuation>
  <ix:continuation id="Text_ba6a171da9294812a4a91832efce6f8c271" continuedAt="Text_ba6a171da9294812a4a91832efce6f8c272"><ix:continuation id="Text_f9b88b22894d471aa9bb4047dfd4a1136" continuedAt="Text_f9b88b22894d471aa9bb4047dfd4a1137"><ix:nonNumeric name="us-gaap:ScheduleOfInventoryCurrentTableTextBlock" id="Text_42918dc083b14298bf3e140fca4a1e1b" contextRef="c20210101to20211231" escape="true" continuedAt="Text_0af0c826c8b54aa8875a1612841d5b231">
<div style="display:none;"><br /></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Our inventory consisted of the following (in thousands):</div>
</ix:nonNumeric></ix:continuation></ix:continuation>
  <ix:continuation id="Text_ba6a171da9294812a4a91832efce6f8c272" continuedAt="Text_ba6a171da9294812a4a91832efce6f8c273"><ix:continuation id="Text_f9b88b22894d471aa9bb4047dfd4a1137" continuedAt="Text_f9b88b22894d471aa9bb4047dfd4a1138"><ix:continuation id="Text_0af0c826c8b54aa8875a1612841d5b231" continuedAt="Text_0af0c826c8b54aa8875a1612841d5b232">
<div><br />
  </div>
</ix:continuation></ix:continuation></ix:continuation>
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        </td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;" colspan="1">&#160;</td>

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          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">December 31,</div>
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

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    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;" colspan="1">&#160;</td>

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          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2021</div>
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;" colspan="1">&#160;</td>

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          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2020</div>
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

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          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Raw materials:</div>
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    <td valign="bottom" style="vertical-align: bottom;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="2">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="2">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; white-space: nowrap;" colspan="1">&#160;</td>

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    <td valign="bottom" style="vertical-align: bottom; width: 76%; background-color: #CCEEFF;">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 19.4pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Raw materials- clinical</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
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    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

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          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

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    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" colspan="1">
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" colspan="1">
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

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          <div style="text-align: justify; text-indent: -9pt; margin-left: 28.45pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Total raw materials</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

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  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 76%;">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Work in process</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 76%; padding-bottom: 2px; background-color: #CCEEFF;">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Finished goods</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:InventoryFinishedGoods" id="Fact_518f7488f3314fafb99fe4a5c96254f0" contextRef="c20201231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">3,005</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

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    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" colspan="1">
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    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" colspan="1">
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" colspan="1">
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" colspan="1">&#160;</td>

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</table>
</ix:continuation></ix:continuation></ix:continuation>
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<div style="text-align: left;"><br />
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      <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">F-<span class="DSPFPageNumber">20</span></div>

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<div><ix:continuation id="Text_ba6a171da9294812a4a91832efce6f8c275" continuedAt="Text_ba6a171da9294812a4a91832efce6f8c276"><ix:nonNumeric name="us-gaap:PropertyPlantAndEquipmentPolicyTextBlock" id="Text_cdabff15346b44629390c82abd47c849" contextRef="c20210101to20211231" escape="true" continuedAt="Text_a2f2ea4aa0e84e35afa339927f6a84651">
<div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Property, Plant and Equipment</div>
</ix:nonNumeric></ix:continuation>

  <ix:continuation id="Text_ba6a171da9294812a4a91832efce6f8c276" continuedAt="Text_ba6a171da9294812a4a91832efce6f8c277"><ix:continuation id="Text_a2f2ea4aa0e84e35afa339927f6a84651" continuedAt="Text_a2f2ea4aa0e84e35afa339927f6a84652">
<div><br />
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</ix:continuation></ix:continuation>
  <ix:continuation id="Text_ba6a171da9294812a4a91832efce6f8c277" continuedAt="Text_ba6a171da9294812a4a91832efce6f8c278"><ix:continuation id="Text_a2f2ea4aa0e84e35afa339927f6a84652" continuedAt="Text_a2f2ea4aa0e84e35afa339927f6a84653"><ix:nonNumeric name="us-gaap:PropertyPlantAndEquipmentTextBlock" id="Text_fa1490903d3d4bf4a66e00ec0646e2ed" contextRef="c20210101to20211231" escape="true" continuedAt="Text_7061a9e2b7084dfca92c5ba9c9a3683d1">
<div style="display:none;"><br /></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We carry our property, plant and equipment at cost and depreciate it on the straight-line method
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</ix:continuation></ix:continuation></ix:continuation>
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    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; white-space: nowrap;" colspan="2">
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;" colspan="1">&#160;</td>

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  <tr>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px; white-space: nowrap;" colspan="2">
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" colspan="2">
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" colspan="2">
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

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  <tr>

    <td valign="bottom" style="vertical-align: bottom; background-color: #CCEEFF;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Computer software, laboratory, manufacturing and other equipment</div>
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    <td valign="bottom" style="vertical-align: bottom; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; background-color: #CCEEFF;" colspan="2">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonNumeric name="us-gaap:PropertyPlantAndEquipmentUsefulLife" id="Fact_bee2828c703f419991ca5e4f981c6bfb" contextRef="c20210101to20211231_PropertyPlantAndEquipmentByTypeAxis_EquipmentAndComputerSoftwareMember_RangeAxis_MinimumMember" format="ixt-sec:duryear">3</ix:nonNumeric> to <ix:nonNumeric name="us-gaap:PropertyPlantAndEquipmentUsefulLife" id="Fact_5570d89b49ca4d3bbc122f34e561c666" contextRef="c20210101to20211231_PropertyPlantAndEquipmentByTypeAxis_EquipmentAndComputerSoftwareMember_RangeAxis_MaximumMember" format="ixt-sec:duryear">10</ix:nonNumeric></div>
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; background-color: #CCEEFF;" colspan="1">
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; background-color: #CCEEFF;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

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  <tr>

    <td valign="bottom" style="vertical-align: bottom;">
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    <td valign="bottom" style="vertical-align: bottom;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="2">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonNumeric name="us-gaap:PropertyPlantAndEquipmentUsefulLife" id="Fact_af3476af11bf463db8625923d46c44ce" contextRef="c20210101to20211231_PropertyPlantAndEquipmentByTypeAxis_BuildingAndBuildingImprovementsMember_RangeAxis_MinimumMember" format="ixt-sec:duryear">15</ix:nonNumeric> to <ix:nonNumeric name="us-gaap:PropertyPlantAndEquipmentUsefulLife" id="Fact_86510f26269445ae8f1cd2bd97d35737" contextRef="c20210101to20211231_PropertyPlantAndEquipmentByTypeAxis_BuildingAndBuildingImprovementsMember_RangeAxis_MaximumMember" format="ixt-sec:duryear">40</ix:nonNumeric></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Land improvements</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="2" rowspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:PropertyPlantAndEquipmentGross" id="Fact_56a2f9f0147240f0bd015bba6bf7acb2" contextRef="c20211231_PropertyPlantAndEquipmentByTypeAxis_LandImprovementsMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">10,077</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:PropertyPlantAndEquipmentGross" id="Fact_48464f6662f34caab0d0adfeb2d1483a" contextRef="c20201231_PropertyPlantAndEquipmentByTypeAxis_LandImprovementsMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">8,391</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom;">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Leasehold improvements</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="2">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:PropertyPlantAndEquipmentGross" id="Fact_9274143ded5b4f0ba33136edf1a5c107" contextRef="c20211231_PropertyPlantAndEquipmentByTypeAxis_LeaseholdImprovementsMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">20,144</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:PropertyPlantAndEquipmentGross" id="Fact_a69d39db65ac49c7a52d11122d390f52" contextRef="c20201231_PropertyPlantAndEquipmentByTypeAxis_LeaseholdImprovementsMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">17,263</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px; background-color: #CCEEFF;">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Furniture and fixtures</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; background-color: #CCEEFF;" colspan="2">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:PropertyPlantAndEquipmentGross" id="Fact_4cc9147a7cbc4ee49795347f0fb5a079" contextRef="c20211231_PropertyPlantAndEquipmentByTypeAxis_FurnitureAndFixturesMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">10,591</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

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  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 64%;">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

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  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #CCEEFF;">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Less accumulated depreciation</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:AccumulatedDepreciationDepletionAndAmortizationPropertyPlantAndEquipment" id="Fact_c8c6a3d838c64434aeb0fd3c8a6f6727" contextRef="c20211231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">102,653</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 64%;">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:PropertyPlantAndEquipmentNet" id="Fact_b19aa12690254ebfbb74e114f415ba73" contextRef="c20211231_PropertyPlantAndEquipmentByTypeAxis_PropertyPlantAndEquipmentExcludingLandMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">155,007</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:PropertyPlantAndEquipmentNet" id="Fact_43f79740c06f430d802eb80d4aee36c7" contextRef="c20201231_PropertyPlantAndEquipmentByTypeAxis_PropertyPlantAndEquipmentExcludingLandMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">158,015</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #CCEEFF;">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Land</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:PropertyPlantAndEquipmentGross" id="Fact_34379c34064b4008bd443f086b5b56d2" contextRef="c20211231_PropertyPlantAndEquipmentByTypeAxis_LandMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">23,062</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:PropertyPlantAndEquipmentGross" id="Fact_640721fc5bba475f8612db62b456d80b" contextRef="c20201231_PropertyPlantAndEquipmentByTypeAxis_LandMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">23,062</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 4px;">
          <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#160;Total</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:PropertyPlantAndEquipmentNet" id="Fact_845ce990f2174f7bafb81c35eb3d8604" contextRef="c20211231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">178,069</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:PropertyPlantAndEquipmentNet" id="Fact_c1ac0d6f145b41659e8c734c98f6f1c8" contextRef="c20201231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">181,077</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>


</table>
</ix:continuation></ix:continuation></ix:continuation>
  <ix:continuation id="Text_ba6a171da9294812a4a91832efce6f8c280" continuedAt="Text_ba6a171da9294812a4a91832efce6f8c281"><ix:continuation id="Text_a2f2ea4aa0e84e35afa339927f6a84655" continuedAt="Text_a2f2ea4aa0e84e35afa339927f6a84656">
<div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 12pt;"><br />
  </div>
</ix:continuation></ix:continuation>
  <ix:continuation id="Text_ba6a171da9294812a4a91832efce6f8c281" continuedAt="Text_ba6a171da9294812a4a91832efce6f8c282"><ix:continuation id="Text_a2f2ea4aa0e84e35afa339927f6a84656">
<div style="display:none;"><br /></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We depreciate our leasehold improvements using the shorter of the estimated useful life or remaining lease term.</div>
</ix:continuation></ix:continuation>
  <ix:continuation id="Text_ba6a171da9294812a4a91832efce6f8c282" continuedAt="Text_ba6a171da9294812a4a91832efce6f8c283">
<div><br />
  </div>
</ix:continuation>
  <ix:continuation id="Text_ba6a171da9294812a4a91832efce6f8c283" continuedAt="Text_ba6a171da9294812a4a91832efce6f8c284"><ix:nonNumeric name="us-gaap:FairValueOfFinancialInstrumentsPolicy" id="Text_1c1a3fa5b06c4f8eb0d08a8a2d8e1c26" contextRef="c20210101to20211231" escape="true" continuedAt="Text_acd2d21405bb4454b9c7635cb95a7ce31">
<div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Fair Value of Financial Instruments</div>
</ix:nonNumeric></ix:continuation>
  <ix:continuation id="Text_ba6a171da9294812a4a91832efce6f8c284" continuedAt="Text_ba6a171da9294812a4a91832efce6f8c285"><ix:continuation id="Text_acd2d21405bb4454b9c7635cb95a7ce31" continuedAt="Text_acd2d21405bb4454b9c7635cb95a7ce32">
<div style="display:none;"><br /></div>
<div style="text-align: justify; text-indent: 36pt;"><br />
  </div>
</ix:continuation></ix:continuation>
  <ix:continuation id="Text_ba6a171da9294812a4a91832efce6f8c285" continuedAt="Text_ba6a171da9294812a4a91832efce6f8c286"><ix:continuation id="Text_acd2d21405bb4454b9c7635cb95a7ce32">
<div style="display:none;"><br /></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We have estimated the fair value of our financial instruments. The amounts reported for cash, accounts receivable,
    accounts payable and accrued expenses approximate the fair value because of their short maturities. We report our investment securities at their estimated fair value based on quoted market prices for identical or similar instruments.</div>
</ix:continuation></ix:continuation>
  <ix:continuation id="Text_ba6a171da9294812a4a91832efce6f8c286" continuedAt="Text_ba6a171da9294812a4a91832efce6f8c287">
<div><br />
  </div>
</ix:continuation>
  <ix:continuation id="Text_ba6a171da9294812a4a91832efce6f8c287" continuedAt="Text_ba6a171da9294812a4a91832efce6f8c288"><ix:nonNumeric name="us-gaap:LesseeLeasesPolicyTextBlock" id="Text_5a1cbe260fe343ccafe9ff400e9af2db" contextRef="c20210101to20211231" escape="true" continuedAt="Text_5e2c82fe50004f2aa6c632fb24150e9e1">
<div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Leases</div>
</ix:nonNumeric></ix:continuation>
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<div><br />
  </div>
</ix:continuation></ix:continuation>
  <ix:continuation id="Text_ba6a171da9294812a4a91832efce6f8c289" continuedAt="Text_ba6a171da9294812a4a91832efce6f8c290"><ix:continuation id="Text_5e2c82fe50004f2aa6c632fb24150e9e2" continuedAt="Text_5e2c82fe50004f2aa6c632fb24150e9e3">
<div style="display:none;"><br /></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We determine if an arrangement contains a lease at inception. We currently only have operating leases. We recognize a
    right-of-use operating lease asset and associated short- and long-term operating lease liability on our consolidated balance sheet for operating leases greater than one year. Our right-of-use assets represent our right to use an underlying asset for
    the lease term and our lease liabilities represent our obligation to make lease payments arising from the lease arrangement. We recognize our right-of-use operating lease assets and lease liabilities based on the present value of the future minimum
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    liabilities for the new lease term.</div>
</ix:continuation></ix:continuation>
  <ix:continuation id="Text_ba6a171da9294812a4a91832efce6f8c290" continuedAt="Text_ba6a171da9294812a4a91832efce6f8c291"><ix:continuation id="Text_5e2c82fe50004f2aa6c632fb24150e9e3" continuedAt="Text_5e2c82fe50004f2aa6c632fb24150e9e4">
<div><br />
  </div>
</ix:continuation></ix:continuation>
  <ix:continuation id="Text_ba6a171da9294812a4a91832efce6f8c291" continuedAt="Text_ba6a171da9294812a4a91832efce6f8c292"><ix:continuation id="Text_5e2c82fe50004f2aa6c632fb24150e9e4">
<div style="display:none;"><br /></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">As our leases do not provide an interest rate implicit in the lease, we used our incremental borrowing rate, based on the
    information available on the date we adopted Topic 842 (January 2019), as of the lease inception date or at the lease option extension date in determining the present value of future payments. We recognize rent expense for our minimum lease payments on
    a straight-line basis over the expected term of our lease. We recognize period expenses, such as common area maintenance expenses, in the period we incur the expense.</div>
</ix:continuation></ix:continuation>
  <ix:continuation id="Text_ba6a171da9294812a4a91832efce6f8c292" continuedAt="Text_ba6a171da9294812a4a91832efce6f8c293">
<div><br />
  </div>
</ix:continuation>
  <ix:continuation id="Text_ba6a171da9294812a4a91832efce6f8c293" continuedAt="Text_ba6a171da9294812a4a91832efce6f8c294"><ix:nonNumeric name="us-gaap:ImpairmentOrDisposalOfLongLivedAssetsIncludingIntangibleAssetsPolicyPolicyTextBlock" id="Text_72f861d09ee741518162baaf74392e58" contextRef="c20210101to20211231" escape="true" continuedAt="Text_9278c3f95c2b4c28bceb009de28fc4461">
<div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Long-Lived Assets</div>
</ix:nonNumeric></ix:continuation>
  <ix:continuation id="Text_ba6a171da9294812a4a91832efce6f8c294" continuedAt="Text_ba6a171da9294812a4a91832efce6f8c295"><ix:continuation id="Text_9278c3f95c2b4c28bceb009de28fc4461" continuedAt="Text_9278c3f95c2b4c28bceb009de28fc4462">
<div style="display:none;"><br /></div>
<div style="text-align: justify; text-indent: 36pt;"><br />
  </div>
</ix:continuation></ix:continuation>
  <ix:continuation id="Text_ba6a171da9294812a4a91832efce6f8c295" continuedAt="Text_ba6a171da9294812a4a91832efce6f8c296"><ix:continuation id="Text_9278c3f95c2b4c28bceb009de28fc4462">
<div style="display:none;"><br /></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We evaluate long-lived assets, which include property, plant and equipment and patent costs, for impairment on at least a
    quarterly basis and whenever events or changes in circumstances indicate that we may not be able to recover the carrying amount of such assets. We recorded charges of $<ix:nonFraction name="us-gaap:ImpairmentOfIntangibleAssetsFinitelived" id="Fact_1f00325938654d8aaa92961967dd4fe1" contextRef="c20210101to20211231" unitRef="U001" decimals="-5" scale="6" format="ixt:numdotdecimal">2.7</ix:nonFraction> million, $<ix:nonFraction name="us-gaap:ImpairmentOfIntangibleAssetsFinitelived" id="Fact_d4bb9e72c83944a891eb6db91aae4474" contextRef="c20200101to20201231" unitRef="U001" decimals="-5" scale="6" format="ixt:numdotdecimal">1.9</ix:nonFraction> million and $<ix:nonFraction name="us-gaap:ImpairmentOfIntangibleAssetsFinitelived" id="Fact_42a5e2e524a746bebd539b59be5602e1" contextRef="c20190101to20191231" unitRef="U001" decimals="-5" scale="6" format="ixt:numdotdecimal">2.2</ix:nonFraction> million for the years ended December 31, 2021, 2020 and 2019, respectively, related to the
    write-down of patents.</div>
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<div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Use of Estimates</div>
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<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We prepare our consolidated financial statements in conformity with accounting principles generally accepted in the U.S.
    that require us to make estimates and assumptions that affect the amounts reported in our consolidated financial statements and accompanying notes. Actual results could differ from our estimates.</div>
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<div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Stock-Based Compensation Expense</div>
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<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We measure stock-based compensation expense for equity-classified awards, principally related to stock options, RSUs,
    PRSUs and stock purchase rights under our ESPP based on the estimated fair value of the award on the date of grant. We recognize the value of the portion of the award that we ultimately expect to vest as stock-based compensation expense over the
    requisite service period in our consolidated statements of operations. We reduce stock-based compensation expense for estimated forfeitures at the time of grant and revise in subsequent periods if actual forfeitures differ from those estimates. We use
    the Black-Scholes model to estimate the fair value of stock options granted and stock purchase rights under our ESPP.</div>
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  </div>
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  <ix:continuation id="Text_ba6a171da9294812a4a91832efce6f8c305" continuedAt="Text_ba6a171da9294812a4a91832efce6f8c306"><ix:continuation id="Text_0abef78f68bc40148a295c245339f4954" continuedAt="Text_0abef78f68bc40148a295c245339f4955">
<div style="display:none;"><br /></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">On the grant date, we use our stock price and assumptions regarding a number of variables to determine the estimated fair
    value of stock-based payment awards. These variables include, but are not limited to, our expected stock price volatility over the term of the awards, and actual and projected employee stock option exercise behaviors. The expected term of stock options
    granted represents the period of time that we expect them to be outstanding. We estimate the expected term of options granted based on historical exercise patterns.</div>
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  </div>
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  <ix:continuation id="Text_ba6a171da9294812a4a91832efce6f8c307" continuedAt="Text_ba6a171da9294812a4a91832efce6f8c308"><ix:continuation id="Text_0abef78f68bc40148a295c245339f4956" continuedAt="Text_0abef78f68bc40148a295c245339f4957">
<div style="display:none;"><br /></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We recognize compensation expense for stock options granted, RSUs, PRSUs and stock purchase rights under the ESPP using
    the accelerated multiple-option approach. Under the accelerated multiple-option approach (also known as the graded-vesting method), we recognize compensation expense over the requisite service period for each separately vesting tranche of the award as
    though the award were in substance multiple awards, which results in the expense being front-loaded over the vesting period.</div>
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  <ix:continuation id="Text_ba6a171da9294812a4a91832efce6f8c309" continuedAt="Text_ba6a171da9294812a4a91832efce6f8c310"><ix:continuation id="Text_0abef78f68bc40148a295c245339f4958" continuedAt="Text_0abef78f68bc40148a295c245339f4959">
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<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">In December 2020, we amended and restated the
      Akcea 2015 equity plan, including renaming the plan as the Ionis Pharmaceuticals, Inc. 2020 Equity Incentive Plan, or 2020 Plan. As a result, all employees are now under an Ionis stock plan and subject to the same Black-Scholes assumptions</span>.</div>
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<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;">RSU&#8217;s:</div>
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  </div>
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  <ix:continuation id="Text_ba6a171da9294812a4a91832efce6f8c313" continuedAt="Text_ba6a171da9294812a4a91832efce6f8c314"><ix:continuation id="Text_0abef78f68bc40148a295c245339f49512" continuedAt="Text_0abef78f68bc40148a295c245339f49513">
<div style="display:none;"><br /></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">The fair value of RSUs is based on the market price of our common stock on the date of grant. The RSUs we have granted to
    employees vest annually over a <ix:nonNumeric name="us-gaap:ShareBasedCompensationArrangementByShareBasedPaymentAwardAwardVestingPeriod1" id="Fact_9c07a9a996a942cfa5196c4e73d65a5f" contextRef="c20210101to20211231_AwardTypeAxis_RestrictedStockUnitsRSUMember_GranteeStatusAxis_ShareBasedPaymentArrangementEmployeeMember" format="ixt-sec:durwordsen">four-year</ix:nonNumeric> period. The RSUs we granted to our board of directors prior to June 2020 vest annually over a <ix:nonNumeric name="us-gaap:ShareBasedCompensationArrangementByShareBasedPaymentAwardAwardVestingPeriod1" id="Fact_a9d4677fe482460496896805b6e948d8" contextRef="c20210101to20211231_AwardDateAxis_GrantedPriorToJune2020Member_AwardTypeAxis_RestrictedStockUnitsRSUMember_GranteeStatusAxis_ShareBasedPaymentArrangementBoardOfDirectorMember" format="ixt-sec:durwordsen">four-year</ix:nonNumeric> period. RSUs granted to our board of directors after June 2020 fully vest after <ix:nonNumeric name="us-gaap:ShareBasedCompensationArrangementByShareBasedPaymentAwardAwardVestingPeriod1" id="Fact_317dd58aff2644f5948252ec0ede060a" contextRef="c20210101to20211231_AwardDateAxis_GrantedAfterJune2020Member_AwardTypeAxis_RestrictedStockUnitsRSUMember_GranteeStatusAxis_ShareBasedPaymentArrangementBoardOfDirectorMember" format="ixt-sec:durwordsen">one year</ix:nonNumeric>.</div>
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<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;">PRSU&#8217;s:</div>
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<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Beginning in 2020, we added PRSU awards to the compensation for our Chief Executive Officer, Dr. Brett Monia. Under the
    terms of the grants, <span style="-sec-ix-hidden:Fact_65d15117ab79462e81dfb8bbb86a0107"><span style="-sec-ix-hidden:Fact_e9934b85c6af480197be8d0d8b5ea434"><span style="-sec-ix-hidden:Fact_5599af32346c4fce91fa6d27caf4b474">one third</span></span></span> of the PRSUs may vest at the end of <ix:nonFraction name="ions:ShareBasedCompensationArrangementByShareBasedPaymentAwardNumberOfPerformancePeriods" id="Fact_4556558cf7c146f081140dde2cf15e02" contextRef="c20210101to20211231_AwardTypeAxis_PerformanceSharesMember_GranteeStatusAxis_ChiefExecutiveOfficerMember" unitRef="U011" decimals="INF" scale="0" format="ixt-sec:numwordsen">three</ix:nonFraction> separate performance periods spread over the <ix:nonNumeric name="us-gaap:ShareBasedCompensationArrangementByShareBasedPaymentAwardAwardVestingPeriod1" id="Fact_9ee4b8f0d0fc415d8fedacb7e025157a" contextRef="c20210101to20211231_AwardTypeAxis_PerformanceSharesMember_GranteeStatusAxis_ChiefExecutiveOfficerMember" format="ixt-sec:durwordsen">three years</ix:nonNumeric> following the date of
    grant (i.e., the <ix:nonNumeric name="us-gaap:ShareBasedCompensationArrangementByShareBasedPaymentAwardAwardVestingPeriod1" id="Fact_4a3b1878ccda46faa7e3dcc5b7ecf3f1" contextRef="c20210101to20211231_AwardTypeAxis_PerformanceSharesMember_GranteeStatusAxis_ChiefExecutiveOfficerMember_VestingAxis_ShareBasedCompensationAwardTrancheOneMember" format="ixt-sec:durwordsen">one-year</ix:nonNumeric> period commencing on the date of grant and ending on the first anniversary of the date of grant; the <ix:nonNumeric name="us-gaap:ShareBasedCompensationArrangementByShareBasedPaymentAwardAwardVestingPeriod1" id="Fact_10bf9fa3aeef4afaa6e49f9def9210ca" contextRef="c20210101to20211231_AwardTypeAxis_PerformanceSharesMember_GranteeStatusAxis_ChiefExecutiveOfficerMember_VestingAxis_ShareBasedCompensationAwardTrancheTwoMember" format="ixt-sec:durwordsen">two-year</ix:nonNumeric> period commencing on the date of grant and ending on the second anniversary of the date of grant; and the <ix:nonNumeric name="us-gaap:ShareBasedCompensationArrangementByShareBasedPaymentAwardAwardVestingPeriod1" id="Fact_cb84749fad7546409795da36a9b7b020" contextRef="c20210101to20211231_AwardTypeAxis_PerformanceSharesMember_GranteeStatusAxis_ChiefExecutiveOfficerMember_VestingAxis_ShareBasedCompensationAwardTrancheThreeMember" format="ixt-sec:durwordsen">three-year</ix:nonNumeric> period commencing on the date of grant and ending on the third anniversary of the date of grant) based on our relative total shareholder return, or TSR, as compared to a
    peer group of companies, and as measured, in each case, at the end of the applicable performance period. Under the terms of the grants <ix:nonFraction name="ions:ShareBasedCompensationArrangementByShareBasedPaymentAwardNumberOfUnitsGuaranteedToVest" id="Fact_ff5f5a5a72cb44c38314ac19e661c09e" contextRef="c20210101to20211231_AwardTypeAxis_PerformanceSharesMember_GranteeStatusAxis_ChiefExecutiveOfficerMember" unitRef="U002" decimals="0" scale="0" format="ixt-sec:numwordsen">no</ix:nonFraction> number
    of PRSUs is guaranteed to vest and the actual number of PRSUs that will vest at the end of each performance period may be anywhere from <ix:nonFraction name="ions:ShareBasedCompensationArrangementByShareBasedPaymentAwardPercentageOfUnitsGuaranteedToVest" id="Fact_b0b7848e22764764b4bcbddd5a2927ff" contextRef="c20210101to20211231_AwardTypeAxis_PerformanceSharesMember_GranteeStatusAxis_ChiefExecutiveOfficerMember_RangeAxis_MinimumMember" unitRef="U003" decimals="INF" scale="0" format="ixt-sec:numwordsen">zero</ix:nonFraction> to
    <ix:nonFraction name="ions:ShareBasedCompensationArrangementByShareBasedPaymentAwardPercentageOfUnitsGuaranteedToVest" id="Fact_1370c49d2caf4b69b350f951933b5194" contextRef="c20210101to20211231_AwardTypeAxis_PerformanceSharesMember_GranteeStatusAxis_ChiefExecutiveOfficerMember_RangeAxis_MaximumMember" unitRef="U003" decimals="2" scale="-2" format="ixt:numdotdecimal">150</ix:nonFraction> percent of the target number depending on our relative TSR.</div>
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<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We determined the fair value of Dr. Monia&#8217;s PRSUs using a Monte Carlo model because the performance target is based on our
    relative TSR, which represents a market condition. We are recognizing the grant date fair value of these awards as stock-based compensation expense using the accelerated multiple-option approach over the vesting period. The weighted-average grant date
    fair value of PRSUs granted to Dr. Monia for the years ended December 31, 2021 and 2020 were $<ix:nonFraction name="us-gaap:ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsGrantsInPeriodWeightedAverageGrantDateFairValue" id="Fact_eb052e2b452448a18d648f4458bf70f7" contextRef="c20210101to20211231_AwardTypeAxis_PerformanceSharesMember_GranteeStatusAxis_ChiefExecutiveOfficerMember" unitRef="U004" decimals="2" scale="0" format="ixt:numdotdecimal">77.17</ix:nonFraction> and $<ix:nonFraction name="us-gaap:ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsGrantsInPeriodWeightedAverageGrantDateFairValue" id="Fact_87ecde595f294888875881a9664cb785" contextRef="c20200101to20201231_AwardTypeAxis_PerformanceSharesMember_GranteeStatusAxis_ChiefExecutiveOfficerMember" unitRef="U004" decimals="2" scale="0" format="ixt:numdotdecimal">93.09</ix:nonFraction> per share, respectively.</div>
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<div style="display:none;"><br /></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">See Note 4, <span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Stockholders&#8217;
      Equity,</span> for additional information regarding our stock-based compensation plans.</div>
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<div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Accumulated Other Comprehensive Loss</div>
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  <ix:continuation id="Text_ba6a171da9294812a4a91832efce6f8c324" continuedAt="Text_ba6a171da9294812a4a91832efce6f8c325"><ix:continuation id="Text_8df8eea541c844e3b3764d9f32c3dcb01" continuedAt="Text_8df8eea541c844e3b3764d9f32c3dcb02">
<div><br />
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<div style="display:none;"><br /></div>
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<div style="text-align: justify;"><br />
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    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">

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    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;" colspan="1">&#160;</td>

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          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Year Ended December 31,</div>
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

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  <tr>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;" colspan="1">&#160;</td>

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    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" colspan="2">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2020</div>
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" colspan="2">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2019</div>
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

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    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">
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    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
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    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
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    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:StockholdersEquityIncludingPortionAttributableToNoncontrollingInterest" id="Fact_19707e9f0bad40fbb1dba6349904c9f1" contextRef="c20191231_StatementEquityComponentsAxis_AociIncludingPortionAttributableToNoncontrollingInterestMember" unitRef="U001" decimals="-3" scale="3" sign="-" format="ixt:numdotdecimal">25,290</ix:nonFraction></div>
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
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    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
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    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:StockholdersEquityIncludingPortionAttributableToNoncontrollingInterest" id="Fact_1a98a410f1db4d8f8fc817d58996446f" contextRef="c20181231_StatementEquityComponentsAxis_AociIncludingPortionAttributableToNoncontrollingInterestMember" unitRef="U001" decimals="-3" scale="3" sign="-" format="ixt:numdotdecimal">32,016</ix:nonFraction></div>
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
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  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 64%;">
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    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:OtherComprehensiveIncomeLossBeforeReclassificationsNetOfTax" id="Fact_8f26788799e14b9bb1344435140f818a" contextRef="c20190101to20191231_StatementEquityComponentsAxis_AccumulatedNetInvestmentGainLossIncludingPortionAttributableToNoncontrollingInterestMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">6,633</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 18pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Currency translation adjustment</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:OtherComprehensiveIncomeLossBeforeReclassificationsNetOfTax" id="Fact_0a2161241cf748ad98c7b5a37ef210e4" contextRef="c20210101to20211231_StatementEquityComponentsAxis_AccumulatedForeignCurrencyAdjustmentIncludingPortionAttributableToNoncontrollingInterestMember" unitRef="U001" decimals="-3" scale="3" sign="-" format="ixt:numdotdecimal">111</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:OtherComprehensiveIncomeLossBeforeReclassificationsNetOfTax" id="Fact_ad85fd5199354df78b105b0532f640eb" contextRef="c20200101to20201231_StatementEquityComponentsAxis_AccumulatedForeignCurrencyAdjustmentIncludingPortionAttributableToNoncontrollingInterestMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">617</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:OtherComprehensiveIncomeLossBeforeReclassificationsNetOfTax" id="Fact_2cf95908fea8415aa5b562ff94646094" contextRef="c20190101to20191231_StatementEquityComponentsAxis_AccumulatedForeignCurrencyAdjustmentIncludingPortionAttributableToNoncontrollingInterestMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">93</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 2px;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 18pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Adjustments to other comprehensive loss from purchase of noncontrolling interest of Akcea
            Therapeutics, Inc.</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="ions:OtherComprehensiveIncomeLossAdjustmentsFromPurchaseOfNoncontrollingInterestOfSubsidiary" id="Fact_f683c0979c77433b84f2d78fcb77892f" contextRef="c20210101to20211231" unitRef="U001" decimals="-3" scale="3" format="ixt:zerodash">&#8212;</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="ions:OtherComprehensiveIncomeLossAdjustmentsFromPurchaseOfNoncontrollingInterestOfSubsidiary" id="Fact_73c93e34a7b04c7d95b78e202472bd93" contextRef="c20200101to20201231" unitRef="U001" decimals="-3" scale="3" sign="-" format="ixt:numdotdecimal">127</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="ions:OtherComprehensiveIncomeLossAdjustmentsFromPurchaseOfNoncontrollingInterestOfSubsidiary" id="Fact_87cd5d2b3825448daf6f69c617a273ab" contextRef="c20190101to20191231" unitRef="U001" decimals="-3" scale="3" format="ixt:zerodash">&#8212;</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #CCEEFF;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Net other comprehensive loss for the period</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:OtherComprehensiveIncomeLossNetOfTax" id="Fact_2ce128cedcb64e06a3c8d4d1586e4c6e" contextRef="c20210101to20211231" unitRef="U001" decimals="-3" scale="3" sign="-" format="ixt:numdotdecimal">11,597</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:OtherComprehensiveIncomeLossNetOfTax" id="Fact_a2223b8bb7e44f6f89e44f7a99d65ec1" contextRef="c20200101to20201231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">4,219</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:OtherComprehensiveIncomeLossNetOfTax" id="Fact_15d14efe39a949dabe720e0cc4f8a8d2" contextRef="c20190101to20191231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">6,726</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 4px;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Ending balance accumulated other comprehensive loss</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:StockholdersEquityIncludingPortionAttributableToNoncontrollingInterest" id="Fact_92c6a81d4cc548c79c16aa702d293bfc" contextRef="c20201231_StatementEquityComponentsAxis_AociIncludingPortionAttributableToNoncontrollingInterestMember" unitRef="U001" decimals="-3" scale="3" sign="-" format="ixt:numdotdecimal">21,071</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:StockholdersEquityIncludingPortionAttributableToNoncontrollingInterest" id="Fact_d50f6f2316fb42a59ada44dcc1e3f6fc" contextRef="c20191231_StatementEquityComponentsAxis_AociIncludingPortionAttributableToNoncontrollingInterestMember" unitRef="U001" decimals="-3" scale="3" sign="-" format="ixt:numdotdecimal">25,290</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

  </tr>


</table>
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<div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">________________</div>
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<div>
    <table cellspacing="0" cellpadding="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">


  <tr>

    <td style="width: 18pt; vertical-align: top; align: right;">
            <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(1)</div>
          </td>

    <td style="width: auto; vertical-align: top;">
            <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:footnote id="Foot_c173053f21eb48f2baac71e2bf36f606" footnoteRole="http://www.xbrl.org/2003/role/footnote" xml:lang="en-US">We did <ix:nonFraction name="us-gaap:OtherComprehensiveIncomeLossTax" id="Fact_8a44be227c064d7eaec920b423ef7df6" contextRef="c20200101to20201231" unitRef="U001" decimals="-6" scale="6" format="ixt-sec:numwordsen"><ix:nonFraction name="us-gaap:OtherComprehensiveIncomeLossTax" id="Fact_51731348898e477f98ddd1af36189c22" contextRef="c20210101to20211231" unitRef="U001" decimals="-6" scale="6" format="ixt-sec:numwordsen">no</ix:nonFraction></ix:nonFraction>t have tax expense included in our other comprehensive loss for the years ended December 31, 2021 and 2020. For the year ended December 31,
              2019, we had a tax benefit of $<ix:nonFraction name="us-gaap:OtherComprehensiveIncomeLossTax" id="Fact_5760e35e9cbb4b309eabc1063cb761ae" contextRef="c20190101to20191231" unitRef="U001" decimals="-5" scale="6" sign="-" format="ixt:numdotdecimal">1.4</ix:nonFraction>
              million included in other comprehensive loss.</ix:footnote>&#160;</div>
          </td>

  </tr>


</table>
    </div>
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<div><br />
  </div>
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<div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Convertible Debt</div>
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<div><br />
  </div>
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<div style="display:none;"><br /></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;">Adoption of ASU 2020-06</div>
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<div><br />
  </div>
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<div style="display:none;"><br /></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">In August 2020, the FASB issued ASU 2020-06, which simplifies the accounting for convertible debt instruments, amends the
    guidance on derivative scope exceptions for contracts in an entity&#8217;s own equity, and modifies the guidance on diluted earnings per share calculations. We adopted ASU 2020-06 on January 1, 2021 under the full retrospective approach, which required us to
    revise our prior period financial statements. This guidance impacted our accounting for outstanding convertible debt. At January 1, 2021, we had <ix:nonFraction name="ions:DebtInstrumentNumberOfConvertibleNotes" id="Fact_10f5114021fc4f5bb04196fe30354c8a" contextRef="c20201231" unitRef="U012" decimals="INF" scale="0" format="ixt-sec:numwordsen">two</ix:nonFraction>
    outstanding convertible notes, our <ix:nonFraction name="us-gaap:DebtInstrumentInterestRateStatedPercentage" id="Fact_637081ace1c3467395b29f412ee7c215" contextRef="c20201231_DebtInstrumentAxis_ConvertibleSeniorNotes0125PercentMember" unitRef="U003" decimals="5" scale="-2" format="ixt:numdotdecimal">0.125</ix:nonFraction>% Notes, which mature in December 2024, and our <ix:nonFraction name="us-gaap:DebtInstrumentInterestRateStatedPercentage" id="Fact_a46bb952d6de4d50baf76555b13539e5" contextRef="c20201231_DebtInstrumentAxis_ConvertibleSeniorNotes1PercentMember" unitRef="U003" decimals="2" scale="-2" format="ixt:numdotdecimal">1</ix:nonFraction>% Notes, which matured in November 2021. In April 2021, we completed a $<ix:nonFraction name="us-gaap:DebtInstrumentFaceAmount" id="Fact_b21bb227d58d40ff936cec8e66406925" contextRef="c20210430_DebtInstrumentAxis_ConvertibleSeniorNotes0PercentMember" unitRef="U001" decimals="-5" scale="6" format="ixt:numdotdecimal">632.5</ix:nonFraction> million
    offering of <ix:nonFraction name="us-gaap:DebtInstrumentInterestRateStatedPercentage" id="Fact_9fd92dee75c04780a37b699d06ef1cd1" contextRef="c20210430_DebtInstrumentAxis_ConvertibleSeniorNotes0PercentMember" unitRef="U003" decimals="2" scale="-2" format="ixt:numdotdecimal">0</ix:nonFraction>% Notes primarily to repurchase a majority of our <ix:nonFraction name="us-gaap:DebtInstrumentInterestRateStatedPercentage" id="Fact_e881c18962ca456b8b5e64e6d7a428e4" contextRef="c20201231_DebtInstrumentAxis_ConvertibleSeniorNotes1PercentMember" unitRef="U003" decimals="2" scale="-2" format="ixt:numdotdecimal">1</ix:nonFraction>% Notes. We accounted for our <ix:nonFraction name="us-gaap:DebtInstrumentInterestRateStatedPercentage" id="Fact_accb91d2166f4aa8bb48a1463f90e696" contextRef="c20210430_DebtInstrumentAxis_ConvertibleSeniorNotes0PercentMember" unitRef="U003" decimals="2" scale="-2" format="ixt:numdotdecimal">0</ix:nonFraction>% Notes under ASU 2020-06 at issuance. Refer to Note
    3, <span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Long-Term Obligations and Commitments</span>, for further information.</div>
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<div><br />
  </div>
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<div style="display:none;"><br /></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">The updated guidance eliminates the cash conversion accounting model we previously followed in Accounting Standard
    Codification, or ASC, 470-20, which required us to separate each of our convertible debt instruments at issuance into two units of accounting, a liability component, based on our nonconvertible debt borrowing rate at issuance, and an equity component.
    Under ASU 2020-06, we now account for each of our convertible debt instruments as a single unit of accounting, a liability, because we concluded that the conversion features do not require bifurcation as a derivative under ASC 815-15 and we did not
    issue our convertible debt instruments at a substantial premium. Since we adopted ASU 2020-06 using the full retrospective approach, we were required to apply the guidance to all convertible debt instruments we had outstanding as of January 1, 2019. We
    recomputed the basis of each convertible debt instrument as if we accounted for each as a single unit of accounting at issuance. This update included recalculating the amortization of debt issuance costs using an updated effective interest rate. As a
    result of adopting ASU 2020-06, we recorded a cumulative adjustment to decrease our additional paid in capital and our accumulated deficit at January 1, 2019. We have updated these financial statements to reflect the cumulative adjustment for the
    periods presented. We have labeled our prior period financial statements &#8220;as revised&#8221; to indicate the change required under the new accounting guidance. Below is a summary of the change in our balance sheet at December 31, 2020 and statement of
    operations from the years ended December 31, 2020 and 2019 under the ASC 470-20 legacy guidance compared to the new ASU 2020-06 guidance we adopted:</div>
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<div style="display:none;"><br /></div>
<div style="text-align: justify; text-indent: 36pt;"><br />
  </div>
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    <div class="DSPFPageFooter">
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    </div>

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  <ix:continuation id="Text_ba6a171da9294812a4a91832efce6f8c340" continuedAt="Text_ba6a171da9294812a4a91832efce6f8c341"><ix:continuation id="Text_c897996155364bbead33024eac5f5ed79" continuedAt="Text_c897996155364bbead33024eac5f5ed710"><ix:nonNumeric name="us-gaap:ScheduleOfNewAccountingPronouncementsAndChangesInAccountingPrinciplesTextBlock" id="Text_25c9c214e8864981ba5f5886a01ad143" contextRef="c20210101to20211231" escape="true" continuedAt="Text_b80b5fbc384f4637a6e3d21350d4b9fa1">
<div style="display:none;"><br /></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">The following table summarizes the adjustments we made to the consolidated balance sheet we
    originally reported at December 31, 2020 to adopt ASU 2020-06 (in thousands):</div>
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<div><br />
  </div>
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  <ix:continuation id="Text_ba6a171da9294812a4a91832efce6f8c342" continuedAt="Text_ba6a171da9294812a4a91832efce6f8c343"><ix:continuation id="Text_c897996155364bbead33024eac5f5ed711" continuedAt="Text_c897996155364bbead33024eac5f5ed712"><ix:continuation id="Text_b80b5fbc384f4637a6e3d21350d4b9fa2" continuedAt="Text_b80b5fbc384f4637a6e3d21350d4b9fa3">
<table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;" class="cfttable">


  <tr>

    <td valign="bottom" style="vertical-align: top; padding-bottom: 2px;">

        </td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: top; border-bottom: #000000 solid 2px;" colspan="10">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">December 31, 2020</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: top; padding-bottom: 2px;">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" colspan="2">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">As Previously</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Reported</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" colspan="2">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">ASU 2020-06</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Adjustment</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" colspan="2">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">As Revised</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: top; width: 64%; background-color: #CCEEFF;">
          <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:DebtInstrumentInterestRateStatedPercentage" id="Fact_871bb9ed289a4ed0b3854abf338a41ba" contextRef="c20201231_DebtInstrumentAxis_ConvertibleSeniorNotes1PercentMember" unitRef="U003" decimals="2" scale="-2" format="ixt:numdotdecimal">1</ix:nonFraction> percent convertible
            senior notes</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:ConvertibleDebtCurrent" id="Fact_e181df6b88c947f9bee58c0a330d3abf" contextRef="c20201231_RestatementAxis_ScenarioPreviouslyReportedMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">293,161</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:ConvertibleDebtCurrent" id="Fact_248c35433bfe4921b51508174d13ced4" contextRef="c20201231_AdjustmentsForNewAccountingPronouncementsAxis_AccountingStandardsUpdate202006Member_RestatementAxis_RevisionOfPriorPeriodAccountingStandardsUpdateAdjustmentMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">15,648</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:ConvertibleDebtCurrent" id="Fact_ec8485075b2b44b09208abd68dc186f0" contextRef="c20201231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">308,809</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: top; width: 64%;">
          <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:DebtInstrumentInterestRateStatedPercentage" id="Fact_3a8d86e145b94af193ca818b7e2de3fa" contextRef="c20201231_DebtInstrumentAxis_ConvertibleSeniorNotes0125PercentMember" unitRef="U003" decimals="5" scale="-2" format="ixt:numdotdecimal">0.125</ix:nonFraction> percent convertible
            senior notes</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:ConvertibleDebtNoncurrent" id="Fact_68d817d8bc8f49ee8a69dd9b4e7340cb" contextRef="c20201231_AdjustmentsForNewAccountingPronouncementsAxis_AccountingStandardsUpdate202006Member_DebtInstrumentAxis_ConvertibleSeniorNotes0125PercentMember_RestatementAxis_RevisionOfPriorPeriodAccountingStandardsUpdateAdjustmentMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">84,417</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:ConvertibleDebtNoncurrent" id="Fact_4447ab6a2fe64bc2b9ca6554745ac9a0" contextRef="c20201231_DebtInstrumentAxis_ConvertibleSeniorNotes0125PercentMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">540,136</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: top; width: 64%; background-color: #CCEEFF;">
          <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Additional paid-in-capital</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:AdditionalPaidInCapitalCommonStock" id="Fact_a74622efee484715a6fda70f68ab0aa7" contextRef="c20201231_RestatementAxis_ScenarioPreviouslyReportedMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">2,113,646</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:AdditionalPaidInCapitalCommonStock" id="Fact_8953c0527f204290a3f668cf8ab52736" contextRef="c20201231_AdjustmentsForNewAccountingPronouncementsAxis_AccountingStandardsUpdate202006Member_RestatementAxis_RevisionOfPriorPeriodAccountingStandardsUpdateAdjustmentMember" unitRef="U001" decimals="-3" scale="3" sign="-" format="ixt:numdotdecimal">218,127</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:AdditionalPaidInCapitalCommonStock" id="Fact_38b9919e607b443188577907741abe67" contextRef="c20201231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">1,895,519</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: top; width: 64%;">
          <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Accumulated deficit</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:RetainedEarningsAccumulatedDeficit" id="Fact_a09ae60a75624fe29245457035a48bb0" contextRef="c20201231_RestatementAxis_ScenarioPreviouslyReportedMember" unitRef="U001" decimals="-3" scale="3" sign="-" format="ixt:numdotdecimal">1,249,368</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:RetainedEarningsAccumulatedDeficit" id="Fact_04bbfd3b05884ee2acb95f085a5b1ba2" contextRef="c20201231_AdjustmentsForNewAccountingPronouncementsAxis_AccountingStandardsUpdate202006Member_RestatementAxis_RevisionOfPriorPeriodAccountingStandardsUpdateAdjustmentMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">118,062</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:RetainedEarningsAccumulatedDeficit" id="Fact_8e169f86084c43809f5b9c35013247a1" contextRef="c20201231" unitRef="U001" decimals="-3" scale="3" sign="-" format="ixt:numdotdecimal">1,131,306</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

  </tr>


</table>
</ix:continuation></ix:continuation></ix:continuation>
  <ix:continuation id="Text_ba6a171da9294812a4a91832efce6f8c343" continuedAt="Text_ba6a171da9294812a4a91832efce6f8c344"><ix:continuation id="Text_c897996155364bbead33024eac5f5ed712" continuedAt="Text_c897996155364bbead33024eac5f5ed713"><ix:continuation id="Text_b80b5fbc384f4637a6e3d21350d4b9fa3" continuedAt="Text_b80b5fbc384f4637a6e3d21350d4b9fa4">
<div><br />
  </div>
</ix:continuation></ix:continuation></ix:continuation>
  <ix:continuation id="Text_ba6a171da9294812a4a91832efce6f8c344" continuedAt="Text_ba6a171da9294812a4a91832efce6f8c345"><ix:continuation id="Text_c897996155364bbead33024eac5f5ed713" continuedAt="Text_c897996155364bbead33024eac5f5ed714">
<div style="display:none;"><br /></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#160;<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">Under ASU 2020-06, our revised
      ending balances for our </span><ix:nonFraction name="us-gaap:DebtInstrumentInterestRateStatedPercentage" id="Fact_91557e6638b84a3f80984fe74d772c70" contextRef="c20201231_DebtInstrumentAxis_ConvertibleSeniorNotes1PercentMember" unitRef="U003" decimals="2" scale="-2" format="ixt:numdotdecimal">1</ix:nonFraction>%<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> Notes and </span><ix:nonFraction name="us-gaap:DebtInstrumentInterestRateStatedPercentage" id="Fact_c0c33e5520c541d9b0b5453636031c9d" contextRef="c20201231_DebtInstrumentAxis_ConvertibleSeniorNotes0125PercentMember" unitRef="U003" decimals="5" scale="-2" format="ixt:numdotdecimal">0.125</ix:nonFraction>%<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> Notes as of December 31, 2020 represent the principal
      balance of each convertible debt instrument less debt issuance costs. Additionally, because we have deferred tax assets related to our convertible debt instruments, we also adjusted these amounts as part of our adoption of ASU 2020-06. However,
      because we have a full valuation allowance on our deferred tax assets, there was </span><ix:nonFraction name="us-gaap:DeferredIncomeTaxAssetsNet" id="Fact_bcdef8d450e641ad93f05be8360a2df2" contextRef="c20201231_AdjustmentsForNewAccountingPronouncementsAxis_AccountingStandardsUpdate202006Member_RestatementAxis_RevisionOfPriorPeriodAccountingStandardsUpdateAdjustmentMember" unitRef="U001" decimals="-3" scale="3" format="ixt-sec:numwordsen">no</ix:nonFraction><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> impact to our consolidated balance sheet related to our deferred tax assets.</span></div>
</ix:continuation></ix:continuation>
  <ix:continuation id="Text_ba6a171da9294812a4a91832efce6f8c345" continuedAt="Text_ba6a171da9294812a4a91832efce6f8c346"><ix:continuation id="Text_c897996155364bbead33024eac5f5ed714" continuedAt="Text_c897996155364bbead33024eac5f5ed715">
<div><br />
  </div>
</ix:continuation></ix:continuation>
  <ix:continuation id="Text_ba6a171da9294812a4a91832efce6f8c346" continuedAt="Text_ba6a171da9294812a4a91832efce6f8c347"><ix:continuation id="Text_c897996155364bbead33024eac5f5ed715" continuedAt="Text_c897996155364bbead33024eac5f5ed716">
<div style="display:none;"><br /></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#160;<ix:continuation id="Text_b80b5fbc384f4637a6e3d21350d4b9fa4" continuedAt="Text_b80b5fbc384f4637a6e3d21350d4b9fa5"><span style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; color: #000000;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">The following
      tables summarize the adjustments we made to the consolidated statement of operations we originally reported for the years ended December 31, 2020 and 2019 to adopt ASU 2020-06 (in thousands):</span></span></ix:continuation></div>
</ix:continuation></ix:continuation>
  <ix:continuation id="Text_ba6a171da9294812a4a91832efce6f8c347" continuedAt="Text_ba6a171da9294812a4a91832efce6f8c348"><ix:continuation id="Text_c897996155364bbead33024eac5f5ed716" continuedAt="Text_c897996155364bbead33024eac5f5ed717"><ix:continuation id="Text_b80b5fbc384f4637a6e3d21350d4b9fa5" continuedAt="Text_b80b5fbc384f4637a6e3d21350d4b9fa6">
<div><br />
  </div>
</ix:continuation></ix:continuation></ix:continuation>
  <ix:continuation id="Text_ba6a171da9294812a4a91832efce6f8c348" continuedAt="Text_ba6a171da9294812a4a91832efce6f8c349"><ix:continuation id="Text_c897996155364bbead33024eac5f5ed717" continuedAt="Text_c897996155364bbead33024eac5f5ed718"><ix:continuation id="Text_b80b5fbc384f4637a6e3d21350d4b9fa6" continuedAt="Text_b80b5fbc384f4637a6e3d21350d4b9fa7">
<table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;" class="cfttable">


  <tr>

    <td valign="bottom" style="vertical-align: top; padding-bottom: 2px;">

        </td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: top; border-bottom: #000000 solid 2px;" colspan="10">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Year Ended December 31, 2020</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: top; padding-bottom: 2px;">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" colspan="2">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">As Previously</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Reported</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" colspan="2">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">ASU 2020-06</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Adjustment</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" colspan="2">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">As Revised</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: top; width: 64%; background-color: #CCEEFF;">
          <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Interest expense</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:InterestExpense" id="Fact_25b225c5019b4ef7a0fe3d91feb917e3" contextRef="c20200101to20201231_RestatementAxis_ScenarioPreviouslyReportedMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">44,990</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:InterestExpense" id="Fact_cb9773cdf0c24efcad399583cf089072" contextRef="c20200101to20201231_AdjustmentsForNewAccountingPronouncementsAxis_AccountingStandardsUpdate202006Member_RestatementAxis_RevisionOfPriorPeriodAccountingStandardsUpdateAdjustmentMember" unitRef="U001" decimals="-3" scale="3" sign="-" format="ixt:numdotdecimal">35,480</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:InterestExpense" id="Fact_67925cc26b2148868d7bafb6a58fffc6" contextRef="c20200101to20201231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">9,510</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: top; width: 64%;">
          <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Loss before income tax expense</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:IncomeLossFromContinuingOperationsBeforeIncomeTaxesExtraordinaryItemsNoncontrollingInterest" id="Fact_f9c63a22962f452bb9e55caf724ca080" contextRef="c20200101to20201231_RestatementAxis_ScenarioPreviouslyReportedMember" unitRef="U001" decimals="-3" scale="3" sign="-" format="ixt:numdotdecimal">170,032</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:IncomeLossFromContinuingOperationsBeforeIncomeTaxesExtraordinaryItemsNoncontrollingInterest" id="Fact_7c6ca8f665d345949cccfd45d260c561" contextRef="c20200101to20201231_AdjustmentsForNewAccountingPronouncementsAxis_AccountingStandardsUpdate202006Member_RestatementAxis_RevisionOfPriorPeriodAccountingStandardsUpdateAdjustmentMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">35,480</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">
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        </td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: top; width: 64%; background-color: #CCEEFF;">
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        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:IncomeTaxExpenseBenefit" id="Fact_6af7718640874a03bc43214c13f0d682" contextRef="c20200101to20201231_AdjustmentsForNewAccountingPronouncementsAxis_AccountingStandardsUpdate202006Member_RestatementAxis_RevisionOfPriorPeriodAccountingStandardsUpdateAdjustmentMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">28,457</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:IncomeTaxExpenseBenefit" id="Fact_4614f82f1a0f4d6c8d05b8360557c400" contextRef="c20200101to20201231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">345,191</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: top; width: 64%;">
          <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Net loss</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:ProfitLoss" id="Fact_cca598f8e28846908c0bf84ab63e077f" contextRef="c20200101to20201231_RestatementAxis_ScenarioPreviouslyReportedMember" unitRef="U001" decimals="-3" scale="3" sign="-" format="ixt:numdotdecimal">486,766</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:ProfitLoss" id="Fact_85bf56cda680410dbc8bffd7e7f768ac" contextRef="c20200101to20201231_AdjustmentsForNewAccountingPronouncementsAxis_AccountingStandardsUpdate202006Member_RestatementAxis_RevisionOfPriorPeriodAccountingStandardsUpdateAdjustmentMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">7,023</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:ProfitLoss" id="Fact_1887ff0af0384a39aa9a2eae6c623b37" contextRef="c20200101to20201231" unitRef="U001" decimals="-3" scale="3" sign="-" format="ixt:numdotdecimal">479,743</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: top; width: 64%; background-color: #CCEEFF;">
          <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Net loss attributable to Ionis Pharmaceuticals, Inc. common stockholders</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:NetIncomeLoss" id="Fact_ece1464b83c14c928d322d88f235ddda" contextRef="c20200101to20201231_RestatementAxis_ScenarioPreviouslyReportedMember" unitRef="U001" decimals="-3" scale="3" sign="-" format="ixt:numdotdecimal">451,286</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:NetIncomeLoss" id="Fact_31799a1125e046a1910bbb8ababa1775" contextRef="c20200101to20201231_AdjustmentsForNewAccountingPronouncementsAxis_AccountingStandardsUpdate202006Member_RestatementAxis_RevisionOfPriorPeriodAccountingStandardsUpdateAdjustmentMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">7,023</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:NetIncomeLoss" id="Fact_10fb623665044bd6a257b484c2ba8e03" contextRef="c20200101to20201231" unitRef="U001" decimals="-3" scale="3" sign="-" format="ixt:numdotdecimal">444,263</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: top; width: 64%;">
          <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Basic and diluted net loss per share</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:EarningsPerShareDiluted" id="Fact_d198b4dc58204bf086370ac023665cb2" contextRef="c20200101to20201231_RestatementAxis_ScenarioPreviouslyReportedMember" unitRef="U004" decimals="2" sign="-" scale="0" format="ixt:numdotdecimal"><ix:nonFraction name="us-gaap:EarningsPerShareBasic" id="Fact_33040aac6a8d4c26ab52adfcd2eb9d24" contextRef="c20200101to20201231_RestatementAxis_ScenarioPreviouslyReportedMember" unitRef="U004" decimals="2" sign="-" scale="0" format="ixt:numdotdecimal">3.23</ix:nonFraction></ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:EarningsPerShareDiluted" id="Fact_0680c272c2ac4d05ba9002d205394f82" contextRef="c20200101to20201231_AdjustmentsForNewAccountingPronouncementsAxis_AccountingStandardsUpdate202006Member_RestatementAxis_RevisionOfPriorPeriodAccountingStandardsUpdateAdjustmentMember" unitRef="U004" decimals="2" scale="0" format="ixt:numdotdecimal"><ix:nonFraction name="us-gaap:EarningsPerShareBasic" id="Fact_222c5baf8f664d909f004d20b9dfe550" contextRef="c20200101to20201231_AdjustmentsForNewAccountingPronouncementsAxis_AccountingStandardsUpdate202006Member_RestatementAxis_RevisionOfPriorPeriodAccountingStandardsUpdateAdjustmentMember" unitRef="U004" decimals="2" scale="0" format="ixt:numdotdecimal">0.05</ix:nonFraction></ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:EarningsPerShareDiluted" id="Fact_13fe6f1f31d740e98b9e146c1b7abf91" contextRef="c20200101to20201231" unitRef="U004" decimals="2" sign="-" scale="0" format="ixt:numdotdecimal"><ix:nonFraction name="us-gaap:EarningsPerShareBasic" id="Fact_4897872de8d741a8b8a88bedc64bd6a3" contextRef="c20200101to20201231" unitRef="U004" decimals="2" sign="-" scale="0" format="ixt:numdotdecimal">3.18</ix:nonFraction></ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

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</ix:continuation></ix:continuation></ix:continuation>
  <ix:continuation id="Text_ba6a171da9294812a4a91832efce6f8c349" continuedAt="Text_ba6a171da9294812a4a91832efce6f8c350"><ix:continuation id="Text_c897996155364bbead33024eac5f5ed718" continuedAt="Text_c897996155364bbead33024eac5f5ed719"><ix:continuation id="Text_b80b5fbc384f4637a6e3d21350d4b9fa7" continuedAt="Text_b80b5fbc384f4637a6e3d21350d4b9fa8">
<div><br />
  </div>
</ix:continuation></ix:continuation></ix:continuation>
  <ix:continuation id="Text_ba6a171da9294812a4a91832efce6f8c350" continuedAt="Text_ba6a171da9294812a4a91832efce6f8c351"><ix:continuation id="Text_c897996155364bbead33024eac5f5ed719" continuedAt="Text_c897996155364bbead33024eac5f5ed720"><ix:continuation id="Text_b80b5fbc384f4637a6e3d21350d4b9fa8" continuedAt="Text_b80b5fbc384f4637a6e3d21350d4b9fa9">
<table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;" class="cfttable">


  <tr>

    <td valign="bottom" style="vertical-align: top; padding-bottom: 2px;">

        </td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: top; border-bottom: #000000 solid 2px;" colspan="10">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Year Ended December 31, 2019</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: top; padding-bottom: 2px;">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" colspan="2">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">As Previously</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Reported</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" colspan="2">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">ASU 2020-06</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Adjustment</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" colspan="2">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">As Revised</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: top; width: 64%; background-color: #CCEEFF;">
          <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Interest expense</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:InterestExpense" id="Fact_4e2e4f74c7654642ae24f84d15891796" contextRef="c20190101to20191231_RestatementAxis_ScenarioPreviouslyReportedMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">48,768</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:InterestExpense" id="Fact_508e3676737f40b09ac1fda148823f9d" contextRef="c20190101to20191231_AdjustmentsForNewAccountingPronouncementsAxis_AccountingStandardsUpdate202006Member_RestatementAxis_RevisionOfPriorPeriodAccountingStandardsUpdateAdjustmentMember" unitRef="U001" decimals="-3" scale="3" sign="-" format="ixt:numdotdecimal">36,328</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:InterestExpense" id="Fact_b200402d5b6d44f2bebfa6bedf31d6a9" contextRef="c20190101to20191231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">12,440</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: top; width: 64%;">
          <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Loss on early retirement of debt</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:GainsLossesOnExtinguishmentOfDebt" id="Fact_69d643f46a464986b6149b0eb7782330" contextRef="c20190101to20191231_RestatementAxis_ScenarioPreviouslyReportedMember" unitRef="U001" decimals="-3" scale="3" sign="-" format="ixt:numdotdecimal">21,865</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:GainsLossesOnExtinguishmentOfDebt" id="Fact_f89ab8c5306243e3a28d22b03001c12c" contextRef="c20190101to20191231_AdjustmentsForNewAccountingPronouncementsAxis_AccountingStandardsUpdate202006Member_RestatementAxis_RevisionOfPriorPeriodAccountingStandardsUpdateAdjustmentMember" unitRef="U001" decimals="-3" scale="3" sign="-" format="ixt:numdotdecimal">44,331</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:GainsLossesOnExtinguishmentOfDebt" id="Fact_4212dfc2e0b3470ab9338c301b0c9969" contextRef="c20190101to20191231" unitRef="U001" decimals="-3" scale="3" sign="-" format="ixt:numdotdecimal">66,196</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: top; width: 64%; background-color: #CCEEFF;">
          <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Income before income tax benefit (expense)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:IncomeLossFromContinuingOperationsBeforeIncomeTaxesExtraordinaryItemsNoncontrollingInterest" id="Fact_da78ad65282b4e1790c8a295973f146c" contextRef="c20190101to20191231_RestatementAxis_ScenarioPreviouslyReportedMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">346,769</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:IncomeLossFromContinuingOperationsBeforeIncomeTaxesExtraordinaryItemsNoncontrollingInterest" id="Fact_f40dd0eb3a774230937c096269fa4469" contextRef="c20190101to20191231_AdjustmentsForNewAccountingPronouncementsAxis_AccountingStandardsUpdate202006Member_RestatementAxis_RevisionOfPriorPeriodAccountingStandardsUpdateAdjustmentMember" unitRef="U001" decimals="-3" scale="3" sign="-" format="ixt:numdotdecimal">8,003</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:IncomeLossFromContinuingOperationsBeforeIncomeTaxesExtraordinaryItemsNoncontrollingInterest" id="Fact_530b105ccae04e848a42cf5db8595c2e" contextRef="c20190101to20191231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">338,766</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: top; width: 64%;">
          <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Income tax expense</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:IncomeTaxExpenseBenefit" id="Fact_2b867f83220c4e53b32cca8a2e22351c" contextRef="c20190101to20191231_RestatementAxis_ScenarioPreviouslyReportedMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">43,507</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:IncomeTaxExpenseBenefit" id="Fact_d3f9f4084843419ca6bffe7c52ad7dc8" contextRef="c20190101to20191231_AdjustmentsForNewAccountingPronouncementsAxis_AccountingStandardsUpdate202006Member_RestatementAxis_RevisionOfPriorPeriodAccountingStandardsUpdateAdjustmentMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">8,000</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:IncomeTaxExpenseBenefit" id="Fact_4bf8c57d1fd241cebc601f1bf363d70e" contextRef="c20190101to20191231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">51,507</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: top; width: 64%; background-color: #CCEEFF;">
          <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Net income</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:ProfitLoss" id="Fact_b778fe619ee740df8fed988ad6d66a2d" contextRef="c20190101to20191231_RestatementAxis_ScenarioPreviouslyReportedMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">303,262</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:ProfitLoss" id="Fact_385181c3362f48408feaf6fee529a8b9" contextRef="c20190101to20191231_AdjustmentsForNewAccountingPronouncementsAxis_AccountingStandardsUpdate202006Member_RestatementAxis_RevisionOfPriorPeriodAccountingStandardsUpdateAdjustmentMember" unitRef="U001" decimals="-3" scale="3" sign="-" format="ixt:numdotdecimal">16,003</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:ProfitLoss" id="Fact_2a94dd177549404f9677032f1d16dfc4" contextRef="c20190101to20191231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">287,259</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: top; width: 64%;">
          <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Net income attributable to Ionis Pharmaceuticals, Inc. common stockholders</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:NetIncomeLoss" id="Fact_fbb19a01525c412098437d489416341e" contextRef="c20190101to20191231_RestatementAxis_ScenarioPreviouslyReportedMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">294,146</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:NetIncomeLoss" id="Fact_362cd71c8d2c40fe970364c253d783dd" contextRef="c20190101to20191231_AdjustmentsForNewAccountingPronouncementsAxis_AccountingStandardsUpdate202006Member_RestatementAxis_RevisionOfPriorPeriodAccountingStandardsUpdateAdjustmentMember" unitRef="U001" decimals="-3" scale="3" sign="-" format="ixt:numdotdecimal">16,003</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:NetIncomeLoss" id="Fact_80f30ea2e4944c8dac011e3499458dde" contextRef="c20190101to20191231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">278,143</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: top; width: 64%; background-color: #CCEEFF;">
          <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Basic net income per share</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:EarningsPerShareBasic" id="Fact_f373c8f95789452ba7af5026c6558eb1" contextRef="c20190101to20191231_RestatementAxis_ScenarioPreviouslyReportedMember" unitRef="U004" decimals="2" scale="0" format="ixt:numdotdecimal">2.12</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:EarningsPerShareBasic" id="Fact_3918bdb7cdb841a488f479dd6b72ec0c" contextRef="c20190101to20191231_AdjustmentsForNewAccountingPronouncementsAxis_AccountingStandardsUpdate202006Member_RestatementAxis_RevisionOfPriorPeriodAccountingStandardsUpdateAdjustmentMember" unitRef="U004" decimals="2" sign="-" scale="0" format="ixt:numdotdecimal">0.12</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:EarningsPerShareBasic" id="Fact_1bf5a279fa8e474bb4e5fa3b280da912" contextRef="c20190101to20191231" unitRef="U004" decimals="2" scale="0" format="ixt:numdotdecimal">2.00</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: top; width: 64%;">
          <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Diluted net income per share</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:EarningsPerShareDiluted" id="Fact_9c15272507ad48e4b6b9eecb5f3284ef" contextRef="c20190101to20191231_RestatementAxis_ScenarioPreviouslyReportedMember" unitRef="U004" decimals="2" scale="0" format="ixt:numdotdecimal">2.08</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:EarningsPerShareDiluted" id="Fact_30d0ba409d7f4a44b73d8833c04e370c" contextRef="c20190101to20191231_AdjustmentsForNewAccountingPronouncementsAxis_AccountingStandardsUpdate202006Member_RestatementAxis_RevisionOfPriorPeriodAccountingStandardsUpdateAdjustmentMember" unitRef="U004" decimals="2" sign="-" scale="0" format="ixt:numdotdecimal">0.18</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:EarningsPerShareDiluted" id="Fact_6d230cd47be941c2ac767f5add65a740" contextRef="c20190101to20191231" unitRef="U004" decimals="2" scale="0" format="ixt:numdotdecimal">1.90</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>


</table>
</ix:continuation></ix:continuation></ix:continuation>
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<div><br />
  </div>
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<div style="display:none;"><br /></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Under ASU 2020-06, our revised interest expense is lower because we are no longer recording non-cash
    interest expense related to a debt discount. This decrease was partially offset by the increase in interest expense related to the amortization of debt issuance costs because we no longer allocate a portion of our debt issuance costs to stockholders&#8217;
    equity at issuance. Instead, the entire debt issuance costs were recorded as a contra-liability on our consolidated balance sheet at issuance and we are amortizing them over the contractual term using an updated effective interest rate. Our updated
    effective interest rates for our <ix:nonFraction name="us-gaap:DebtInstrumentInterestRateStatedPercentage" id="Fact_a49fc4f195774a4faaa28f85053ab116" contextRef="c20201231_DebtInstrumentAxis_ConvertibleSeniorNotes1PercentMember" unitRef="U003" decimals="2" scale="-2" format="ixt:numdotdecimal">1</ix:nonFraction>% Notes and <ix:nonFraction name="us-gaap:DebtInstrumentInterestRateStatedPercentage" id="Fact_81fd4fed46394e0bb8ed7dd5ec39034b" contextRef="c20201231_DebtInstrumentAxis_ConvertibleSeniorNotes0125PercentMember" unitRef="U003" decimals="5" scale="-2" format="ixt:numdotdecimal">0.125</ix:nonFraction>%
    Notes were <ix:nonFraction name="us-gaap:DebtInstrumentInterestRateEffectivePercentage" id="Fact_e600d115953a466fb30727c075ff8940" contextRef="c20211231_DebtInstrumentAxis_ConvertibleSeniorNotes1PercentMember" unitRef="U003" decimals="3" scale="-2" format="ixt:numdotdecimal">1.4</ix:nonFraction> percent and <ix:nonFraction name="us-gaap:DebtInstrumentInterestRateEffectivePercentage" id="Fact_859af9fd23ec4cefbc0803d642c69e48" contextRef="c20211231_DebtInstrumentAxis_ConvertibleSeniorNotes0125PercentMember" unitRef="U003" decimals="3" scale="-2" format="ixt:numdotdecimal">0.5</ix:nonFraction> percent,
    respectively.</div>
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    <div class="DSPFPageFooter">
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    </div>

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<div style="display:none;"><br /></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">The following tables summarize the adjustments we made to our consolidated statements of
    stockholders&#8217; equity we originally reported at December 31, 2020 and 2019 to adopt ASU 2020-06 (in thousands):</div>
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  </div>
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<table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;" class="cfttable">


  <tr>

    <td valign="bottom" style="vertical-align: top; padding-bottom: 2px;">

        </td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: top; border-bottom: #000000 solid 2px;" colspan="10">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">December 31, 2020</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: top; padding-bottom: 2px;">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" colspan="2">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">As Previously</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Reported</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" colspan="2">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">ASU 2020-06</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Adjustment</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" colspan="2">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">As Revised</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: top; width: 64%; background-color: #CCEEFF;">
          <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Additional paid-in-capital</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:StockholdersEquityIncludingPortionAttributableToNoncontrollingInterest" id="Fact_dac0a5fdad774438bc4131d691a66fff" contextRef="c20201231_RestatementAxis_ScenarioPreviouslyReportedMember_StatementEquityComponentsAxis_AdditionalPaidInCapitalMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">2,113,646</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:StockholdersEquityIncludingPortionAttributableToNoncontrollingInterest" id="Fact_e631050ac3584cc288b76c415e26ff94" contextRef="c20201231_AdjustmentsForNewAccountingPronouncementsAxis_AccountingStandardsUpdate202006Member_RestatementAxis_RevisionOfPriorPeriodAccountingStandardsUpdateAdjustmentMember_StatementEquityComponentsAxis_AdditionalPaidInCapitalMember" unitRef="U001" decimals="-3" scale="3" sign="-" format="ixt:numdotdecimal">218,127</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:StockholdersEquityIncludingPortionAttributableToNoncontrollingInterest" id="Fact_3c4ff11a57fe46d2835b2d326aebe25b" contextRef="c20201231_StatementEquityComponentsAxis_AdditionalPaidInCapitalMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">1,895,519</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: top; width: 64%;">
          <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Accumulated deficit</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:StockholdersEquityIncludingPortionAttributableToNoncontrollingInterest" id="Fact_52d2abca51ac4c34b792eba3b5e01a19" contextRef="c20201231_RestatementAxis_ScenarioPreviouslyReportedMember_StatementEquityComponentsAxis_RetainedEarningsMember" unitRef="U001" decimals="-3" scale="3" sign="-" format="ixt:numdotdecimal">1,249,368</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:StockholdersEquityIncludingPortionAttributableToNoncontrollingInterest" id="Fact_63d0a7ba04b54f4596effebe4f0d5092" contextRef="c20201231_AdjustmentsForNewAccountingPronouncementsAxis_AccountingStandardsUpdate202006Member_RestatementAxis_RevisionOfPriorPeriodAccountingStandardsUpdateAdjustmentMember_StatementEquityComponentsAxis_RetainedEarningsMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">118,062</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:StockholdersEquityIncludingPortionAttributableToNoncontrollingInterest" id="Fact_c180d070bfd24f75a2c94077e3cc21b8" contextRef="c20201231_StatementEquityComponentsAxis_RetainedEarningsMember" unitRef="U001" decimals="-3" scale="3" sign="-" format="ixt:numdotdecimal">1,131,306</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: top; width: 64%; background-color: #CCEEFF;">
          <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Total stockholders&#8217; equity</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:StockholdersEquityIncludingPortionAttributableToNoncontrollingInterest" id="Fact_331f4422413b4fc18ba3db7923ac11f3" contextRef="c20201231_RestatementAxis_ScenarioPreviouslyReportedMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">843,347</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:StockholdersEquityIncludingPortionAttributableToNoncontrollingInterest" id="Fact_dfa11add072f4b96ababb48e87cff6c9" contextRef="c20201231_AdjustmentsForNewAccountingPronouncementsAxis_AccountingStandardsUpdate202006Member_RestatementAxis_RevisionOfPriorPeriodAccountingStandardsUpdateAdjustmentMember" unitRef="U001" decimals="-3" scale="3" sign="-" format="ixt:numdotdecimal">100,065</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:StockholdersEquityIncludingPortionAttributableToNoncontrollingInterest" id="Fact_a9f8bab9b49348798ffa52f4f91ae62c" contextRef="c20201231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">743,282</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>


</table>
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<div><br />
  </div>
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<table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;" class="cfttable">


  <tr>

    <td valign="bottom" style="vertical-align: top; padding-bottom: 2px;">

        </td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: top; border-bottom: #000000 solid 2px;" colspan="10">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">December 31, 2019</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: top; padding-bottom: 2px;">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" colspan="2">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">As Previously</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Reported</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" colspan="2">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">ASU 2020-06</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Adjustment</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" colspan="2">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">As Revised</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: top; width: 64%; background-color: #CCEEFF;">
          <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Additional paid-in-capital</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:StockholdersEquityIncludingPortionAttributableToNoncontrollingInterest" id="Fact_fa011eee185741d5aa650b9ba5887de6" contextRef="c20191231_AdjustmentsForNewAccountingPronouncementsAxis_AccountingStandardsUpdate202006Member_RestatementAxis_RevisionOfPriorPeriodAccountingStandardsUpdateAdjustmentMember_StatementEquityComponentsAxis_AdditionalPaidInCapitalMember" unitRef="U001" decimals="-3" scale="3" sign="-" format="ixt:numdotdecimal">218,128</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:StockholdersEquityIncludingPortionAttributableToNoncontrollingInterest" id="Fact_491af5529728462f81abab775b239e79" contextRef="c20191231_StatementEquityComponentsAxis_AdditionalPaidInCapitalMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">1,985,650</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: top; width: 64%;">
          <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Accumulated deficit</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:StockholdersEquityIncludingPortionAttributableToNoncontrollingInterest" id="Fact_bf4089f274044f39b77f426eed56bb87" contextRef="c20191231_RestatementAxis_ScenarioPreviouslyReportedMember_StatementEquityComponentsAxis_RetainedEarningsMember" unitRef="U001" decimals="-3" scale="3" sign="-" format="ixt:numdotdecimal">707,534</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:StockholdersEquityIncludingPortionAttributableToNoncontrollingInterest" id="Fact_c2dd77a691454a46b61ffa2b413acd48" contextRef="c20191231_AdjustmentsForNewAccountingPronouncementsAxis_AccountingStandardsUpdate202006Member_RestatementAxis_RevisionOfPriorPeriodAccountingStandardsUpdateAdjustmentMember_StatementEquityComponentsAxis_RetainedEarningsMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">111,039</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:StockholdersEquityIncludingPortionAttributableToNoncontrollingInterest" id="Fact_35a78750c3624c87b4c150b526f04222" contextRef="c20191231_StatementEquityComponentsAxis_RetainedEarningsMember" unitRef="U001" decimals="-3" scale="3" sign="-" format="ixt:numdotdecimal">596,495</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: top; width: 64%; background-color: #CCEEFF;">
          <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Total stockholders&#8217; equity</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:StockholdersEquityIncludingPortionAttributableToNoncontrollingInterest" id="Fact_f19b3e4fc4e44159af5350810ca4d78d" contextRef="c20191231_RestatementAxis_ScenarioPreviouslyReportedMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">1,684,547</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:StockholdersEquityIncludingPortionAttributableToNoncontrollingInterest" id="Fact_90da4863e94649b286e5acfc1f94db07" contextRef="c20191231_AdjustmentsForNewAccountingPronouncementsAxis_AccountingStandardsUpdate202006Member_RestatementAxis_RevisionOfPriorPeriodAccountingStandardsUpdateAdjustmentMember" unitRef="U001" decimals="-3" scale="3" sign="-" format="ixt:numdotdecimal">107,088</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:StockholdersEquityIncludingPortionAttributableToNoncontrollingInterest" id="Fact_b330685254bd4056b67f9a8e242f99e7" contextRef="c20191231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">1,577,459</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>


</table>
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<div style="display:none;"><br /></div>
<div style="text-align: justify; text-indent: 36pt;"><br />
  </div>
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<div><br />
  </div>
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  <ix:continuation id="Text_ba6a171da9294812a4a91832efce6f8c361" continuedAt="Text_ba6a171da9294812a4a91832efce6f8c362"><ix:nonNumeric name="us-gaap:DerivativesPolicyTextBlock" id="Text_aa6c21ff1d40469fbb64ee19c123e452" contextRef="c20210101to20211231" escape="true" continuedAt="Text_ed84f673ce8749908ed0533207afbc041">
<div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Call Spread</div>
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<div><br />
  </div>
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  <ix:continuation id="Text_ba6a171da9294812a4a91832efce6f8c363" continuedAt="Text_ba6a171da9294812a4a91832efce6f8c364"><ix:continuation id="Text_ed84f673ce8749908ed0533207afbc042">
<div style="display:none;"><br /></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">In conjunction with the issuance of our <ix:nonFraction name="us-gaap:DebtInstrumentInterestRateStatedPercentage" id="Fact_fe2e410b891c4e8f90e9c7af0b2fd97c" contextRef="c20210430_DebtInstrumentAxis_ConvertibleSeniorNotes0PercentMember" unitRef="U003" decimals="2" scale="-2" format="ixt:numdotdecimal">0</ix:nonFraction>% Notes and <ix:nonFraction name="us-gaap:DebtInstrumentInterestRateStatedPercentage" id="Fact_ad09e792f7534196a47d6e0a5fba48da" contextRef="c20191231_DebtInstrumentAxis_ConvertibleSeniorNotes0125PercentMember" unitRef="U003" decimals="5" scale="-2" format="ixt:numdotdecimal">0.125</ix:nonFraction>% Notes in April 2021 and December 2019, respectively, we entered
    into call spread transactions, which were comprised of purchasing note hedges and selling warrants. We account for the note hedges and warrants as separate freestanding financial instruments and treat each instrument as a separate unit of accounting.
    We determined that the note hedges and warrants do not meet the definition of a liability using the guidance contained in ASC Topic 480; therefore, we account for the note hedges and warrants using the Derivatives and Hedging &#8211; Contracts in Entity&#8217;s
    Own Equity accounting guidance contained in ASC Topic 815. We determined that the note hedges and warrants meet the definition of a derivative, are indexed to our stock and meet the criteria to be classified in shareholders&#8217; equity. We recorded the
    aggregate amount paid for the note hedges and the aggregate amount received for the warrants as additional paid-in capital in our consolidated balance sheet. We reassess our ability to continue to classify the note hedges and warrants in shareholders&#8217;
    equity at each reporting period.</div>
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<div><br />
  </div>
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<div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Segment Information</div>
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<div><br />
  </div>
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<div style="display:none;"><br /></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">In 2021, we began operating as a single segment, Ionis operations, because our chief decision maker reviews operating
    results on an aggregate basis and manages our operations as a <span style="-sec-ix-hidden:Fact_33bc30118e9548358994c912eadf2161">single</span> operating segment. Previously, we had operated as <ix:nonFraction name="us-gaap:NumberOfOperatingSegments" id="Fact_a315f651d2c042c59a48e5688cd8c8d7" contextRef="c20200101to20201231" unitRef="U013" decimals="INF" scale="0" format="ixt-sec:numwordsen">two</ix:nonFraction> operating segments, Ionis Core and Akcea Therapeutics. We completed the Akcea Merger in October 2020 and fully integrated Akcea&#8217;s operations into ours
    as of January 1, 2021<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">.</span></div>
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<div><br />
  </div>
</ix:continuation>
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<div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Fair Value Measurements</div>
</ix:nonNumeric></ix:continuation>
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<div><br />
  </div>
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<div style="display:none;"><br /></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We use a three-tier fair value hierarchy to prioritize the inputs used in our fair value measurements. These tiers
    include: Level 1, defined as observable inputs such as quoted prices in active markets for identical assets, which includes our money market funds and treasury securities classified as available-for-sale securities and our investment in equity
    securities in publicly held biotechnology companies; Level 2, defined as inputs other than quoted prices in active markets that are either directly or indirectly observable, which includes our fixed income securities and commercial paper classified as
    available-for-sale securities; and Level 3, defined as unobservable inputs in which little or no market data exists, therefore requiring us to develop our own assumptions. We classify most of our securities as Level 2. We obtain the fair value of our
    Level 2 investments from our custodian bank or from a professional pricing service. We validate the fair value of our Level 2 investments by understanding the pricing model used by the custodian banks or professional pricing service provider and
    comparing that fair value to the fair value based on observable market prices.</div>
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  </div>
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  <ix:continuation id="Text_ba6a171da9294812a4a91832efce6f8c373" continuedAt="Text_ba6a171da9294812a4a91832efce6f8c374"><ix:continuation id="Text_e1776993fe3140afba06a44187c1a0ed4" continuedAt="Text_e1776993fe3140afba06a44187c1a0ed5"><ix:nonNumeric name="us-gaap:FairValueAssetsMeasuredOnRecurringBasisTextBlock" id="Text_d6b095fbb9c24159b20f66ec3f602d33" contextRef="c20210101to20211231" escape="true" continuedAt="Text_dcd5eeb9533f48aba216d416aaa1d9701">
<div style="display:none;"><br /></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">The following tables present the major security types we held at December 31, 2021 and 2020&#160;<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">that we regularly measure and carry at fair value</span>. As of December 31, 2021, our Bicycle investment was subject to trading restrictions that extend to the third quarter of 2022; as
    a result, we included a lack of marketability discount in valuing this investment, which is a Level 3 input. As of December 31, 2020, we did <ix:nonFraction name="us-gaap:AssetsFairValueDisclosure" id="Fact_383c2be74fbb451496ae77e1495ae311" contextRef="c20201231_FairValueByFairValueHierarchyLevelAxis_FairValueInputsLevel3Member_FairValueByMeasurementFrequencyAxis_FairValueMeasurementsRecurringMember" unitRef="U001" decimals="-3" scale="3" format="ixt-sec:numwordsen">no</ix:nonFraction>t
    have any investments that we valued using Level 3 inputs. The following tables segregate each security type by the level within the fair value hierarchy of the valuation techniques we utilized to determine the respective securities&#8217; fair value (in
    thousands):</div>
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<div><br />
  </div>
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<table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;" class="cfttable">


  <tr>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px; white-space: nowrap;" colspan="2">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">At</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">December 31, 2021</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px; white-space: nowrap;" colspan="2">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Quoted Prices in</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Active Markets</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">(Level 1)</div>
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px; white-space: nowrap;" colspan="2">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Significant Other</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Observable Inputs</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">(Level 2)</div>
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px; white-space: nowrap;" colspan="2">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Significant</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Unobservable Inputs</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">(Level 3)</div>
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 52%; background-color: #CCEEFF;">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Cash equivalents (1)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:CashAndCashEquivalentsFairValueDisclosure" id="Fact_9849f6d4c9f24dc0ae5c30734da85ccb" contextRef="c20211231_FairValueByMeasurementFrequencyAxis_FairValueMeasurementsRecurringMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">541,199</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:CashAndCashEquivalentsFairValueDisclosure" id="Fact_72bd376635824ddb81158c2a5c18655e" contextRef="c20211231_FairValueByFairValueHierarchyLevelAxis_FairValueInputsLevel1Member_FairValueByMeasurementFrequencyAxis_FairValueMeasurementsRecurringMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">541,199</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:CashAndCashEquivalentsFairValueDisclosure" id="Fact_5441dd14eeec4d3e885d51a4f88ccf80" contextRef="c20211231_FairValueByFairValueHierarchyLevelAxis_FairValueInputsLevel2Member_FairValueByMeasurementFrequencyAxis_FairValueMeasurementsRecurringMember" unitRef="U001" decimals="-3" scale="3" format="ixt:zerodash">&#8212;</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:CashAndCashEquivalentsFairValueDisclosure" id="Fact_06522bfe72844bec9ec2ebbd1fc64c90" contextRef="c20211231_FairValueByFairValueHierarchyLevelAxis_FairValueInputsLevel3Member_FairValueByMeasurementFrequencyAxis_FairValueMeasurementsRecurringMember" unitRef="U001" decimals="-3" scale="3" format="ixt:zerodash">&#8212;</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 52%;">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Corporate debt securities (2)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:AvailableForSaleSecuritiesDebtSecurities" id="Fact_e73ddade0807452f9b4c91b358c1ee45" contextRef="c20211231_FairValueByMeasurementFrequencyAxis_FairValueMeasurementsRecurringMember_FinancialInstrumentAxis_CorporateDebtSecuritiesMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">764,059</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:AvailableForSaleSecuritiesDebtSecurities" id="Fact_8c58cfb938454b61a68557fc7bc10f1f" contextRef="c20211231_FairValueByFairValueHierarchyLevelAxis_FairValueInputsLevel1Member_FairValueByMeasurementFrequencyAxis_FairValueMeasurementsRecurringMember_FinancialInstrumentAxis_CorporateDebtSecuritiesMember" unitRef="U001" decimals="-3" scale="3" format="ixt:zerodash">&#8212;</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:AvailableForSaleSecuritiesDebtSecurities" id="Fact_6c223935ab254c4889b2e08ffc6563ce" contextRef="c20211231_FairValueByFairValueHierarchyLevelAxis_FairValueInputsLevel2Member_FairValueByMeasurementFrequencyAxis_FairValueMeasurementsRecurringMember_FinancialInstrumentAxis_CorporateDebtSecuritiesMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">764,059</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:AvailableForSaleSecuritiesDebtSecurities" id="Fact_74086b9efda04d37848492c56565276d" contextRef="c20211231_FairValueByFairValueHierarchyLevelAxis_FairValueInputsLevel3Member_FairValueByMeasurementFrequencyAxis_FairValueMeasurementsRecurringMember_FinancialInstrumentAxis_CorporateDebtSecuritiesMember" unitRef="U001" decimals="-3" scale="3" format="ixt:zerodash">&#8212;</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 52%; background-color: #CCEEFF;">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Debt securities issued by U.S. government agencies (2)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:AvailableForSaleSecuritiesDebtSecurities" id="Fact_54a9c39e40c3477f8faa20d0f0844dcb" contextRef="c20211231_FairValueByMeasurementFrequencyAxis_FairValueMeasurementsRecurringMember_FinancialInstrumentAxis_USGovernmentAgenciesDebtSecuritiesMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">120,868</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:AvailableForSaleSecuritiesDebtSecurities" id="Fact_c8b23347e64e40ac94a069520e6eebb9" contextRef="c20211231_FairValueByFairValueHierarchyLevelAxis_FairValueInputsLevel1Member_FairValueByMeasurementFrequencyAxis_FairValueMeasurementsRecurringMember_FinancialInstrumentAxis_USGovernmentAgenciesDebtSecuritiesMember" unitRef="U001" decimals="-3" scale="3" format="ixt:zerodash">&#8212;</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:AvailableForSaleSecuritiesDebtSecurities" id="Fact_5ef8a576816b4325834e3589fde900a1" contextRef="c20211231_FairValueByFairValueHierarchyLevelAxis_FairValueInputsLevel2Member_FairValueByMeasurementFrequencyAxis_FairValueMeasurementsRecurringMember_FinancialInstrumentAxis_USGovernmentAgenciesDebtSecuritiesMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">120,868</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:AvailableForSaleSecuritiesDebtSecurities" id="Fact_5594303d325b409c96e02208877b100e" contextRef="c20211231_FairValueByFairValueHierarchyLevelAxis_FairValueInputsLevel3Member_FairValueByMeasurementFrequencyAxis_FairValueMeasurementsRecurringMember_FinancialInstrumentAxis_USGovernmentAgenciesDebtSecuritiesMember" unitRef="U001" decimals="-3" scale="3" format="ixt:zerodash">&#8212;</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 52%;">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Debt securities issued by the U.S. Treasury (2)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:AvailableForSaleSecuritiesDebtSecurities" id="Fact_e839171386cc4f36bfdbeb1c8b7bd55e" contextRef="c20211231_FairValueByMeasurementFrequencyAxis_FairValueMeasurementsRecurringMember_FinancialInstrumentAxis_USTreasurySecuritiesMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">182,634</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:AvailableForSaleSecuritiesDebtSecurities" id="Fact_90237b621f724e2ebcd00a2d38d17840" contextRef="c20211231_FairValueByFairValueHierarchyLevelAxis_FairValueInputsLevel1Member_FairValueByMeasurementFrequencyAxis_FairValueMeasurementsRecurringMember_FinancialInstrumentAxis_USTreasurySecuritiesMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">182,634</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:AvailableForSaleSecuritiesDebtSecurities" id="Fact_c1c64e6b1f2c41f69cc91434c48a6cdc" contextRef="c20211231_FairValueByFairValueHierarchyLevelAxis_FairValueInputsLevel2Member_FairValueByMeasurementFrequencyAxis_FairValueMeasurementsRecurringMember_FinancialInstrumentAxis_USTreasurySecuritiesMember" unitRef="U001" decimals="-3" scale="3" format="ixt:zerodash">&#8212;</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:AvailableForSaleSecuritiesDebtSecurities" id="Fact_0fc68f8affef4ba8b1789487917d3cbe" contextRef="c20211231_FairValueByFairValueHierarchyLevelAxis_FairValueInputsLevel3Member_FairValueByMeasurementFrequencyAxis_FairValueMeasurementsRecurringMember_FinancialInstrumentAxis_USTreasurySecuritiesMember" unitRef="U001" decimals="-3" scale="3" format="ixt:zerodash">&#8212;</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 52%; background-color: #CCEEFF;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Debt securities issued by states of the U.S. and political subdivisions of the states (3)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:AvailableForSaleSecuritiesDebtSecurities" id="Fact_b7ecf4d0425243e1b1b144bb33f88aaf" contextRef="c20211231_FairValueByMeasurementFrequencyAxis_FairValueMeasurementsRecurringMember_FinancialInstrumentAxis_USStatesAndPoliticalSubdivisionsMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">174,464</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:AvailableForSaleSecuritiesDebtSecurities" id="Fact_b841a3c5613f4c588d01f7c416dbba9e" contextRef="c20211231_FairValueByFairValueHierarchyLevelAxis_FairValueInputsLevel1Member_FairValueByMeasurementFrequencyAxis_FairValueMeasurementsRecurringMember_FinancialInstrumentAxis_USStatesAndPoliticalSubdivisionsMember" unitRef="U001" decimals="-3" scale="3" format="ixt:zerodash">&#8212;</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:AvailableForSaleSecuritiesDebtSecurities" id="Fact_e210cf87ff064f29b08b7fc73e108544" contextRef="c20211231_FairValueByFairValueHierarchyLevelAxis_FairValueInputsLevel2Member_FairValueByMeasurementFrequencyAxis_FairValueMeasurementsRecurringMember_FinancialInstrumentAxis_USStatesAndPoliticalSubdivisionsMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">174,464</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
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            <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Other municipal debt securities (2)</div>
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    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

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    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

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            <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Investment in Bicycle Therapeutics plc (4)</div>
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        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

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  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 52%; padding-bottom: 2px;">
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            <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Investment in ProQR Therapeutics N.V. (4)</div>
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    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" colspan="1">
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" colspan="1">
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" colspan="1">
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" colspan="1">
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

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    <td valign="bottom" style="vertical-align: bottom; width: 52%; padding-bottom: 4px; background-color: #CCEEFF;">
          <div style="text-align: justify; text-indent: -8.9pt; margin-left: 22.55pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Total</div>
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    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
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    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" colspan="1">
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
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    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:AssetsFairValueDisclosure" id="Fact_6cae9a3fe66246f4ac9a720cb39ef760" contextRef="c20211231_FairValueByFairValueHierarchyLevelAxis_FairValueInputsLevel1Member_FairValueByMeasurementFrequencyAxis_FairValueMeasurementsRecurringMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">727,708</ix:nonFraction></div>
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
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    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" colspan="1">
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
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    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:AssetsFairValueDisclosure" id="Fact_fffc079c922848e88f49da112d37ead5" contextRef="c20211231_FairValueByFairValueHierarchyLevelAxis_FairValueInputsLevel3Member_FairValueByMeasurementFrequencyAxis_FairValueMeasurementsRecurringMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">14,330</ix:nonFraction></div>
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

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</ix:continuation></ix:continuation></ix:continuation>
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    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">

        </td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px; white-space: nowrap;" colspan="2">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">At</div>
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

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    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
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    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:CashAndCashEquivalentsFairValueDisclosure" id="Fact_bee1b7168baf4e7ab838f80884d19001" contextRef="c20201231_FairValueByFairValueHierarchyLevelAxis_FairValueInputsLevel1Member_FairValueByMeasurementFrequencyAxis_FairValueMeasurementsRecurringMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">221,125</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:CashAndCashEquivalentsFairValueDisclosure" id="Fact_d508b24489c14037aa4ee2cbbdeb0bce" contextRef="c20201231_FairValueByFairValueHierarchyLevelAxis_FairValueInputsLevel2Member_FairValueByMeasurementFrequencyAxis_FairValueMeasurementsRecurringMember" unitRef="U001" decimals="-3" scale="3" format="ixt:zerodash">&#8212;</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 64%;">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Corporate debt securities (5)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:AvailableForSaleSecuritiesDebtSecurities" id="Fact_ca774641af4b4144bd68543025639338" contextRef="c20201231_FairValueByMeasurementFrequencyAxis_FairValueMeasurementsRecurringMember_FinancialInstrumentAxis_CorporateDebtSecuritiesMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">846,315</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:AvailableForSaleSecuritiesDebtSecurities" id="Fact_35ae36c048694830a348eb14503bc637" contextRef="c20201231_FairValueByFairValueHierarchyLevelAxis_FairValueInputsLevel1Member_FairValueByMeasurementFrequencyAxis_FairValueMeasurementsRecurringMember_FinancialInstrumentAxis_CorporateDebtSecuritiesMember" unitRef="U001" decimals="-3" scale="3" format="ixt:zerodash">&#8212;</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:AvailableForSaleSecuritiesDebtSecurities" id="Fact_b6f68fdeb93345aa85972334125c3d3f" contextRef="c20201231_FairValueByFairValueHierarchyLevelAxis_FairValueInputsLevel2Member_FairValueByMeasurementFrequencyAxis_FairValueMeasurementsRecurringMember_FinancialInstrumentAxis_CorporateDebtSecuritiesMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">846,315</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Debt securities issued by U.S. government agencies (2)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:AvailableForSaleSecuritiesDebtSecurities" id="Fact_02808f1c46224f2b8f9f7cf77ad7486d" contextRef="c20201231_FairValueByMeasurementFrequencyAxis_FairValueMeasurementsRecurringMember_FinancialInstrumentAxis_USGovernmentAgenciesDebtSecuritiesMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">174,861</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:AvailableForSaleSecuritiesDebtSecurities" id="Fact_105e0f8a8df0477f8ebdfe2afde13f95" contextRef="c20201231_FairValueByFairValueHierarchyLevelAxis_FairValueInputsLevel1Member_FairValueByMeasurementFrequencyAxis_FairValueMeasurementsRecurringMember_FinancialInstrumentAxis_USGovernmentAgenciesDebtSecuritiesMember" unitRef="U001" decimals="-3" scale="3" format="ixt:zerodash">&#8212;</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:AvailableForSaleSecuritiesDebtSecurities" id="Fact_be0fcb80d2ed422598d21e49540671f2" contextRef="c20201231_FairValueByFairValueHierarchyLevelAxis_FairValueInputsLevel2Member_FairValueByMeasurementFrequencyAxis_FairValueMeasurementsRecurringMember_FinancialInstrumentAxis_USGovernmentAgenciesDebtSecuritiesMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">174,861</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 64%;">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Debt securities issued by the U.S. Treasury (6)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:AvailableForSaleSecuritiesDebtSecurities" id="Fact_cad25cfe73424f5eacbb14bd396f2ddc" contextRef="c20201231_FairValueByMeasurementFrequencyAxis_FairValueMeasurementsRecurringMember_FinancialInstrumentAxis_USTreasurySecuritiesMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">358,497</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:AvailableForSaleSecuritiesDebtSecurities" id="Fact_ad23151d38c24bc9bffb7ceef6b79448" contextRef="c20201231_FairValueByFairValueHierarchyLevelAxis_FairValueInputsLevel1Member_FairValueByMeasurementFrequencyAxis_FairValueMeasurementsRecurringMember_FinancialInstrumentAxis_USTreasurySecuritiesMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">358,497</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:AvailableForSaleSecuritiesDebtSecurities" id="Fact_d1d509cd4fe34f85b04c4ade135d578b" contextRef="c20201231_FairValueByFairValueHierarchyLevelAxis_FairValueInputsLevel2Member_FairValueByMeasurementFrequencyAxis_FairValueMeasurementsRecurringMember_FinancialInstrumentAxis_USTreasurySecuritiesMember" unitRef="U001" decimals="-3" scale="3" format="ixt:zerodash">&#8212;</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Debt securities issued by states of the U.S. and political subdivisions of the states (2)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:AvailableForSaleSecuritiesDebtSecurities" id="Fact_635722e3df584c4fb49d7dd02a3097ab" contextRef="c20201231_FairValueByMeasurementFrequencyAxis_FairValueMeasurementsRecurringMember_FinancialInstrumentAxis_USStatesAndPoliticalSubdivisionsMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">136,309</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:AvailableForSaleSecuritiesDebtSecurities" id="Fact_b6283b419353435e86736586fd2801a6" contextRef="c20201231_FairValueByFairValueHierarchyLevelAxis_FairValueInputsLevel1Member_FairValueByMeasurementFrequencyAxis_FairValueMeasurementsRecurringMember_FinancialInstrumentAxis_USStatesAndPoliticalSubdivisionsMember" unitRef="U001" decimals="-3" scale="3" format="ixt:zerodash">&#8212;</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:AvailableForSaleSecuritiesDebtSecurities" id="Fact_f6b1dad9ce234c4a99e4294e0ba8873e" contextRef="c20201231_FairValueByFairValueHierarchyLevelAxis_FairValueInputsLevel2Member_FairValueByMeasurementFrequencyAxis_FairValueMeasurementsRecurringMember_FinancialInstrumentAxis_USStatesAndPoliticalSubdivisionsMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">136,309</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 64%;">
          <div>
            <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Other municipal debt securities (2)</div>
          </div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:AvailableForSaleSecuritiesDebtSecurities" id="Fact_f87d5044d87e411dbb358075e59e08e7" contextRef="c20201231_FairValueByMeasurementFrequencyAxis_FairValueMeasurementsRecurringMember_FinancialInstrumentAxis_OtherDebtSecuritiesMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">6,225</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:AvailableForSaleSecuritiesDebtSecurities" id="Fact_d9a86a5df4264afa8ff96dabb04201a9" contextRef="c20201231_FairValueByFairValueHierarchyLevelAxis_FairValueInputsLevel1Member_FairValueByMeasurementFrequencyAxis_FairValueMeasurementsRecurringMember_FinancialInstrumentAxis_OtherDebtSecuritiesMember" unitRef="U001" decimals="-3" scale="3" format="ixt:zerodash">&#8212;</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:AvailableForSaleSecuritiesDebtSecurities" id="Fact_305334cdb3d74056ba1a189774c8789a" contextRef="c20201231_FairValueByFairValueHierarchyLevelAxis_FairValueInputsLevel2Member_FairValueByMeasurementFrequencyAxis_FairValueMeasurementsRecurringMember_FinancialInstrumentAxis_OtherDebtSecuritiesMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">6,225</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #CCEEFF;">
          <div>
            <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Investment in ProQR Therapeutics N.V. (4)</div>
          </div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:EquitySecuritiesFvNi" id="Fact_7c0601176d014f509bd086fd6bd23850" contextRef="c20201231_FairValueByMeasurementFrequencyAxis_FairValueMeasurementsRecurringMember_ScheduleOfEquityMethodInvestmentEquityMethodInvesteeNameAxis_ProqrTherapeuticsNVMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">2,031</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:EquitySecuritiesFvNi" id="Fact_71e35947c9fd42d587bf10b2b9030358" contextRef="c20201231_FairValueByFairValueHierarchyLevelAxis_FairValueInputsLevel1Member_FairValueByMeasurementFrequencyAxis_FairValueMeasurementsRecurringMember_ScheduleOfEquityMethodInvestmentEquityMethodInvesteeNameAxis_ProqrTherapeuticsNVMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">2,031</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:EquitySecuritiesFvNi" id="Fact_b461fb3b62e1408f9826e0a1f6e57152" contextRef="c20201231_FairValueByFairValueHierarchyLevelAxis_FairValueInputsLevel2Member_FairValueByMeasurementFrequencyAxis_FairValueMeasurementsRecurringMember_ScheduleOfEquityMethodInvestmentEquityMethodInvesteeNameAxis_ProqrTherapeuticsNVMember" unitRef="U001" decimals="-3" scale="3" format="ixt:zerodash">&#8212;</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 4px;">
          <div style="text-align: justify; text-indent: -8.9pt; margin-left: 22.55pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Total</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:AssetsFairValueDisclosure" id="Fact_af0b142c77c34301a20bbf069f427a45" contextRef="c20201231_FairValueByMeasurementFrequencyAxis_FairValueMeasurementsRecurringMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">1,745,363</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:AssetsFairValueDisclosure" id="Fact_e35481b183c34b34b9643c9ec6ea5339" contextRef="c20201231_FairValueByFairValueHierarchyLevelAxis_FairValueInputsLevel1Member_FairValueByMeasurementFrequencyAxis_FairValueMeasurementsRecurringMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">581,653</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:AssetsFairValueDisclosure" id="Fact_d5726ba3e6264418bd08a22ea1c98749" contextRef="c20201231_FairValueByFairValueHierarchyLevelAxis_FairValueInputsLevel2Member_FairValueByMeasurementFrequencyAxis_FairValueMeasurementsRecurringMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">1,163,710</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>


</table>
</ix:continuation></ix:continuation></ix:continuation>
  <ix:continuation id="Text_ba6a171da9294812a4a91832efce6f8c378" continuedAt="Text_ba6a171da9294812a4a91832efce6f8c379"><ix:continuation id="Text_e1776993fe3140afba06a44187c1a0ed9" continuedAt="Text_e1776993fe3140afba06a44187c1a0ed10"><ix:continuation id="Text_dcd5eeb9533f48aba216d416aaa1d9705" continuedAt="Text_dcd5eeb9533f48aba216d416aaa1d9706">
<div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">________________</div>
</ix:continuation></ix:continuation></ix:continuation>
  <ix:continuation id="Text_ba6a171da9294812a4a91832efce6f8c379" continuedAt="Text_ba6a171da9294812a4a91832efce6f8c380"><ix:continuation id="Text_e1776993fe3140afba06a44187c1a0ed10" continuedAt="Text_e1776993fe3140afba06a44187c1a0ed11"><ix:continuation id="Text_dcd5eeb9533f48aba216d416aaa1d9706" continuedAt="Text_dcd5eeb9533f48aba216d416aaa1d9707">
<table cellspacing="0" cellpadding="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">


  <tr>

    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(1)</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:footnote id="Foot_ad43559c353f456eac7c04729a412d6f" footnoteRole="http://www.xbrl.org/2003/role/footnote" xml:lang="en-US">Included in cash and cash
            equivalents on our consolidated balance sheet.</ix:footnote></div>
        </td>

  </tr>


</table>
</ix:continuation></ix:continuation></ix:continuation>
  <ix:continuation id="Text_ba6a171da9294812a4a91832efce6f8c380" continuedAt="Text_ba6a171da9294812a4a91832efce6f8c381"><ix:continuation id="Text_e1776993fe3140afba06a44187c1a0ed11" continuedAt="Text_e1776993fe3140afba06a44187c1a0ed12"><ix:continuation id="Text_dcd5eeb9533f48aba216d416aaa1d9707" continuedAt="Text_dcd5eeb9533f48aba216d416aaa1d9708">
<div><br />
  </div>
</ix:continuation></ix:continuation></ix:continuation>
  <ix:continuation id="Text_ba6a171da9294812a4a91832efce6f8c381" continuedAt="Text_ba6a171da9294812a4a91832efce6f8c382"><ix:continuation id="Text_e1776993fe3140afba06a44187c1a0ed12" continuedAt="Text_e1776993fe3140afba06a44187c1a0ed13"><ix:continuation id="Text_dcd5eeb9533f48aba216d416aaa1d9708" continuedAt="Text_dcd5eeb9533f48aba216d416aaa1d9709">
<table cellspacing="0" cellpadding="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">


  <tr>

    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(2)</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:footnote id="Foot_77eb85d4142a44a68a7c6b25a7169d1c" footnoteRole="http://www.xbrl.org/2003/role/footnote" xml:lang="en-US">Included in short-term
            investments.</ix:footnote></div>
        </td>

  </tr>


</table>
</ix:continuation></ix:continuation></ix:continuation>
  <ix:continuation id="Text_ba6a171da9294812a4a91832efce6f8c382" continuedAt="Text_ba6a171da9294812a4a91832efce6f8c383"><ix:continuation id="Text_e1776993fe3140afba06a44187c1a0ed13" continuedAt="Text_e1776993fe3140afba06a44187c1a0ed14"><ix:continuation id="Text_dcd5eeb9533f48aba216d416aaa1d9709" continuedAt="Text_dcd5eeb9533f48aba216d416aaa1d97010">
<div><br />
  </div>
</ix:continuation></ix:continuation></ix:continuation>
  <ix:continuation id="Text_ba6a171da9294812a4a91832efce6f8c383" continuedAt="Text_ba6a171da9294812a4a91832efce6f8c384"><ix:continuation id="Text_e1776993fe3140afba06a44187c1a0ed14" continuedAt="Text_e1776993fe3140afba06a44187c1a0ed15"><ix:continuation id="Text_dcd5eeb9533f48aba216d416aaa1d97010" continuedAt="Text_dcd5eeb9533f48aba216d416aaa1d97011">
<table cellspacing="0" cellpadding="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">


  <tr>

    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(3)</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:footnote id="Foot_cc6012bb3041434399bdb287399a913a" footnoteRole="http://www.xbrl.org/2003/role/footnote" xml:lang="en-US">$<ix:nonFraction name="us-gaap:AvailableForSaleSecuritiesDebtSecurities" id="Fact_ce470ce0da684fc0965a0abdbc5bdb8f" contextRef="c20211231_BalanceSheetLocationAxis_CashAndCashEquivalentsMember_FairValueByMeasurementFrequencyAxis_FairValueMeasurementsRecurringMember_FinancialInstrumentAxis_CorporateDebtSecuritiesMember" unitRef="U001" decimals="-5" scale="6" format="ixt:numdotdecimal">2.3</ix:nonFraction> million included in cash and cash equivalents on our consolidated balance sheet, with the difference included in short-term investments on our
            consolidated balance sheet.</ix:footnote></div>
        </td>

  </tr>


</table>
</ix:continuation></ix:continuation></ix:continuation>
  <ix:continuation id="Text_ba6a171da9294812a4a91832efce6f8c384" continuedAt="Text_ba6a171da9294812a4a91832efce6f8c385"><ix:continuation id="Text_e1776993fe3140afba06a44187c1a0ed15" continuedAt="Text_e1776993fe3140afba06a44187c1a0ed16"><ix:continuation id="Text_dcd5eeb9533f48aba216d416aaa1d97011" continuedAt="Text_dcd5eeb9533f48aba216d416aaa1d97012">
<div><br />
  </div>
</ix:continuation></ix:continuation></ix:continuation>
  <ix:continuation id="Text_ba6a171da9294812a4a91832efce6f8c385" continuedAt="Text_ba6a171da9294812a4a91832efce6f8c386"><ix:continuation id="Text_e1776993fe3140afba06a44187c1a0ed16" continuedAt="Text_e1776993fe3140afba06a44187c1a0ed17"><ix:continuation id="Text_dcd5eeb9533f48aba216d416aaa1d97012" continuedAt="Text_dcd5eeb9533f48aba216d416aaa1d97013">
<table cellspacing="0" cellpadding="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">


  <tr>

    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(4)</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:footnote id="Foot_f0e1d58ea08e4b55a4c7703dd1e397d3" footnoteRole="http://www.xbrl.org/2003/role/footnote" xml:lang="en-US">Included in other current assets
            on our consolidated balance sheet.</ix:footnote></div>
        </td>

  </tr>


</table>
</ix:continuation></ix:continuation></ix:continuation>
  <ix:continuation id="Text_ba6a171da9294812a4a91832efce6f8c386" continuedAt="Text_ba6a171da9294812a4a91832efce6f8c387"><ix:continuation id="Text_e1776993fe3140afba06a44187c1a0ed17" continuedAt="Text_e1776993fe3140afba06a44187c1a0ed18"><ix:continuation id="Text_dcd5eeb9533f48aba216d416aaa1d97013" continuedAt="Text_dcd5eeb9533f48aba216d416aaa1d97014">
<div><br />
  </div>
</ix:continuation></ix:continuation></ix:continuation>
  <ix:continuation id="Text_ba6a171da9294812a4a91832efce6f8c387" continuedAt="Text_ba6a171da9294812a4a91832efce6f8c388"><ix:continuation id="Text_e1776993fe3140afba06a44187c1a0ed18" continuedAt="Text_e1776993fe3140afba06a44187c1a0ed19"><ix:continuation id="Text_dcd5eeb9533f48aba216d416aaa1d97014" continuedAt="Text_dcd5eeb9533f48aba216d416aaa1d97015">
<table cellspacing="0" cellpadding="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">


  <tr>

    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(5)</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:footnote id="Foot_c498c367d1f949d4a789172bf48c4121" footnoteRole="http://www.xbrl.org/2003/role/footnote" xml:lang="en-US">$<ix:nonFraction name="us-gaap:AvailableForSaleSecuritiesDebtSecurities" id="Fact_901bc85a32f541369ef5a8de46f7eb74" contextRef="c20201231_BalanceSheetLocationAxis_CashAndCashEquivalentsMember_FairValueByMeasurementFrequencyAxis_FairValueMeasurementsRecurringMember_FinancialInstrumentAxis_CorporateDebtSecuritiesMember" unitRef="U001" decimals="-5" scale="6" format="ixt:numdotdecimal">10.0</ix:nonFraction> million included in cash and cash equivalents on our consolidated balance sheet, with the difference included in short-term investments on our
            consolidated balance sheet.</ix:footnote></div>
        </td>

  </tr>


</table>
</ix:continuation></ix:continuation></ix:continuation>
  <ix:continuation id="Text_ba6a171da9294812a4a91832efce6f8c388" continuedAt="Text_ba6a171da9294812a4a91832efce6f8c389"><ix:continuation id="Text_e1776993fe3140afba06a44187c1a0ed19" continuedAt="Text_e1776993fe3140afba06a44187c1a0ed20"><ix:continuation id="Text_dcd5eeb9533f48aba216d416aaa1d97015" continuedAt="Text_dcd5eeb9533f48aba216d416aaa1d97016">
<div><br />
  </div>
</ix:continuation></ix:continuation></ix:continuation>
  <ix:continuation id="Text_ba6a171da9294812a4a91832efce6f8c389" continuedAt="Text_ba6a171da9294812a4a91832efce6f8c390"><ix:continuation id="Text_e1776993fe3140afba06a44187c1a0ed20" continuedAt="Text_e1776993fe3140afba06a44187c1a0ed21"><ix:continuation id="Text_dcd5eeb9533f48aba216d416aaa1d97016">
<table cellspacing="0" cellpadding="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">


  <tr>

    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(6)</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:footnote id="Foot_7f9ebb5194d04d4294eb3dd811ff49fa" footnoteRole="http://www.xbrl.org/2003/role/footnote" xml:lang="en-US">$<ix:nonFraction name="us-gaap:AvailableForSaleSecuritiesDebtSecurities" id="Fact_0be87ae2076b4d75a7c41aba90d2f514" contextRef="c20201231_BalanceSheetLocationAxis_CashAndCashEquivalentsMember_FairValueByMeasurementFrequencyAxis_FairValueMeasurementsRecurringMember_FinancialInstrumentAxis_USGovernmentAgenciesDebtSecuritiesMember" unitRef="U001" decimals="-5" scale="6">17.5</ix:nonFraction> million included in cash and cash equivalents on our consolidated balance sheet, with the difference included in short-term investments on our
            consolidated balance sheet.</ix:footnote></div>
        </td>

  </tr>


</table>
</ix:continuation></ix:continuation></ix:continuation>

  <ix:continuation id="Text_ba6a171da9294812a4a91832efce6f8c390" continuedAt="Text_ba6a171da9294812a4a91832efce6f8c391"><ix:continuation id="Text_e1776993fe3140afba06a44187c1a0ed21" continuedAt="Text_e1776993fe3140afba06a44187c1a0ed22">
<div><br />
  </div>
</ix:continuation></ix:continuation>
  <ix:continuation id="Text_ba6a171da9294812a4a91832efce6f8c391" continuedAt="Text_ba6a171da9294812a4a91832efce6f8c392"><ix:continuation id="Text_e1776993fe3140afba06a44187c1a0ed22" continuedAt="Text_e1776993fe3140afba06a44187c1a0ed23">
<div style="display:none;"><br /></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;">Convertible Notes</div>
</ix:continuation></ix:continuation>
  <ix:continuation id="Text_ba6a171da9294812a4a91832efce6f8c392" continuedAt="Text_ba6a171da9294812a4a91832efce6f8c393"><ix:continuation id="Text_e1776993fe3140afba06a44187c1a0ed23" continuedAt="Text_e1776993fe3140afba06a44187c1a0ed24">
<div><br />
  </div>
</ix:continuation></ix:continuation>
  <ix:continuation id="Text_ba6a171da9294812a4a91832efce6f8c393" continuedAt="Text_ba6a171da9294812a4a91832efce6f8c394"><ix:continuation id="Text_e1776993fe3140afba06a44187c1a0ed24">
<div style="display:none;"><br /></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Our <ix:nonFraction name="us-gaap:DebtInstrumentInterestRateStatedPercentage" id="Fact_bd322b8313e14411b434a697d8be9cf3" contextRef="c20211231_DebtInstrumentAxis_ConvertibleSeniorNotes0125PercentMember" unitRef="U003" decimals="5" scale="-2" format="ixt:numdotdecimal">0.125</ix:nonFraction>% Notes and <ix:nonFraction name="us-gaap:DebtInstrumentInterestRateStatedPercentage" id="Fact_47cf6f98169049fbac9d864c715e8edb" contextRef="c20211231_DebtInstrumentAxis_ConvertibleSeniorNotes0PercentMember" unitRef="U003" decimals="2" scale="-2" format="ixt:numdotdecimal">0</ix:nonFraction>% Notes had a fair value of $<ix:nonFraction name="us-gaap:NotesPayableFairValueDisclosure" id="Fact_4dd54a5e498144848bb917146895383f" contextRef="c20211231_DebtInstrumentAxis_ConvertibleSeniorNotes0125PercentMember_FairValueByFairValueHierarchyLevelAxis_FairValueInputsLevel2Member_FairValueByMeasurementFrequencyAxis_FairValueMeasurementsRecurringMember" unitRef="U001" decimals="-5" scale="6" format="ixt:numdotdecimal">495.4</ix:nonFraction> million and $<ix:nonFraction name="us-gaap:NotesPayableFairValueDisclosure" id="Fact_f0e3f2364810404e841460fd9d182b2b" contextRef="c20211231_DebtInstrumentAxis_ConvertibleSeniorNotes0PercentMember_FairValueByFairValueHierarchyLevelAxis_FairValueInputsLevel2Member_FairValueByMeasurementFrequencyAxis_FairValueMeasurementsRecurringMember" unitRef="U001" decimals="-5" scale="6" format="ixt:numdotdecimal">559.2</ix:nonFraction> million at December 31, 2021, respectively. We determine the fair value of our notes based on quoted market prices for these notes, which are Level 2
    measurements because the notes do not trade regularly.</div>
</ix:continuation></ix:continuation>
  <ix:continuation id="Text_ba6a171da9294812a4a91832efce6f8c394" continuedAt="Text_ba6a171da9294812a4a91832efce6f8c395">
<div><br />
  </div>
</ix:continuation></div>

  <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" class="DSPFPageBreakArea">
    <div class="DSPFPageFooter">
      <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">F-<span class="DSPFPageNumber">26</span></div>

    </div>

    <div style="page-break-after:always;" class="DSPFPageBreak">
      <hr style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;" /></div>


  </div>
<div><ix:continuation id="Text_ba6a171da9294812a4a91832efce6f8c395" continuedAt="Text_ba6a171da9294812a4a91832efce6f8c396"><ix:nonNumeric name="us-gaap:IncomeTaxPolicyTextBlock" id="Text_ea1db2e5fbf346468e0ca231e0179de4" contextRef="c20210101to20211231" escape="true" continuedAt="Text_17a64d3abb454031915b099b4a9a46d01">
<div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Income Taxes</div>
</ix:nonNumeric></ix:continuation>

  <ix:continuation id="Text_ba6a171da9294812a4a91832efce6f8c396" continuedAt="Text_ba6a171da9294812a4a91832efce6f8c397"><ix:continuation id="Text_17a64d3abb454031915b099b4a9a46d01" continuedAt="Text_17a64d3abb454031915b099b4a9a46d02">
<div><br />
  </div>
</ix:continuation></ix:continuation>
  <ix:continuation id="Text_ba6a171da9294812a4a91832efce6f8c397" continuedAt="Text_ba6a171da9294812a4a91832efce6f8c398"><ix:continuation id="Text_17a64d3abb454031915b099b4a9a46d02" continuedAt="Text_17a64d3abb454031915b099b4a9a46d03">
<div style="display:none;"><br /></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We account for income taxes using the asset and liability method, which requires the recognition of deferred tax assets and liabilities
    for the expected future tax consequences of events that have been recognized in our financial statements or tax returns. In addition, deferred tax assets are recorded for the future benefit of utilizing net operating losses and research and development
    credit carryforwards. We record a valuation allowance when necessary to reduce our net deferred tax assets to the amount expected to be realized.</div>
</ix:continuation></ix:continuation>
  <ix:continuation id="Text_ba6a171da9294812a4a91832efce6f8c398" continuedAt="Text_ba6a171da9294812a4a91832efce6f8c399"><ix:continuation id="Text_17a64d3abb454031915b099b4a9a46d03" continuedAt="Text_17a64d3abb454031915b099b4a9a46d04">
<div><br />
  </div>
</ix:continuation></ix:continuation>
  <ix:continuation id="Text_ba6a171da9294812a4a91832efce6f8c399" continuedAt="Text_ba6a171da9294812a4a91832efce6f8c400"><ix:continuation id="Text_17a64d3abb454031915b099b4a9a46d04" continuedAt="Text_17a64d3abb454031915b099b4a9a46d05">
<div style="display:none;"><br /></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We apply the authoritative accounting guidance prescribing a threshold and measurement attribute for the financial recognition and
    measurement of a tax position taken or expected to be taken in a tax return. We recognize liabilities for uncertain tax positions based on a two-step process. The first step is to evaluate the tax position for recognition by determining if the weight
    of available evidence indicates that it is more likely than not that the position will be sustained on audit, including resolution of related appeals or litigation processes, if any. The second step requires us to estimate and measure the tax benefit
    as the largest amount that is more than 50 percent likely to be realized upon ultimate settlement.</div>
</ix:continuation></ix:continuation>
  <ix:continuation id="Text_ba6a171da9294812a4a91832efce6f8c400" continuedAt="Text_ba6a171da9294812a4a91832efce6f8c401"><ix:continuation id="Text_17a64d3abb454031915b099b4a9a46d05" continuedAt="Text_17a64d3abb454031915b099b4a9a46d06">
<div><br />
  </div>
</ix:continuation></ix:continuation>
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<div style="display:none;"><br /></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We are required to use significant judgment in evaluating our uncertain tax positions and determining our provision for income taxes.
    Although we believe our reserves are reasonable, no assurance can be given that the final tax outcome of these matters will not be different from that which is reflected in our historical income tax provisions and accruals. We adjust these reserves for
    changing facts and circumstances, such as the closing of a tax audit or the refinement of an estimate. To the extent that the final tax outcome of these matters is different than the amounts recorded, such differences may impact the provision for
    income taxes in the period in which such determination is made.</div>
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<div><br />
  </div>
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<div style="display:none;"><br /></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We are also required to use significant judgment in determining any valuation allowance recorded against our deferred tax assets. In
    assessing the need for a valuation allowance, we consider all available evidence, including scheduled reversal of deferred tax liabilities, past operating results, the feasibility of tax planning strategies and estimates of future taxable income. We
    base our estimates of future taxable income on assumptions that are consistent with our plans. The assumptions we use represent our best estimates and involve inherent uncertainties and the application of our judgment. Should actual amounts differ from
    our estimates, the amount of our tax expense and liabilities we recognize could be materially impacted. We record a valuation allowance to reduce the balance of our net deferred tax assets to the amount we believe is more-likely-than-not to be
    realized.</div>
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<div><br />
  </div>
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<div style="display:none;"><br /></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We do not provide for a U.S. income tax liability and foreign withholding taxes on undistributed foreign earnings of our foreign
    subsidiaries.</div>
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<div><br />
  </div>
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  <ix:continuation id="Text_ba6a171da9294812a4a91832efce6f8c407" continuedAt="Text_ba6a171da9294812a4a91832efce6f8c408"><ix:nonNumeric name="us-gaap:NewAccountingPronouncementsPolicyPolicyTextBlock" id="Text_d5b8727afd8049b8b94bc44800d513c0" contextRef="c20210101to20211231" escape="true" continuedAt="Text_75c07c7b5b5548bda90636061015db311">
<div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Impact of Recently Issued Accounting Standards</div>
</ix:nonNumeric></ix:continuation>
  <ix:continuation id="Text_ba6a171da9294812a4a91832efce6f8c408" continuedAt="Text_ba6a171da9294812a4a91832efce6f8c409"><ix:continuation id="Text_75c07c7b5b5548bda90636061015db311" continuedAt="Text_75c07c7b5b5548bda90636061015db312">
<div><br />
  </div>
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  <ix:continuation id="Text_ba6a171da9294812a4a91832efce6f8c409"><ix:continuation id="Text_75c07c7b5b5548bda90636061015db312">
<div style="display:none;"><br /></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">As disclosed in the &#8220;Convertible Debt&#8221; policy above within this footnote, we adopted the simplified accounting for
    convertible debt instrument guidance (ASU 2020-06) on January 1, 2021. Refer to the section above for the impact of adoption. We do not expect any other recently issued accounting standards to have a material impact to our financial results.</div>
</ix:continuation></ix:continuation></div>

  <div><br />
  </div>
<div><ix:nonNumeric name="us-gaap:InvestmentTextBlock" id="Text_9571e0c61df44815a452af9dc71349ef" contextRef="c20210101to20211231" escape="true" continuedAt="Text_84765f4c1362403c9feaa38f9187754f1">
<div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2. Investments</div>
</ix:nonNumeric>

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<div><br />
  </div>
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<div style="display:none;"><br /></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">The following table summarizes the contract maturity of the available-for-sale securities we held as of
    December 31, 2021:</div>
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  <ix:continuation id="Text_84765f4c1362403c9feaa38f9187754f3" continuedAt="Text_84765f4c1362403c9feaa38f9187754f4"><ix:continuation id="Text_2ddd7ffed5274efdade7b59eef1417de1" continuedAt="Text_2ddd7ffed5274efdade7b59eef1417de2">
<div><br />
  </div>
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<table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;" class="cfttable">


  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 88%; background-color: #CCEEFF;">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="text-indent: 0pt;"><ix:nonNumeric name="ions:MaximumContractMaturityPeriodRange1" id="Fact_a0389bbbc04d444aa9945a16f2f77b47" contextRef="c20210101to20211231" format="ixt-sec:durwordsen">One year</ix:nonNumeric></span> or less</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="ions:AvailableForSaleSecuritiesDebtMaturitiesWithinOneYearPercentage" id="Fact_e1a84f7ba1234915827448c633c10e96" contextRef="c20211231" unitRef="U003" decimals="2" scale="-2" format="ixt:numdotdecimal">51</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">%</div>
        </td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 88%; background-color: #FFFFFF;">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">After <span style="text-indent: 0pt;"><ix:nonNumeric name="ions:MaximumContractMaturityPeriodRange1" id="Fact_a9a809b245674eb5912c14df728dc0f0" contextRef="c20210101to20211231" format="ixt-sec:durwordsen">one year</ix:nonNumeric></span> but within <span style="text-indent: 0pt;"><ix:nonNumeric name="ions:MaximumContractMaturityPeriodRange2" id="Fact_d1dd3aa1c3444cc8babea1f02c42cb74" contextRef="c20210101to20211231" format="ixt-sec:durwordsen">two years</ix:nonNumeric></span></div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="ions:AvailableForSaleSecuritiesDebtMaturitiesAfterOneThroughTwoYearsPercentage" id="Fact_54f16a3082454b16a1368f8660393627" contextRef="c20211231" unitRef="U003" decimals="2" scale="-2" format="ixt:numdotdecimal">34</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">%</div>
        </td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 88%; padding-bottom: 2px; background-color: #CCEEFF;">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">After <span style="text-indent: 0pt;"><ix:nonNumeric name="ions:MaximumContractMaturityPeriodRange2" id="Fact_649df9025a904bcfad6dc6ab6bd4c304" contextRef="c20210101to20211231" format="ixt-sec:durwordsen">two years</ix:nonNumeric></span> but within <span style="text-indent: 0pt;"><span style="-sec-ix-hidden:Fact_5b50da2d62974df399b2ebfcfccf0c30">three and a half years</span></span></div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="ions:AvailableForSaleSecuritiesDebtMaturitiesAfterTwoThroughThreeAndOneHalfYearsPercentage" id="Fact_d60e9c8e586b428c886b9d9653ac0f6e" contextRef="c20211231" unitRef="U003" decimals="2" scale="-2" format="ixt:numdotdecimal">15</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">%</div>
        </td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 88%; padding-bottom: 4px; background-color: #FFFFFF;">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Total</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="ions:AvailableForSaleSecuritiesDebtMaturitiesTotalPercentage" id="Fact_298fc5ad20a2442399af2cd8e8215ece" contextRef="c20211231" unitRef="U003" decimals="2" scale="-2" format="ixt:numdotdecimal">100</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">%</div>
        </td>

  </tr>


</table>
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<div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 12pt;"><br />
  </div>
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<div style="display:none;"><br /></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">As illustrated above, at December 31, 2021, <ix:nonFraction name="ions:AvailableForSaleSecuritiesDebtMaturitiesWithinTwoYearsPercentage" id="Fact_971b070bcf6846b8970847cdbaef1457" contextRef="c20211231" unitRef="U003" decimals="2" scale="-2" format="ixt:numdotdecimal">85</ix:nonFraction> percent of our available-for-sale securities had a maturity of less than <ix:nonNumeric name="ions:MaximumContractMaturityPeriodRange2" id="Fact_e4aa3be8fcd040d0bcd0def824af337d" contextRef="c20210101to20211231" format="ixt-sec:durwordsen">two years</ix:nonNumeric>.</div>
</ix:continuation>
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<div><br />
  </div>
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<div style="display:none;"><br /></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">All of our available-for-sale securities are available to us for use in our current operations. As a result, we categorize
    all of these securities as current assets even though the stated maturity of some individual securities may be one year or more beyond the balance sheet date.</div>
</ix:continuation>
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<div><br />
  </div>
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<div style="display:none;"><br /></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">At December 31, 2021,
    we had an ownership interest of less than 20 percent <span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">in <ix:nonFraction name="ions:NumberOfPrivatelyHeldCompaniesInWhichEntityHasEquityInvestment" id="Fact_c487d989afb240aaae9be0536d4b8656" contextRef="c20211231" unitRef="U009" decimals="INF" scale="0" format="ixt-sec:numwordsen">seven</ix:nonFraction>
      private companies and <ix:nonFraction name="ions:NumberOfPubliclyHeldCompaniesInWhichEntityHasEquityInvestment" id="Fact_cc8fa179d30548a7b52fcdc75fe7eeee" contextRef="c20211231" unitRef="U009" decimals="INF" scale="0" format="ixt-sec:numwordsen">three</ix:nonFraction> public companies with which we conduct business. The privately-held companies are </span>Aro Biotherapeutics,
    Atlantic Pharmaceuticals Limited, Dynacure SAS, Empirico, Inc., Flamingo Therapeutics BV, YourBio Health, Inc. and Suzhou-Ribo Life Science Co, Ltd. The publicly traded companies are Antisense Therapeutics Ltd., Bicycle and ProQR.</div>
</ix:continuation></div>

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    <div class="DSPFPageFooter">
      <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">F-<span class="DSPFPageNumber">27</span></div>

    </div>

    <div style="page-break-after:always;" class="DSPFPageBreak">
      <hr style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;" /></div>


  </div>
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<div><br />
  </div>
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<div style="display:none;"><br /></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">The following is a summary of our investments (in thousands):</div>
</ix:nonNumeric></ix:continuation>
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<div><br />
  </div>
</ix:continuation></ix:continuation>
  <ix:continuation id="Text_84765f4c1362403c9feaa38f9187754f14" continuedAt="Text_84765f4c1362403c9feaa38f9187754f15"><ix:continuation id="Text_2f47b7d9951c4dc597b770da2e1648132" continuedAt="Text_2f47b7d9951c4dc597b770da2e1648133">
<table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;" class="cfttable">


  <tr>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">

        </td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="2">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Amortized</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" colspan="6">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Gross Unrealized</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="2">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Estimated</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">December 31, 2021</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" colspan="2">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"> Cost</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" colspan="2">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Gains</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" colspan="2">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Losses</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" colspan="2">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Fair Value</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Available-for-sale securities:</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="2">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="2">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="2">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="2">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 52%; background-color: #CCEEFF;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Corporate debt securities (1)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:AvailableForSaleDebtSecuritiesAmortizedCostBasis" id="Fact_bc9e70d55b674cc9b6be541478de94e8" contextRef="c20211231_FinancialInstrumentAxis_CorporateDebtSecuritiesMember_InvestmentSecondaryCategorizationAxis_SecuritiesWithMaturityOfOneYearOrLessMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">383,870</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:AvailableForSaleDebtSecuritiesAccumulatedGrossUnrealizedGainBeforeTax" id="Fact_0c24393396f14a5fadd7e6d9dd062834" contextRef="c20211231_FinancialInstrumentAxis_CorporateDebtSecuritiesMember_InvestmentSecondaryCategorizationAxis_SecuritiesWithMaturityOfOneYearOrLessMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">728</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:AvailableForSaleDebtSecuritiesAccumulatedGrossUnrealizedLossBeforeTax" id="Fact_615e6981ef5c43e4afa6a302941c0754" contextRef="c20211231_FinancialInstrumentAxis_CorporateDebtSecuritiesMember_InvestmentSecondaryCategorizationAxis_SecuritiesWithMaturityOfOneYearOrLessMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">226</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:AvailableForSaleSecuritiesDebtSecurities" id="Fact_0a185c2049a6469e81e8e4df671bb2f5" contextRef="c20211231_FinancialInstrumentAxis_CorporateDebtSecuritiesMember_InvestmentSecondaryCategorizationAxis_SecuritiesWithMaturityOfOneYearOrLessMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">384,372</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 52%; background-color: #FFFFFF;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Debt securities issued by U.S. government agencies</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:AvailableForSaleDebtSecuritiesAmortizedCostBasis" id="Fact_c9d17af33c554c64ac738dfbdb48494c" contextRef="c20211231_FinancialInstrumentAxis_USGovernmentAgenciesDebtSecuritiesMember_InvestmentSecondaryCategorizationAxis_SecuritiesWithMaturityOfOneYearOrLessMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">48,493</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:AvailableForSaleDebtSecuritiesAccumulatedGrossUnrealizedGainBeforeTax" id="Fact_e61b3c1e7a7a45d7a7ce7d512404dfea" contextRef="c20211231_FinancialInstrumentAxis_USGovernmentAgenciesDebtSecuritiesMember_InvestmentSecondaryCategorizationAxis_SecuritiesWithMaturityOfOneYearOrLessMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">19</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:AvailableForSaleDebtSecuritiesAccumulatedGrossUnrealizedLossBeforeTax" id="Fact_8cd5ebaff4ff47b59a6f49c94f90f5e4" contextRef="c20211231_FinancialInstrumentAxis_USGovernmentAgenciesDebtSecuritiesMember_InvestmentSecondaryCategorizationAxis_SecuritiesWithMaturityOfOneYearOrLessMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">18</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:AvailableForSaleSecuritiesDebtSecurities" id="Fact_dc66d2f463f54767abee4fc4f62595f6" contextRef="c20211231_FinancialInstrumentAxis_USGovernmentAgenciesDebtSecuritiesMember_InvestmentSecondaryCategorizationAxis_SecuritiesWithMaturityOfOneYearOrLessMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">48,494</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 52%; background-color: #CCEEFF;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Debt securities issued by the U.S. Treasury (1)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:AvailableForSaleDebtSecuritiesAmortizedCostBasis" id="Fact_f00bcd75b4b842ec98fdc045c48c2576" contextRef="c20211231_FinancialInstrumentAxis_USTreasurySecuritiesMember_InvestmentSecondaryCategorizationAxis_SecuritiesWithMaturityOfOneYearOrLessMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">45,424</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:AvailableForSaleDebtSecuritiesAccumulatedGrossUnrealizedGainBeforeTax" id="Fact_d6b1880a34fc425f848f593694e21d3b" contextRef="c20211231_FinancialInstrumentAxis_USTreasurySecuritiesMember_InvestmentSecondaryCategorizationAxis_SecuritiesWithMaturityOfOneYearOrLessMember" unitRef="U001" decimals="-3" scale="3" format="ixt:zerodash">&#8212;</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:AvailableForSaleDebtSecuritiesAccumulatedGrossUnrealizedLossBeforeTax" id="Fact_52ee12eba4604cd6beb6d916ef074d49" contextRef="c20211231_FinancialInstrumentAxis_USTreasurySecuritiesMember_InvestmentSecondaryCategorizationAxis_SecuritiesWithMaturityOfOneYearOrLessMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">64</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:AvailableForSaleSecuritiesDebtSecurities" id="Fact_93f61f2dcaf249fe8c2941b0bedb2ad6" contextRef="c20211231_FinancialInstrumentAxis_USTreasurySecuritiesMember_InvestmentSecondaryCategorizationAxis_SecuritiesWithMaturityOfOneYearOrLessMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">45,360</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 52%; padding-bottom: 2px; background-color: #FFFFFF;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Debt securities issued by states of the U.S. and political subdivisions of the states</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:AvailableForSaleDebtSecuritiesAmortizedCostBasis" id="Fact_f17e37bd45aa4fdbae4827a34aa7dac9" contextRef="c20211231_FinancialInstrumentAxis_USStatesAndPoliticalSubdivisionsMember_InvestmentSecondaryCategorizationAxis_SecuritiesWithMaturityOfOneYearOrLessMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">134,770</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:AvailableForSaleDebtSecuritiesAccumulatedGrossUnrealizedGainBeforeTax" id="Fact_8da02b683fe94c99ae3334fe0583bcbf" contextRef="c20211231_FinancialInstrumentAxis_USStatesAndPoliticalSubdivisionsMember_InvestmentSecondaryCategorizationAxis_SecuritiesWithMaturityOfOneYearOrLessMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">45</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:AvailableForSaleDebtSecuritiesAccumulatedGrossUnrealizedLossBeforeTax" id="Fact_f5548b5e22d64358b14bff13c4cde745" contextRef="c20211231_FinancialInstrumentAxis_USStatesAndPoliticalSubdivisionsMember_InvestmentSecondaryCategorizationAxis_SecuritiesWithMaturityOfOneYearOrLessMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">37</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:AvailableForSaleSecuritiesDebtSecurities" id="Fact_5215ece6e8674be582ac13fad8e0e02f" contextRef="c20211231_FinancialInstrumentAxis_USStatesAndPoliticalSubdivisionsMember_InvestmentSecondaryCategorizationAxis_SecuritiesWithMaturityOfOneYearOrLessMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">134,778</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 52%; padding-bottom: 2px; background-color: #CCEEFF;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Total securities with a maturity of one year or less</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:AvailableForSaleDebtSecuritiesAmortizedCostBasis" id="Fact_06b37f3d76b24645b428aed40ef7519d" contextRef="c20211231_FinancialInstrumentAxis_DebtSecuritiesMember_InvestmentSecondaryCategorizationAxis_SecuritiesWithMaturityOfOneYearOrLessMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">612,557</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:AvailableForSaleDebtSecuritiesAccumulatedGrossUnrealizedGainBeforeTax" id="Fact_868aecd154b3411fad39ee7f067ae085" contextRef="c20211231_FinancialInstrumentAxis_DebtSecuritiesMember_InvestmentSecondaryCategorizationAxis_SecuritiesWithMaturityOfOneYearOrLessMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">792</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
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    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 52%; background-color: #FFFFFF;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Corporate debt securities</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:AvailableForSaleDebtSecuritiesAccumulatedGrossUnrealizedLossBeforeTax" id="Fact_4f2e99491c92483882c5013894e5a3b4" contextRef="c20211231_FinancialInstrumentAxis_CorporateDebtSecuritiesMember_InvestmentSecondaryCategorizationAxis_SecuritiesWithMaturityOfMoreThanOneYearMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">2,644</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:AvailableForSaleSecuritiesDebtSecurities" id="Fact_8078467ba1d947589f274b1470ccc8c7" contextRef="c20211231_FinancialInstrumentAxis_CorporateDebtSecuritiesMember_InvestmentSecondaryCategorizationAxis_SecuritiesWithMaturityOfMoreThanOneYearMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">379,687</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 52%; background-color: #CCEEFF;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Debt securities issued by U.S. government agencies</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:AvailableForSaleDebtSecuritiesAmortizedCostBasis" id="Fact_e4c79d28e0dd438c896e0c5148cdbae0" contextRef="c20211231_FinancialInstrumentAxis_USGovernmentAgenciesDebtSecuritiesMember_InvestmentSecondaryCategorizationAxis_SecuritiesWithMaturityOfMoreThanOneYearMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">72,935</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:AvailableForSaleDebtSecuritiesAccumulatedGrossUnrealizedGainBeforeTax" id="Fact_c3fb53b35b5e4f0a801fb17377bbe452" contextRef="c20211231_FinancialInstrumentAxis_USGovernmentAgenciesDebtSecuritiesMember_InvestmentSecondaryCategorizationAxis_SecuritiesWithMaturityOfMoreThanOneYearMember" unitRef="U001" decimals="-3" scale="3" format="ixt:zerodash">&#8212;</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:AvailableForSaleDebtSecuritiesAccumulatedGrossUnrealizedLossBeforeTax" id="Fact_f20247b6d2f84ccbbb1dbab68b9cd3d6" contextRef="c20211231_FinancialInstrumentAxis_USGovernmentAgenciesDebtSecuritiesMember_InvestmentSecondaryCategorizationAxis_SecuritiesWithMaturityOfMoreThanOneYearMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">561</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:AvailableForSaleSecuritiesDebtSecurities" id="Fact_a656c02b450b4ae39000dbd1d10a2d67" contextRef="c20211231_FinancialInstrumentAxis_USGovernmentAgenciesDebtSecuritiesMember_InvestmentSecondaryCategorizationAxis_SecuritiesWithMaturityOfMoreThanOneYearMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">72,374</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 52%; background-color: #FFFFFF;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Debt securities issued by the U.S. Treasury</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:AvailableForSaleDebtSecuritiesAmortizedCostBasis" id="Fact_160b2612c5ff403daa0b23ecdd2866db" contextRef="c20211231_FinancialInstrumentAxis_USTreasurySecuritiesMember_InvestmentSecondaryCategorizationAxis_SecuritiesWithMaturityOfMoreThanOneYearMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">137,635</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:AvailableForSaleDebtSecuritiesAccumulatedGrossUnrealizedGainBeforeTax" id="Fact_b1272ac8ac42497ba65853e630ea020a" contextRef="c20211231_FinancialInstrumentAxis_USTreasurySecuritiesMember_InvestmentSecondaryCategorizationAxis_SecuritiesWithMaturityOfMoreThanOneYearMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">139</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:AvailableForSaleDebtSecuritiesAccumulatedGrossUnrealizedLossBeforeTax" id="Fact_803581e2009f4b95bf2af6ab10413c74" contextRef="c20211231_FinancialInstrumentAxis_USTreasurySecuritiesMember_InvestmentSecondaryCategorizationAxis_SecuritiesWithMaturityOfMoreThanOneYearMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">500</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:AvailableForSaleSecuritiesDebtSecurities" id="Fact_32fdcfaa188c4467a9bc336b98ee4765" contextRef="c20211231_FinancialInstrumentAxis_USTreasurySecuritiesMember_InvestmentSecondaryCategorizationAxis_SecuritiesWithMaturityOfMoreThanOneYearMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">137,274</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 52%; background-color: #CCEEFF;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Debt securities issued by states of the U.S. and political subdivisions of the states</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:AvailableForSaleDebtSecuritiesAmortizedCostBasis" id="Fact_4ae16ba11af3451383afc794f381425b" contextRef="c20211231_FinancialInstrumentAxis_USStatesAndPoliticalSubdivisionsMember_InvestmentSecondaryCategorizationAxis_SecuritiesWithMaturityOfMoreThanOneYearMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">39,909</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:AvailableForSaleDebtSecuritiesAccumulatedGrossUnrealizedGainBeforeTax" id="Fact_fee237831c094d6db8d66deaea062f6b" contextRef="c20211231_FinancialInstrumentAxis_USStatesAndPoliticalSubdivisionsMember_InvestmentSecondaryCategorizationAxis_SecuritiesWithMaturityOfMoreThanOneYearMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">1</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:AvailableForSaleDebtSecuritiesAccumulatedGrossUnrealizedLossBeforeTax" id="Fact_b46d7b7d41284f92910e48dd0d37da98" contextRef="c20211231_FinancialInstrumentAxis_USStatesAndPoliticalSubdivisionsMember_InvestmentSecondaryCategorizationAxis_SecuritiesWithMaturityOfMoreThanOneYearMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">224</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:AvailableForSaleSecuritiesDebtSecurities" id="Fact_072a76897a5042d8befaddf252441541" contextRef="c20211231_FinancialInstrumentAxis_USStatesAndPoliticalSubdivisionsMember_InvestmentSecondaryCategorizationAxis_SecuritiesWithMaturityOfMoreThanOneYearMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">39,686</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 52%; padding-bottom: 2px; background-color: #FFFFFF;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Other municipal debt securities</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:AvailableForSaleDebtSecuritiesAmortizedCostBasis" id="Fact_6c8222f000a7424c8a7ed0bf8d85cff3" contextRef="c20211231_FinancialInstrumentAxis_OtherDebtSecuritiesMember_InvestmentSecondaryCategorizationAxis_SecuritiesWithMaturityOfMoreThanOneYearMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">6,136</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:AvailableForSaleDebtSecuritiesAccumulatedGrossUnrealizedGainBeforeTax" id="Fact_0062d9c59fee4f9ba9d6eb036a4bdb3d" contextRef="c20211231_FinancialInstrumentAxis_OtherDebtSecuritiesMember_InvestmentSecondaryCategorizationAxis_SecuritiesWithMaturityOfMoreThanOneYearMember" unitRef="U001" decimals="-3" scale="3" format="ixt:zerodash">&#8212;</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:AvailableForSaleDebtSecuritiesAccumulatedGrossUnrealizedLossBeforeTax" id="Fact_44ec9429331b405ea2219868b2cfdb87" contextRef="c20211231_FinancialInstrumentAxis_OtherDebtSecuritiesMember_InvestmentSecondaryCategorizationAxis_SecuritiesWithMaturityOfMoreThanOneYearMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">37</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:AvailableForSaleSecuritiesDebtSecurities" id="Fact_f56250cd9b734053925cfd136e9435fa" contextRef="c20211231_FinancialInstrumentAxis_OtherDebtSecuritiesMember_InvestmentSecondaryCategorizationAxis_SecuritiesWithMaturityOfMoreThanOneYearMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">6,099</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 52%; padding-bottom: 2px; background-color: #CCEEFF;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Total securities with a maturity of more than one year</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:AvailableForSaleDebtSecuritiesAmortizedCostBasis" id="Fact_b71803caad4d4886ad41f6bbc5e209f5" contextRef="c20211231_FinancialInstrumentAxis_DebtSecuritiesMember_InvestmentSecondaryCategorizationAxis_SecuritiesWithMaturityOfMoreThanOneYearMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">638,615</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:AvailableForSaleDebtSecuritiesAccumulatedGrossUnrealizedGainBeforeTax" id="Fact_8a0a49d9cc1e4c129249d0be27e415f2" contextRef="c20211231_FinancialInstrumentAxis_DebtSecuritiesMember_InvestmentSecondaryCategorizationAxis_SecuritiesWithMaturityOfMoreThanOneYearMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">471</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:AvailableForSaleDebtSecuritiesAccumulatedGrossUnrealizedLossBeforeTax" id="Fact_0ca92b9c73b2492aadcfbe4f82a50cb4" contextRef="c20211231_FinancialInstrumentAxis_DebtSecuritiesMember_InvestmentSecondaryCategorizationAxis_SecuritiesWithMaturityOfMoreThanOneYearMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">3,966</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:AvailableForSaleSecuritiesDebtSecurities" id="Fact_91167061047b48f4b8610c1a21447584" contextRef="c20211231_FinancialInstrumentAxis_DebtSecuritiesMember_InvestmentSecondaryCategorizationAxis_SecuritiesWithMaturityOfMoreThanOneYearMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">635,120</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 52%; padding-bottom: 2px; background-color: #FFFFFF;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Total available-for-sale securities</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:AvailableForSaleDebtSecuritiesAmortizedCostBasis" id="Fact_a5e37551797746d7832fc5653898ad64" contextRef="c20211231_FinancialInstrumentAxis_DebtSecuritiesMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">1,251,172</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:AvailableForSaleDebtSecuritiesAccumulatedGrossUnrealizedGainBeforeTax" id="Fact_5784263002924b25aff1cb14f626bf7f" contextRef="c20211231_FinancialInstrumentAxis_DebtSecuritiesMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">1,263</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:AvailableForSaleDebtSecuritiesAccumulatedGrossUnrealizedLossBeforeTax" id="Fact_7654b51ce0a5448fa1c5723b77e4a3cd" contextRef="c20211231_FinancialInstrumentAxis_DebtSecuritiesMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">4,311</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:AvailableForSaleSecuritiesDebtSecurities" id="Fact_fb3ebfc0325446129501360d15bf62ff" contextRef="c20211231_FinancialInstrumentAxis_DebtSecuritiesMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">1,248,124</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 52%; background-color: #CCEEFF;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Equity securities:</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 52%; background-color: #FFFFFF;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Total equity securities included in other current assets (2)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:EquitySecuritiesFvNiCost" id="Fact_cef09f69ddec4b3dabee2b4ce3e2377b" contextRef="c20211231_FinancialInstrumentAxis_EquitySecuritiesPubliclyTradedCompaniesMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">11,897</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:EquitySecuritiesFvNiUnrealizedGain" id="Fact_3f654be6d96e41e4b4713c77ccf1c8e3" contextRef="c20210101to20211231_FinancialInstrumentAxis_EquitySecuritiesPubliclyTradedCompaniesMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">7,145</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:EquitySecuritiesFvNiUnrealizedLoss" id="Fact_3d2a388042994347ab5102d669861a7d" contextRef="c20210101to20211231_FinancialInstrumentAxis_EquitySecuritiesPubliclyTradedCompaniesMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">837</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:EquitySecuritiesFvNi" id="Fact_2d87969d9ae34d49b910e43cebb1d676" contextRef="c20211231_FinancialInstrumentAxis_EquitySecuritiesPubliclyTradedCompaniesMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">18,205</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 52%; padding-bottom: 2px; background-color: #CCEEFF;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Total equity securities included in deposits and other assets (3)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:EquitySecuritiesFvNiCost" id="Fact_9ebd36323e384809b15acae0a3551932" contextRef="c20211231_FinancialInstrumentAxis_EquitySecuritiesPrivateCompaniesMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">15,615</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:EquitySecuritiesFvNiUnrealizedGain" id="Fact_aed73c2c4de9479b940ffa549e9fedd0" contextRef="c20210101to20211231_FinancialInstrumentAxis_EquitySecuritiesPrivateCompaniesMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">16,707</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:EquitySecuritiesFvNiUnrealizedLoss" id="Fact_1f1394dc79044e9197f515e0b7bca042" contextRef="c20210101to20211231_FinancialInstrumentAxis_EquitySecuritiesPrivateCompaniesMember" unitRef="U001" decimals="-3" scale="3" format="ixt:zerodash">&#8212;</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:EquitySecuritiesFvNi" id="Fact_acab1218ec2e41199e1b320128741143" contextRef="c20211231_FinancialInstrumentAxis_EquitySecuritiesPrivateCompaniesMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">32,322</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 52%; padding-bottom: 2px; background-color: #FFFFFF;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Total equity securities</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:EquitySecuritiesFvNiUnrealizedGain" id="Fact_c2b1f14b00d941b6b317ee97742c8d96" contextRef="c20210101to20211231_FinancialInstrumentAxis_EquitySecuritiesMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">23,852</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
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    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:EquitySecuritiesFvNiUnrealizedLoss" id="Fact_9d1928afc7224324b66d25fddff38253" contextRef="c20210101to20211231_FinancialInstrumentAxis_EquitySecuritiesMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">837</ix:nonFraction></div>
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
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    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:EquitySecuritiesFvNi" id="Fact_594521b1bd6241bea5eaec95f58271c0" contextRef="c20211231_FinancialInstrumentAxis_EquitySecuritiesMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">50,527</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 52%; padding-bottom: 4px; background-color: #CCEEFF;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Total available-for-sale and equity securities</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="ions:DebtSecuritiesAvailableForSaleAndEquitySecuritiesFvNiCost" id="Fact_afee4ce7ef954363a1010e810f1ae960" contextRef="c20211231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">1,278,684</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="ions:DebtSecuritiesAvailableForSaleAndEquitySecuritiesFvNiGrossUnrealizedGain" id="Fact_a346c4f456874316909407a757ecc1b7" contextRef="c20211231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">25,115</ix:nonFraction></div>
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="ions:DebtSecuritiesAvailableForSaleAndEquitySecuritiesFvNiGrossUnrealizedLoss" id="Fact_0bd6c064edff43c09905fc28e289473e" contextRef="c20211231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">5,148</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="ions:DebtSecuritiesAvailableForSaleAndEquitySecuritiesFvNi" id="Fact_f35d561e61484f2295cadeeb2d03bdbd" contextRef="c20211231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">1,298,651</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>


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<div><br />
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</ix:continuation></ix:continuation>
  <ix:continuation id="Text_84765f4c1362403c9feaa38f9187754f16" continuedAt="Text_84765f4c1362403c9feaa38f9187754f17"><ix:continuation id="Text_2f47b7d9951c4dc597b770da2e1648134" continuedAt="Text_2f47b7d9951c4dc597b770da2e1648135">
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  <tr>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">

        </td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="2">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Amortized</div>
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" colspan="6">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Gross Unrealized</div>
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="2">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Estimated</div>
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

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    <td valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">December 31, 2020</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" colspan="2">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"> Cost</div>
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" colspan="2">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Gains</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" colspan="2">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Losses</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" colspan="2">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Fair Value</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Available-for-sale securities:</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="2">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="2">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="2">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="2">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 52%; background-color: #CCEEFF;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Corporate debt securities (1)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:AvailableForSaleDebtSecuritiesAmortizedCostBasis" id="Fact_8ea119980dc64034994a6b7ad86f848c" contextRef="c20201231_FinancialInstrumentAxis_CorporateDebtSecuritiesMember_InvestmentSecondaryCategorizationAxis_SecuritiesWithMaturityOfOneYearOrLessMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">514,182</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:AvailableForSaleDebtSecuritiesAccumulatedGrossUnrealizedGainBeforeTax" id="Fact_6df2fbe2752e4bd0bb77abf8abe0ae29" contextRef="c20201231_FinancialInstrumentAxis_CorporateDebtSecuritiesMember_InvestmentSecondaryCategorizationAxis_SecuritiesWithMaturityOfOneYearOrLessMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">2,194</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:AvailableForSaleDebtSecuritiesAccumulatedGrossUnrealizedLossBeforeTax" id="Fact_73421ff544c5487b9e733e95b060b569" contextRef="c20201231_FinancialInstrumentAxis_CorporateDebtSecuritiesMember_InvestmentSecondaryCategorizationAxis_SecuritiesWithMaturityOfOneYearOrLessMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">41</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:AvailableForSaleSecuritiesDebtSecurities" id="Fact_c85091a5a55a45a881f09b4c8c70a29c" contextRef="c20201231_FinancialInstrumentAxis_CorporateDebtSecuritiesMember_InvestmentSecondaryCategorizationAxis_SecuritiesWithMaturityOfOneYearOrLessMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">516,335</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 52%; background-color: #FFFFFF;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Debt securities issued by U.S. government agencies</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:AvailableForSaleDebtSecuritiesAmortizedCostBasis" id="Fact_da1b311c89004135b55ecee7befa549d" contextRef="c20201231_FinancialInstrumentAxis_USGovernmentAgenciesDebtSecuritiesMember_InvestmentSecondaryCategorizationAxis_SecuritiesWithMaturityOfOneYearOrLessMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">94,234</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:AvailableForSaleDebtSecuritiesAccumulatedGrossUnrealizedGainBeforeTax" id="Fact_6c6ca7c3257b46848b5da442e9d2b424" contextRef="c20201231_FinancialInstrumentAxis_USGovernmentAgenciesDebtSecuritiesMember_InvestmentSecondaryCategorizationAxis_SecuritiesWithMaturityOfOneYearOrLessMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">354</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:AvailableForSaleDebtSecuritiesAccumulatedGrossUnrealizedLossBeforeTax" id="Fact_f8696120bd5749f081186004728dcfec" contextRef="c20201231_FinancialInstrumentAxis_USGovernmentAgenciesDebtSecuritiesMember_InvestmentSecondaryCategorizationAxis_SecuritiesWithMaturityOfOneYearOrLessMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">2</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;" colspan="1">
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 52%; background-color: #CCEEFF;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Debt securities issued by the U.S. Treasury (1)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:AvailableForSaleDebtSecuritiesAccumulatedGrossUnrealizedGainBeforeTax" id="Fact_2d25c6a792494377addd272a5b8dded6" contextRef="c20201231_FinancialInstrumentAxis_USTreasurySecuritiesMember_InvestmentSecondaryCategorizationAxis_SecuritiesWithMaturityOfOneYearOrLessMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">233</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:AvailableForSaleDebtSecuritiesAccumulatedGrossUnrealizedLossBeforeTax" id="Fact_f56cc4d0d90d4e7fbb8f72585969858c" contextRef="c20201231_FinancialInstrumentAxis_USTreasurySecuritiesMember_InvestmentSecondaryCategorizationAxis_SecuritiesWithMaturityOfOneYearOrLessMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">9</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 52%; background-color: #FFFFFF;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Debt securities issued by states of the U.S. and political subdivisions of the states</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:AvailableForSaleDebtSecuritiesAmortizedCostBasis" id="Fact_2665cd241db44217ad8643b9ae2a63da" contextRef="c20201231_FinancialInstrumentAxis_USStatesAndPoliticalSubdivisionsMember_InvestmentSecondaryCategorizationAxis_SecuritiesWithMaturityOfOneYearOrLessMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">104,271</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:AvailableForSaleDebtSecuritiesAccumulatedGrossUnrealizedGainBeforeTax" id="Fact_5244a18f7849464e8277366dd5790037" contextRef="c20201231_FinancialInstrumentAxis_USStatesAndPoliticalSubdivisionsMember_InvestmentSecondaryCategorizationAxis_SecuritiesWithMaturityOfOneYearOrLessMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">196</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:AvailableForSaleDebtSecuritiesAccumulatedGrossUnrealizedLossBeforeTax" id="Fact_703babc31466440681b56330914ed672" contextRef="c20201231_FinancialInstrumentAxis_USStatesAndPoliticalSubdivisionsMember_InvestmentSecondaryCategorizationAxis_SecuritiesWithMaturityOfOneYearOrLessMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">12</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:AvailableForSaleSecuritiesDebtSecurities" id="Fact_8732df0d6eac436fa8da11aab067289a" contextRef="c20201231_FinancialInstrumentAxis_USStatesAndPoliticalSubdivisionsMember_InvestmentSecondaryCategorizationAxis_SecuritiesWithMaturityOfOneYearOrLessMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">104,455</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 52%; padding-bottom: 2px; background-color: #CCEEFF;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Other municipal debt securities</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:AvailableForSaleDebtSecuritiesAmortizedCostBasis" id="Fact_ecf91cd4117845cabfdc77d8448a9048" contextRef="c20201231_FinancialInstrumentAxis_OtherDebtSecuritiesMember_InvestmentSecondaryCategorizationAxis_SecuritiesWithMaturityOfOneYearOrLessMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">5,191</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:AvailableForSaleDebtSecuritiesAccumulatedGrossUnrealizedGainBeforeTax" id="Fact_e226e0128b44452490ef8f8e9bda0da3" contextRef="c20201231_FinancialInstrumentAxis_OtherDebtSecuritiesMember_InvestmentSecondaryCategorizationAxis_SecuritiesWithMaturityOfOneYearOrLessMember" unitRef="U001" decimals="-3" scale="3" format="ixt:zerodash">&#8212;</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:AvailableForSaleDebtSecuritiesAccumulatedGrossUnrealizedLossBeforeTax" id="Fact_6fce9d4bd430460aa19316ba18bd6833" contextRef="c20201231_FinancialInstrumentAxis_OtherDebtSecuritiesMember_InvestmentSecondaryCategorizationAxis_SecuritiesWithMaturityOfOneYearOrLessMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">7</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:AvailableForSaleSecuritiesDebtSecurities" id="Fact_4961b9925b4f49b79858c21a5bc59ede" contextRef="c20201231_FinancialInstrumentAxis_OtherDebtSecuritiesMember_InvestmentSecondaryCategorizationAxis_SecuritiesWithMaturityOfOneYearOrLessMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">5,184</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 52%; padding-bottom: 2px; background-color: #FFFFFF;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Total securities with a maturity of one year or less</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:AvailableForSaleDebtSecuritiesAmortizedCostBasis" id="Fact_f91f4bf7895e4255b6fb1606547e04c4" contextRef="c20201231_FinancialInstrumentAxis_DebtSecuritiesMember_InvestmentSecondaryCategorizationAxis_SecuritiesWithMaturityOfOneYearOrLessMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">1,025,454</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:AvailableForSaleDebtSecuritiesAccumulatedGrossUnrealizedGainBeforeTax" id="Fact_58f014330e0d46f68ac56681d9bcc775" contextRef="c20201231_FinancialInstrumentAxis_DebtSecuritiesMember_InvestmentSecondaryCategorizationAxis_SecuritiesWithMaturityOfOneYearOrLessMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">2,977</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:AvailableForSaleDebtSecuritiesAccumulatedGrossUnrealizedLossBeforeTax" id="Fact_4d687e924d2549c292e3b98c471a8b1c" contextRef="c20201231_FinancialInstrumentAxis_DebtSecuritiesMember_InvestmentSecondaryCategorizationAxis_SecuritiesWithMaturityOfOneYearOrLessMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">71</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:AvailableForSaleSecuritiesDebtSecurities" id="Fact_5b653caa5875494f883c075c43b1bf5c" contextRef="c20201231_FinancialInstrumentAxis_DebtSecuritiesMember_InvestmentSecondaryCategorizationAxis_SecuritiesWithMaturityOfOneYearOrLessMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">1,028,360</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 52%; background-color: #CCEEFF;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Corporate debt securities</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:AvailableForSaleDebtSecuritiesAmortizedCostBasis" id="Fact_90b66da8071a4a14ae79ae20e35a4725" contextRef="c20201231_FinancialInstrumentAxis_CorporateDebtSecuritiesMember_InvestmentSecondaryCategorizationAxis_SecuritiesWithMaturityOfMoreThanOneYearMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">325,079</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:AvailableForSaleDebtSecuritiesAccumulatedGrossUnrealizedGainBeforeTax" id="Fact_6969869c8ab34390a5923698c47c72bb" contextRef="c20201231_FinancialInstrumentAxis_CorporateDebtSecuritiesMember_InvestmentSecondaryCategorizationAxis_SecuritiesWithMaturityOfMoreThanOneYearMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">4,941</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:AvailableForSaleDebtSecuritiesAccumulatedGrossUnrealizedLossBeforeTax" id="Fact_fa5a358807714f81a4468c02e061a381" contextRef="c20201231_FinancialInstrumentAxis_CorporateDebtSecuritiesMember_InvestmentSecondaryCategorizationAxis_SecuritiesWithMaturityOfMoreThanOneYearMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">40</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 52%; background-color: #FFFFFF;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Debt securities issued by U.S. government agencies</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:AvailableForSaleDebtSecuritiesAccumulatedGrossUnrealizedLossBeforeTax" id="Fact_6dd609ef5c9d4c5abd47201f2f3c3971" contextRef="c20201231_FinancialInstrumentAxis_USGovernmentAgenciesDebtSecuritiesMember_InvestmentSecondaryCategorizationAxis_SecuritiesWithMaturityOfMoreThanOneYearMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">9</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF; white-space: nowrap;" colspan="1">
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        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 52%; background-color: #CCEEFF;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Debt securities issued by the U.S. Treasury</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:AvailableForSaleDebtSecuritiesAccumulatedGrossUnrealizedGainBeforeTax" id="Fact_9e774f36b3824b5da1f596ef542f70e8" contextRef="c20201231_FinancialInstrumentAxis_USTreasurySecuritiesMember_InvestmentSecondaryCategorizationAxis_SecuritiesWithMaturityOfMoreThanOneYearMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">383</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:AvailableForSaleDebtSecuritiesAccumulatedGrossUnrealizedLossBeforeTax" id="Fact_fcf3826f90e44039b289f8286697222d" contextRef="c20201231_FinancialInstrumentAxis_USTreasurySecuritiesMember_InvestmentSecondaryCategorizationAxis_SecuritiesWithMaturityOfMoreThanOneYearMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">4</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:AvailableForSaleSecuritiesDebtSecurities" id="Fact_3834f60c806146fdb57604df4ca44d5f" contextRef="c20201231_FinancialInstrumentAxis_USTreasurySecuritiesMember_InvestmentSecondaryCategorizationAxis_SecuritiesWithMaturityOfMoreThanOneYearMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">50,697</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 52%; background-color: #FFFFFF;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Debt securities issued by states of the U.S. and political subdivisions of the states</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:AvailableForSaleDebtSecuritiesAmortizedCostBasis" id="Fact_3b50fc36268c472c83543a498f74c6a3" contextRef="c20201231_FinancialInstrumentAxis_USStatesAndPoliticalSubdivisionsMember_InvestmentSecondaryCategorizationAxis_SecuritiesWithMaturityOfMoreThanOneYearMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">31,779</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:AvailableForSaleDebtSecuritiesAccumulatedGrossUnrealizedGainBeforeTax" id="Fact_3cc6fe9c6c684eabbb359b5b57a83381" contextRef="c20201231_FinancialInstrumentAxis_USStatesAndPoliticalSubdivisionsMember_InvestmentSecondaryCategorizationAxis_SecuritiesWithMaturityOfMoreThanOneYearMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">91</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:AvailableForSaleDebtSecuritiesAccumulatedGrossUnrealizedLossBeforeTax" id="Fact_f9f79be238454b459039ee2cf29f6635" contextRef="c20201231_FinancialInstrumentAxis_USStatesAndPoliticalSubdivisionsMember_InvestmentSecondaryCategorizationAxis_SecuritiesWithMaturityOfMoreThanOneYearMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">16</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:AvailableForSaleSecuritiesDebtSecurities" id="Fact_285a93f311de42a8b8b01192c7d0cee6" contextRef="c20201231_FinancialInstrumentAxis_USStatesAndPoliticalSubdivisionsMember_InvestmentSecondaryCategorizationAxis_SecuritiesWithMaturityOfMoreThanOneYearMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">31,854</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 52%; padding-bottom: 2px; background-color: #CCEEFF;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Other municipal debt securities</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:AvailableForSaleDebtSecuritiesAmortizedCostBasis" id="Fact_4bf9121fc0804d5798d1a6289635f5d9" contextRef="c20201231_FinancialInstrumentAxis_OtherDebtSecuritiesMember_InvestmentSecondaryCategorizationAxis_SecuritiesWithMaturityOfMoreThanOneYearMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">1,041</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:AvailableForSaleDebtSecuritiesAccumulatedGrossUnrealizedGainBeforeTax" id="Fact_f437f12df65d447e97fa0d457cb8cef8" contextRef="c20201231_FinancialInstrumentAxis_OtherDebtSecuritiesMember_InvestmentSecondaryCategorizationAxis_SecuritiesWithMaturityOfMoreThanOneYearMember" unitRef="U001" decimals="-3" scale="3" format="ixt:zerodash">&#8212;</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:AvailableForSaleDebtSecuritiesAccumulatedGrossUnrealizedLossBeforeTax" id="Fact_c0f6ebbcda8044b09f9d090885923686" contextRef="c20201231_FinancialInstrumentAxis_OtherDebtSecuritiesMember_InvestmentSecondaryCategorizationAxis_SecuritiesWithMaturityOfMoreThanOneYearMember" unitRef="U001" decimals="-3" scale="3" format="ixt:zerodash">&#8212;</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:AvailableForSaleSecuritiesDebtSecurities" id="Fact_c14671d2b253484ead01fa457d0f93ee" contextRef="c20201231_FinancialInstrumentAxis_OtherDebtSecuritiesMember_InvestmentSecondaryCategorizationAxis_SecuritiesWithMaturityOfMoreThanOneYearMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">1,041</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 52%; padding-bottom: 2px; background-color: #FFFFFF;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Total securities with a maturity of more than one year</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:AvailableForSaleDebtSecuritiesAmortizedCostBasis" id="Fact_be05404e83c643348777fa91b0e1b9ba" contextRef="c20201231_FinancialInstrumentAxis_DebtSecuritiesMember_InvestmentSecondaryCategorizationAxis_SecuritiesWithMaturityOfMoreThanOneYearMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">488,316</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:AvailableForSaleDebtSecuritiesAccumulatedGrossUnrealizedGainBeforeTax" id="Fact_80c5acbabb8c4f0bb30f07636779a6ef" contextRef="c20201231_FinancialInstrumentAxis_DebtSecuritiesMember_InvestmentSecondaryCategorizationAxis_SecuritiesWithMaturityOfMoreThanOneYearMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">5,600</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:AvailableForSaleDebtSecuritiesAccumulatedGrossUnrealizedLossBeforeTax" id="Fact_2d2b1cb797c643148d37d334e933eeb2" contextRef="c20201231_FinancialInstrumentAxis_DebtSecuritiesMember_InvestmentSecondaryCategorizationAxis_SecuritiesWithMaturityOfMoreThanOneYearMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">69</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:AvailableForSaleSecuritiesDebtSecurities" id="Fact_2bbc29a667a94cb99ff6c9f040ebeea6" contextRef="c20201231_FinancialInstrumentAxis_DebtSecuritiesMember_InvestmentSecondaryCategorizationAxis_SecuritiesWithMaturityOfMoreThanOneYearMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">493,847</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 52%; padding-bottom: 2px; background-color: #CCEEFF;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Total available-for-sale securities</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:AvailableForSaleDebtSecuritiesAmortizedCostBasis" id="Fact_8caafd476a3541b9aef7c098cc041e94" contextRef="c20201231_FinancialInstrumentAxis_DebtSecuritiesMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">1,513,770</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:AvailableForSaleDebtSecuritiesAccumulatedGrossUnrealizedGainBeforeTax" id="Fact_609132a66d2f4130b140a88c2fb0c89d" contextRef="c20201231_FinancialInstrumentAxis_DebtSecuritiesMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">8,577</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:AvailableForSaleDebtSecuritiesAccumulatedGrossUnrealizedLossBeforeTax" id="Fact_b09e4761e6054b25a622ed40b8db284e" contextRef="c20201231_FinancialInstrumentAxis_DebtSecuritiesMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">140</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:AvailableForSaleSecuritiesDebtSecurities" id="Fact_4de7d9b3be6d447db4b3c3fe0b8f036b" contextRef="c20201231_FinancialInstrumentAxis_DebtSecuritiesMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">1,522,207</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 52%; background-color: #FFFFFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Equity securities:</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 52%; background-color: #CCEEFF;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Total equity securities included in other current assets (2)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:EquitySecuritiesFvNiCost" id="Fact_ddb646a5d0f1447b92caf9f07a627fcd" contextRef="c20201231_FinancialInstrumentAxis_EquitySecuritiesPubliclyTradedCompaniesMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">4,712</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:EquitySecuritiesFvNiUnrealizedGain" id="Fact_88ed4a2745c54e14a622755a003ef7d5" contextRef="c20200101to20201231_FinancialInstrumentAxis_EquitySecuritiesPubliclyTradedCompaniesMember" unitRef="U001" decimals="-3" scale="3" format="ixt:zerodash">&#8212;</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:EquitySecuritiesFvNiUnrealizedLoss" id="Fact_b4cdd38512ef47d9b5d3df0de25143e1" contextRef="c20200101to20201231_FinancialInstrumentAxis_EquitySecuritiesPubliclyTradedCompaniesMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">2,681</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:EquitySecuritiesFvNi" id="Fact_c71d4b805e374b9696b1907d0c3b8708" contextRef="c20201231_FinancialInstrumentAxis_EquitySecuritiesPubliclyTradedCompaniesMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">2,031</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 52%; padding-bottom: 2px; background-color: #FFFFFF;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Total equity securities included in deposits and other assets (3)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:EquitySecuritiesFvNiCost" id="Fact_fd07a2a1606f48d78bc5fb285d90a137" contextRef="c20201231_FinancialInstrumentAxis_EquitySecuritiesPrivateCompaniesMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">15,062</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:EquitySecuritiesFvNiUnrealizedGain" id="Fact_f166a5e138d3457b82d04bfee0b2aaa8" contextRef="c20200101to20201231_FinancialInstrumentAxis_EquitySecuritiesPrivateCompaniesMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">15,938</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:EquitySecuritiesFvNiUnrealizedLoss" id="Fact_377148fd543d4bcd9b069e1883f63342" contextRef="c20200101to20201231_FinancialInstrumentAxis_EquitySecuritiesPrivateCompaniesMember" unitRef="U001" decimals="-3" scale="3" format="ixt:zerodash">&#8212;</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:EquitySecuritiesFvNi" id="Fact_250e88ec455a48818d6c542e743f1801" contextRef="c20201231_FinancialInstrumentAxis_EquitySecuritiesPrivateCompaniesMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">31,000</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 52%; padding-bottom: 2px; background-color: #CCEEFF;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Total equity securities</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:EquitySecuritiesFvNiCost" id="Fact_8cbb173fbf424d2cae5761cfe86aa386" contextRef="c20201231_FinancialInstrumentAxis_EquitySecuritiesMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">19,774</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:EquitySecuritiesFvNiUnrealizedGain" id="Fact_c7bf32577ac44c999892ccbf176d194e" contextRef="c20200101to20201231_FinancialInstrumentAxis_EquitySecuritiesMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">15,938</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:EquitySecuritiesFvNiUnrealizedLoss" id="Fact_7050ac2adf394b31b986c11c8b0618f6" contextRef="c20200101to20201231_FinancialInstrumentAxis_EquitySecuritiesMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">2,681</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:EquitySecuritiesFvNi" id="Fact_b3f9adef6e924b3c91c0bc0573208fed" contextRef="c20201231_FinancialInstrumentAxis_EquitySecuritiesMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">33,031</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 52%; padding-bottom: 4px; background-color: #FFFFFF;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Total available-for-sale and equity securities</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="ions:DebtSecuritiesAvailableForSaleAndEquitySecuritiesFvNiCost" id="Fact_c31aca2dbed748588049458efeea09a7" contextRef="c20201231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">1,533,544</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="ions:DebtSecuritiesAvailableForSaleAndEquitySecuritiesFvNiGrossUnrealizedGain" id="Fact_c255d1502e344319b6e94f49f85ceeb8" contextRef="c20201231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">24,515</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="ions:DebtSecuritiesAvailableForSaleAndEquitySecuritiesFvNiGrossUnrealizedLoss" id="Fact_442681fd5f144b86afca5af925fffb02" contextRef="c20201231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">2,821</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="ions:DebtSecuritiesAvailableForSaleAndEquitySecuritiesFvNi" id="Fact_59bf550c30564d83b459e349c7ec3c12" contextRef="c20201231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">1,555,238</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>


</table>
</ix:continuation></ix:continuation>
  <ix:continuation id="Text_84765f4c1362403c9feaa38f9187754f17" continuedAt="Text_84765f4c1362403c9feaa38f9187754f18"><ix:continuation id="Text_2f47b7d9951c4dc597b770da2e1648135" continuedAt="Text_2f47b7d9951c4dc597b770da2e1648136">
<div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">________________</div>
</ix:continuation></ix:continuation>
  <ix:continuation id="Text_84765f4c1362403c9feaa38f9187754f18" continuedAt="Text_84765f4c1362403c9feaa38f9187754f19"><ix:continuation id="Text_2f47b7d9951c4dc597b770da2e1648136" continuedAt="Text_2f47b7d9951c4dc597b770da2e1648137">
<table cellspacing="0" cellpadding="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">


  <tr>

    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(1)</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:footnote id="Foot_88fe67a8cca841eaa8660167eec626fe" footnoteRole="http://www.xbrl.org/2003/role/footnote" xml:lang="en-US">Includes investments classified
            as cash equivalents on our consolidated balance sheet.</ix:footnote></div>
        </td>

  </tr>


</table>
</ix:continuation></ix:continuation>
  <ix:continuation id="Text_84765f4c1362403c9feaa38f9187754f19" continuedAt="Text_84765f4c1362403c9feaa38f9187754f20"><ix:continuation id="Text_2f47b7d9951c4dc597b770da2e1648137" continuedAt="Text_2f47b7d9951c4dc597b770da2e1648138">
<div><br />
  </div>
</ix:continuation></ix:continuation>
  <ix:continuation id="Text_84765f4c1362403c9feaa38f9187754f20" continuedAt="Text_84765f4c1362403c9feaa38f9187754f21"><ix:continuation id="Text_2f47b7d9951c4dc597b770da2e1648138" continuedAt="Text_2f47b7d9951c4dc597b770da2e1648139">
<table cellspacing="0" cellpadding="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">


  <tr>

    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(2)</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:footnote id="Foot_33f87045331d4d29a03153170558d0a1" footnoteRole="http://www.xbrl.org/2003/role/footnote" xml:lang="en-US">Our equity securities included in other current
            assets consisted of our investments in publicly traded companies. We recognize publicly traded equity securities at fair value.</ix:footnote></div>
        </td>

  </tr>


</table>
</ix:continuation></ix:continuation>
  <ix:continuation id="Text_84765f4c1362403c9feaa38f9187754f21" continuedAt="Text_84765f4c1362403c9feaa38f9187754f22"><ix:continuation id="Text_2f47b7d9951c4dc597b770da2e1648139" continuedAt="Text_2f47b7d9951c4dc597b770da2e16481310">
<div><br />
  </div>
</ix:continuation></ix:continuation>
  <ix:continuation id="Text_84765f4c1362403c9feaa38f9187754f22" continuedAt="Text_84765f4c1362403c9feaa38f9187754f23"><ix:continuation id="Text_2f47b7d9951c4dc597b770da2e16481310">
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  <tr>

    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(3)</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:footnote id="Foot_92f3ab0ee45a44b9baf44a6e4c6792b4" footnoteRole="http://www.xbrl.org/2003/role/footnote" xml:lang="en-US"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">Our equity securities included in deposits and other assets consisted of our investments in privately held companies. We recognize our private company equity securities at</span> cost minus
            impairments, plus or minus changes resulting from observable price changes in orderly transactions for the identical or similar investment of the same issuer<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> on our consolidated balance sheet.</span></ix:footnote></div>
        </td>

  </tr>


</table>
</ix:continuation></ix:continuation>

  <ix:continuation id="Text_84765f4c1362403c9feaa38f9187754f23" continuedAt="Text_84765f4c1362403c9feaa38f9187754f24">
<div><br />
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</ix:continuation></div>

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    </div>

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<div><ix:continuation id="Text_84765f4c1362403c9feaa38f9187754f24" continuedAt="Text_84765f4c1362403c9feaa38f9187754f25"><ix:nonNumeric name="us-gaap:ScheduleOfTemporaryImpairmentLossesInvestmentsTableTextBlock" id="Text_abfd8de3bb27493b80611f0ca9f4f478" contextRef="c20210101to20211231" escape="true" continuedAt="Text_096bee6f46b14fa5afb682a75f17d9a81">
<div style="display:none;"><br /></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">The following is a summary of our investments we
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</ix:nonNumeric></ix:continuation>

  <ix:continuation id="Text_84765f4c1362403c9feaa38f9187754f25" continuedAt="Text_84765f4c1362403c9feaa38f9187754f26"><ix:continuation id="Text_096bee6f46b14fa5afb682a75f17d9a81" continuedAt="Text_096bee6f46b14fa5afb682a75f17d9a82">
<div><br />
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</ix:continuation></ix:continuation>
  <ix:continuation id="Text_84765f4c1362403c9feaa38f9187754f26"><ix:continuation id="Text_096bee6f46b14fa5afb682a75f17d9a82">
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        </td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" colspan="2">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Number of</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Investments</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" colspan="2">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Estimated</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Fair Value</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" colspan="2">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Unrealized</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Losses</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Corporate debt securities</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:DebtSecuritiesAvailableForSaleContinuousUnrealizedLossPositionLessThan12MonthsNumberOfPositions" id="Fact_94c41655616442318f0eb4d43b10e5ce" contextRef="c20211231_FinancialInstrumentAxis_CorporateDebtSecuritiesMember" unitRef="U010" decimals="0" scale="0" format="ixt:numdotdecimal">272</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:DebtSecuritiesAvailableForSaleContinuousUnrealizedLossPositionLessThan12Months" id="Fact_ce6c4ad116a04f9d89623a17bcc4391c" contextRef="c20211231_FinancialInstrumentAxis_CorporateDebtSecuritiesMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">552,966</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:DebtSecuritiesAvailableForSaleContinuousUnrealizedLossPositionLessThan12MonthsAccumulatedLoss" id="Fact_fa10abad216d4c6da9bf72c7cc3485ff" contextRef="c20211231_FinancialInstrumentAxis_CorporateDebtSecuritiesMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">2,870</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 64%;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Debt securities issued by U.S. government agencies</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:DebtSecuritiesAvailableForSaleContinuousUnrealizedLossPositionLessThan12MonthsNumberOfPositions" id="Fact_ba4eff286d094d0a82097b0d8a2aefbf" contextRef="c20211231_FinancialInstrumentAxis_USGovernmentAgenciesDebtSecuritiesMember" unitRef="U010" decimals="0" scale="0" format="ixt:numdotdecimal">15</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:DebtSecuritiesAvailableForSaleContinuousUnrealizedLossPositionLessThan12Months" id="Fact_36af76ee871346e68734d17c0f514d52" contextRef="c20211231_FinancialInstrumentAxis_USGovernmentAgenciesDebtSecuritiesMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">114,338</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:DebtSecuritiesAvailableForSaleContinuousUnrealizedLossPositionLessThan12MonthsAccumulatedLoss" id="Fact_511907af62b14106b1ac379c59cc762d" contextRef="c20211231_FinancialInstrumentAxis_USGovernmentAgenciesDebtSecuritiesMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">579</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Debt securities issued by the U.S. Treasury</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:DebtSecuritiesAvailableForSaleContinuousUnrealizedLossPositionLessThan12MonthsNumberOfPositions" id="Fact_8f2e7e03a88b48c2b6bfc8963d606d50" contextRef="c20211231_FinancialInstrumentAxis_USTreasurySecuritiesMember" unitRef="U010" decimals="0" scale="0" format="ixt:numdotdecimal">13</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:DebtSecuritiesAvailableForSaleContinuousUnrealizedLossPositionLessThan12Months" id="Fact_67e968a239d94bb1b4b117a2ba2ef024" contextRef="c20211231_FinancialInstrumentAxis_USTreasurySecuritiesMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">134,987</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:DebtSecuritiesAvailableForSaleContinuousUnrealizedLossPositionLessThan12MonthsAccumulatedLoss" id="Fact_d0c424847f4d498bb855cdcb5d6789bc" contextRef="c20211231_FinancialInstrumentAxis_USTreasurySecuritiesMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">564</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 64%;">
          <div style="text-align: left; text-indent: -11.2pt; margin-left: 11.2pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Debt securities issued by states of the U.S. and political subdivisions of the states</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #CCEEFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Other municipal debt securities</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:DebtSecuritiesAvailableForSaleContinuousUnrealizedLossPositionLessThan12MonthsNumberOfPositions" id="Fact_eafb10674c5e4a76bc786310722908c2" contextRef="c20211231_FinancialInstrumentAxis_OtherDebtSecuritiesMember" unitRef="U010" decimals="0" scale="0" format="ixt:numdotdecimal">2</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:DebtSecuritiesAvailableForSaleContinuousUnrealizedLossPositionLessThan12Months" id="Fact_6459f8275dbd4a13893be78638ce34c7" contextRef="c20211231_FinancialInstrumentAxis_OtherDebtSecuritiesMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">6,099</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:DebtSecuritiesAvailableForSaleContinuousUnrealizedLossPositionLessThan12MonthsAccumulatedLoss" id="Fact_251f3241197c4358963f5bbb05ed251a" contextRef="c20211231_FinancialInstrumentAxis_OtherDebtSecuritiesMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">37</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 4px;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Total temporarily impaired securities</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:DebtSecuritiesAvailableForSaleContinuousUnrealizedLossPositionLessThan12MonthsNumberOfPositions" id="Fact_ff24bcdcc05442fc8d76b39092f8152c" contextRef="c20211231" unitRef="U010" decimals="0" scale="0" format="ixt:numdotdecimal">727</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:DebtSecuritiesAvailableForSaleContinuousUnrealizedLossPositionLessThan12Months" id="Fact_79754104b6c64388ae4f4c5345eb981e" contextRef="c20211231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">934,791</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:DebtSecuritiesAvailableForSaleContinuousUnrealizedLossPositionLessThan12MonthsAccumulatedLoss" id="Fact_e3604e2d48b04951b8b24655723cbb78" contextRef="c20211231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">4,311</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

  </tr>


</table>
</ix:continuation></ix:continuation></div>

  <div style="text-align: left;"><br />
  </div>
<div><ix:nonNumeric name="us-gaap:DebtDisclosureTextBlock" id="Text_1f7799e29d9c4fd5ac2c30d64ad9a625" contextRef="c20210101to20211231" escape="true" continuedAt="Text_60d2e5dcb36e4dffa7326e0e2cb603a01">
<div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">3. Long-Term Obligations and Commitments</div>
</ix:nonNumeric>

  <ix:continuation id="Text_60d2e5dcb36e4dffa7326e0e2cb603a01" continuedAt="Text_60d2e5dcb36e4dffa7326e0e2cb603a02">
<div><br />
  </div>
</ix:continuation>
  <ix:continuation id="Text_60d2e5dcb36e4dffa7326e0e2cb603a02" continuedAt="Text_60d2e5dcb36e4dffa7326e0e2cb603a03"><ix:nonNumeric name="us-gaap:ScheduleOfDebtInstrumentsTextBlock" id="Text_487975f5bd5542cbb02179bbd1a60f54" contextRef="c20210101to20211231" escape="true" continuedAt="Text_128f7acaa3b64611a059339846d76ec51">
<div style="display:none;"><br /></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">The carrying value of our long-term obligations was as follows (in thousands):</div>
</ix:nonNumeric></ix:continuation>
  <ix:continuation id="Text_60d2e5dcb36e4dffa7326e0e2cb603a03" continuedAt="Text_60d2e5dcb36e4dffa7326e0e2cb603a04"><ix:continuation id="Text_128f7acaa3b64611a059339846d76ec51" continuedAt="Text_128f7acaa3b64611a059339846d76ec52">
<div><br />
  </div>
</ix:continuation></ix:continuation>
  <ix:continuation id="Text_60d2e5dcb36e4dffa7326e0e2cb603a04" continuedAt="Text_60d2e5dcb36e4dffa7326e0e2cb603a05"><ix:continuation id="Text_128f7acaa3b64611a059339846d76ec52" continuedAt="Text_128f7acaa3b64611a059339846d76ec53">
<table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;" class="cfttable">


  <tr>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">

        </td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" colspan="6">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">December 31,</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" colspan="2">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2021</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" colspan="2">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2020</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom;">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="2">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="2">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">(as revised*)</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 76%; background-color: #CCEEFF;">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="text-indent: 0pt;"><ix:nonFraction name="us-gaap:DebtInstrumentInterestRateStatedPercentage" id="Fact_e8724a5b059d4f8799a8feaa202dd539" contextRef="c20211231_DebtInstrumentAxis_ConvertibleSeniorNotes0125PercentMember" unitRef="U003" decimals="5" scale="-2" format="ixt:numdotdecimal"><ix:nonFraction name="us-gaap:DebtInstrumentInterestRateStatedPercentage" id="Fact_9920bf96e5654df4aa2a3882002f67d7" contextRef="c20201231_DebtInstrumentAxis_ConvertibleSeniorNotes0125PercentMember" unitRef="U003" decimals="5" scale="-2" format="ixt:numdotdecimal">0.125</ix:nonFraction></ix:nonFraction> percent</span> convertible senior notes</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:ConvertibleDebt" id="Fact_cc24fb43c0744f1c98325749d3d1c0eb" contextRef="c20211231_DebtInstrumentAxis_ConvertibleSeniorNotes0125PercentMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">542,314</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:ConvertibleDebt" id="Fact_65be5fa6a2434040beb0d9ae2a2ca4aa" contextRef="c20201231_DebtInstrumentAxis_ConvertibleSeniorNotes0125PercentMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">540,136</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 76%;">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="text-indent: 0pt;"><ix:nonFraction name="us-gaap:DebtInstrumentInterestRateStatedPercentage" id="Fact_678c9c8d08e84bc49b41f282f783fa1e" contextRef="c20201231_DebtInstrumentAxis_ConvertibleSeniorNotes1PercentMember" unitRef="U003" decimals="2" scale="-2" format="ixt:numdotdecimal"><ix:nonFraction name="us-gaap:DebtInstrumentInterestRateStatedPercentage" id="Fact_d0d025675d994c9489fb7c521ed3ca93" contextRef="c20211231_DebtInstrumentAxis_ConvertibleSeniorNotes1PercentMember" unitRef="U003" decimals="2" scale="-2" format="ixt:numdotdecimal">1</ix:nonFraction></ix:nonFraction> percent</span> convertible senior notes (1)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:ConvertibleDebt" id="Fact_cab8c72e622844b2bff548c7151f9645" contextRef="c20211231_DebtInstrumentAxis_ConvertibleSeniorNotes1PercentMember" unitRef="U001" decimals="-3" scale="3" format="ixt:zerodash">&#8212;</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:ConvertibleDebt" id="Fact_263762c2879f49e19df48df907a46cf1" contextRef="c20201231_DebtInstrumentAxis_ConvertibleSeniorNotes1PercentMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">308,809</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 76%; background-color: #CCEEFF;">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="text-indent: 0pt;"><ix:nonFraction name="us-gaap:DebtInstrumentInterestRateStatedPercentage" id="Fact_b968d0392956483cbbbe19532ac3d256" contextRef="c20211231_DebtInstrumentAxis_ConvertibleSeniorNotes0PercentMember" unitRef="U003" decimals="2" scale="-2" format="ixt:numdotdecimal">0</ix:nonFraction> percent</span> convertible senior notes</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:ConvertibleDebt" id="Fact_d2942608f57748bdabb18c2dc442d75b" contextRef="c20211231_DebtInstrumentAxis_ConvertibleSeniorNotes0PercentMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">619,119</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:ConvertibleDebt" id="Fact_81ca00edf85442d7a959529afc711233" contextRef="c20201231_DebtInstrumentAxis_ConvertibleSeniorNotes0PercentMember" unitRef="U001" decimals="-3" scale="3" format="ixt:zerodash">&#8212;</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 76%;">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Long-term mortgage debt</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:LoansPayableToBank" id="Fact_7526ddee5b884532b24be01e4d495612" contextRef="c20211231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">59,713</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 76%; padding-bottom: 2px; background-color: #CCEEFF;">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Leases and other obligations</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="ions:LeasesAndOtherObligations" id="Fact_14ee837947184542bf24c811e63d710b" contextRef="c20201231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">30,710</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 76%;">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Total</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="ions:LongTermObligations" id="Fact_67f1e8de33db4b3ba71a251d6969a0e4" contextRef="c20211231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">1,251,050</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="ions:LongTermObligations" id="Fact_0db6c0acf39c4704b8b7fb0682124be0" contextRef="c20201231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">939,639</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 76%; padding-bottom: 2px; background-color: #CCEEFF;">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Less: current portion (1)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="ions:LongTermObligationsCurrent" id="Fact_66f728e151b74fe99d367269b42506b7" contextRef="c20211231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">3,526</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="ions:LongTermObligationsCurrent" id="Fact_6b303576d07b435ebdc0b94cf229a5a7" contextRef="c20201231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">316,110</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 76%; padding-bottom: 4px;">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 18pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Total Long-Term Obligations</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="ions:LongTermObligationsNoncurrent" id="Fact_147209ef0e4d4ccf9a6541966995a76b" contextRef="c20211231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">1,247,524</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="ions:LongTermObligationsNoncurrent" id="Fact_85488b1118b143d68b8dce7fa49d282e" contextRef="c20201231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">623,529</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>


</table>
</ix:continuation></ix:continuation>
  <ix:continuation id="Text_60d2e5dcb36e4dffa7326e0e2cb603a05" continuedAt="Text_60d2e5dcb36e4dffa7326e0e2cb603a06"><ix:continuation id="Text_128f7acaa3b64611a059339846d76ec53" continuedAt="Text_128f7acaa3b64611a059339846d76ec54">
<div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">________________</div>
</ix:continuation></ix:continuation>
  <ix:continuation id="Text_60d2e5dcb36e4dffa7326e0e2cb603a06" continuedAt="Text_60d2e5dcb36e4dffa7326e0e2cb603a07"><ix:continuation id="Text_128f7acaa3b64611a059339846d76ec54">
<table cellspacing="0" cellpadding="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">


  <tr>

    <td style="width: 18pt; vertical-align: top; align: right; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(1)</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:footnote id="Foot_9a970986ba874d05b3ae45569fb070a7" footnoteRole="http://www.xbrl.org/2003/role/footnote" xml:lang="en-US">We classified the carrying value of
            our <ix:nonFraction name="us-gaap:DebtInstrumentInterestRateStatedPercentage" id="Fact_9bb397b184f64a69bb1fbcd90cdbbaac" contextRef="c20201231_DebtInstrumentAxis_ConvertibleSeniorNotes1PercentMember" unitRef="U003" decimals="2" scale="-2" format="ixt:numdotdecimal">1</ix:nonFraction>% Notes as a current liability on our consolidated balance sheet at December 31, 2020 because it matured in November 2021.</ix:footnote></div>
        </td>

  </tr>


</table>
</ix:continuation></ix:continuation>

  <ix:continuation id="Text_60d2e5dcb36e4dffa7326e0e2cb603a07" continuedAt="Text_60d2e5dcb36e4dffa7326e0e2cb603a08">
<div><br />
  </div>
</ix:continuation>
  <ix:continuation id="Text_60d2e5dcb36e4dffa7326e0e2cb603a08" continuedAt="Text_60d2e5dcb36e4dffa7326e0e2cb603a09">
<table cellspacing="0" cellpadding="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">


  <tr>

    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">*</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We revised our 2020 amounts to reflect the simplified convertible instruments accounting guidance, which we adopted retrospectively. Refer to Note 1, <span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Organization and Significant Accounting Policies</span>, for further information.</div>
        </td>

  </tr>


</table>
</ix:continuation>
  <ix:continuation id="Text_60d2e5dcb36e4dffa7326e0e2cb603a09" continuedAt="Text_60d2e5dcb36e4dffa7326e0e2cb603a010">
<div><br />
  </div>
</ix:continuation>
  <ix:continuation id="Text_60d2e5dcb36e4dffa7326e0e2cb603a010" continuedAt="Text_60d2e5dcb36e4dffa7326e0e2cb603a011">
<div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Convertible Debt and Call Spread</div>
</ix:continuation>
  <ix:continuation id="Text_60d2e5dcb36e4dffa7326e0e2cb603a011" continuedAt="Text_60d2e5dcb36e4dffa7326e0e2cb603a012">
<div><br />
  </div>
</ix:continuation>
  <ix:continuation id="Text_60d2e5dcb36e4dffa7326e0e2cb603a012" continuedAt="Text_60d2e5dcb36e4dffa7326e0e2cb603a013">
<div style="display:none;"><br /></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;"><ix:nonFraction name="us-gaap:DebtInstrumentInterestRateStatedPercentage" id="Fact_25aea2ffbf94475285e87d7d006b743d" contextRef="c20211231_DebtInstrumentAxis_ConvertibleSeniorNotes0PercentMember" unitRef="U003" decimals="2" scale="-2" format="ixt:numdotdecimal">0</ix:nonFraction> Percent
    Convertible Senior Notes and Call Spread</div>
</ix:continuation>
  <ix:continuation id="Text_60d2e5dcb36e4dffa7326e0e2cb603a013" continuedAt="Text_60d2e5dcb36e4dffa7326e0e2cb603a014">
<div><br />
  </div>
</ix:continuation>
  <ix:continuation id="Text_60d2e5dcb36e4dffa7326e0e2cb603a014" continuedAt="Text_60d2e5dcb36e4dffa7326e0e2cb603a015">
<div style="display:none;"><br /></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">In April 2021, we completed a $<ix:nonFraction name="us-gaap:DebtInstrumentFaceAmount" id="Fact_eaf4a06a851b4f8a9bb6d2b64d319433" contextRef="c20210430_DebtInstrumentAxis_ConvertibleSeniorNotes0PercentMember" unitRef="U001" decimals="-5" scale="6" format="ixt:numdotdecimal">632.5</ix:nonFraction>
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</ix:continuation>
  <ix:continuation id="Text_60d2e5dcb36e4dffa7326e0e2cb603a015" continuedAt="Text_60d2e5dcb36e4dffa7326e0e2cb603a016">
<div><br />
  </div>
</ix:continuation>
  <ix:continuation id="Text_60d2e5dcb36e4dffa7326e0e2cb603a016" continuedAt="Text_60d2e5dcb36e4dffa7326e0e2cb603a017"><ix:nonNumeric name="us-gaap:ConvertibleDebtTableTextBlock" id="Text_599676c995b8459d807f45a7ee7d2f44" contextRef="c20210101to20211231_DebtInstrumentAxis_ConvertibleSeniorNotes0PercentMember" escape="true" continuedAt="Text_944ba58331764915b5c68caafd74f0561">
<div style="display:none;"><br /></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">At December 31, 2021,
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</ix:nonNumeric></ix:continuation>
  <ix:continuation id="Text_60d2e5dcb36e4dffa7326e0e2cb603a017" continuedAt="Text_60d2e5dcb36e4dffa7326e0e2cb603a018"><ix:continuation id="Text_944ba58331764915b5c68caafd74f0561" continuedAt="Text_944ba58331764915b5c68caafd74f0562">
<div><br />
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</ix:continuation></ix:continuation>
  <ix:continuation id="Text_60d2e5dcb36e4dffa7326e0e2cb603a018" continuedAt="Text_60d2e5dcb36e4dffa7326e0e2cb603a019"><ix:continuation id="Text_944ba58331764915b5c68caafd74f0562">
<table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;" class="cfttable">


  <tr>

    <td valign="bottom" style="vertical-align: top; padding-bottom: 2px;">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: top; border-bottom: #000000 solid 2px;" colspan="2">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><ix:nonFraction name="us-gaap:DebtInstrumentInterestRateStatedPercentage" id="Fact_77fbf92b0b474f9e9bf1d676919a7f5f" contextRef="c20211231_DebtInstrumentAxis_ConvertibleSeniorNotes0PercentMember" unitRef="U003" decimals="2" scale="-2" format="ixt:numdotdecimal">0</ix:nonFraction>%</span> Notes</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: top; width: 88%; background-color: #CCEEFF;">
          <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Outstanding principal balance</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:DebtInstrumentCarryingAmount" id="Fact_f02c925067b14ea988de66e4ccca01ca" contextRef="c20211231_DebtInstrumentAxis_ConvertibleSeniorNotes0PercentMember" unitRef="U001" decimals="-5" scale="6" format="ixt:numdotdecimal">632.5</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: top; width: 88%;">
          <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Unamortized debt issuance costs</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:DeferredFinanceCostsNet" id="Fact_2471a075db484b6caf6b4070d0ce0287" contextRef="c20211231_DebtInstrumentAxis_ConvertibleSeniorNotes0PercentMember" unitRef="U001" decimals="-5" scale="6" format="ixt:numdotdecimal">13.4</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Maturity date</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: top; background-color: #CCEEFF;" colspan="2">
          <div style="text-align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="-sec-ix-hidden:Fact_7dc5959ba24b47e092541cc149b2023c">April 2026</span></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: top;">
          <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Interest rate</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: top;" colspan="2">
          <div style="text-align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:DebtInstrumentInterestRateStatedPercentage" id="Fact_d369f4cb508248bc904dabd698afc31e" contextRef="c20211231_DebtInstrumentAxis_ConvertibleSeniorNotes0PercentMember" unitRef="U003" decimals="2" scale="-2" format="ixt:numdotdecimal">0</ix:nonFraction> percent</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Effective interest rate</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: top; background-color: #CCEEFF;" colspan="2">
          <div style="text-align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:DebtInstrumentInterestRateEffectivePercentage" id="Fact_c75884fa883749c4898cf19e2e6d5982" contextRef="c20211231_DebtInstrumentAxis_ConvertibleSeniorNotes0PercentMember" unitRef="U003" decimals="3" scale="-2" format="ixt:numdotdecimal">0.5</ix:nonFraction> percent</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: top; width: 88%;">
          <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Conversion price per share</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:DebtInstrumentConvertibleConversionPrice1" id="Fact_5727caeff9db4514b294fe1cf3ba76cc" contextRef="c20211231_DebtInstrumentAxis_ConvertibleSeniorNotes0PercentMember" unitRef="U004" decimals="2" scale="0" format="ixt:numdotdecimal">57.84</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: top; width: 88%; background-color: #CCEEFF;">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Effective conversion price per share with call spread</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="ions:DebtInstrumentConvertibleConversionPriceIncludingCallSpread" id="Fact_8e92f6065feb4fa79e17beff5dfd1d24" contextRef="c20211231_DebtInstrumentAxis_ConvertibleSeniorNotes0PercentMember" unitRef="U004" decimals="2" scale="0" format="ixt:numdotdecimal">76.39</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: top; width: 88%;">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Total shares of common stock subject to conversion</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="ions:DebtInstrumentConvertibleSharesSubjectToConversion" id="Fact_d0b23f7508384584aaaf596c6accd57d" contextRef="c20211231_DebtInstrumentAxis_ConvertibleSeniorNotes0PercentMember" unitRef="U002" decimals="-5" scale="6" format="ixt:numdotdecimal">10.9</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>


</table>
</ix:continuation></ix:continuation></div>

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    <div class="DSPFPageFooter">
      <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">F-<span class="DSPFPageNumber">29</span></div>

    </div>

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      <hr style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;" /></div>


  </div>
<div><ix:continuation id="Text_60d2e5dcb36e4dffa7326e0e2cb603a019" continuedAt="Text_60d2e5dcb36e4dffa7326e0e2cb603a020">
<div style="display:none;"><br /></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 12pt;"><br />
  </div>
</ix:continuation>

  <ix:continuation id="Text_60d2e5dcb36e4dffa7326e0e2cb603a020" continuedAt="Text_60d2e5dcb36e4dffa7326e0e2cb603a021">
<div style="display:none;"><br /></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">In conjunction with the April 2021 offering, we entered into a call spread transaction, which was comprised of purchasing
    note hedges and selling warrants, to minimize the impact of potential economic dilution upon conversion of our <span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><ix:nonFraction name="us-gaap:DebtInstrumentInterestRateStatedPercentage" id="Fact_a0b7ae014457461c8b48d86852a5843a" contextRef="c20210430_DebtInstrumentAxis_ConvertibleSeniorNotes0PercentMember" unitRef="U003" decimals="2" scale="-2" format="ixt:numdotdecimal">0</ix:nonFraction>%</span> Notes by increasing the effective conversion price on our <span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><ix:nonFraction name="us-gaap:DebtInstrumentInterestRateStatedPercentage" id="Fact_bfd277a1693540a89d6f5636fcd0fe99" contextRef="c20210430_DebtInstrumentAxis_ConvertibleSeniorNotes0PercentMember" unitRef="U003" decimals="2" scale="-2" format="ixt:numdotdecimal">0</ix:nonFraction>%</span> Notes. We increased our effective conversion price to $<ix:nonFraction name="ions:DebtInstrumentConvertibleConversionPriceIncludingCallSpread" id="Fact_43f7d5c5716846c5a0d7037b0b34e617" contextRef="c20211231_DebtInstrumentAxis_ConvertibleSeniorNotes0PercentMember" unitRef="U004" decimals="2" scale="0" format="ixt:numdotdecimal">76.39</ix:nonFraction>
    with the same number of underlying shares as our <span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><ix:nonFraction name="us-gaap:DebtInstrumentInterestRateStatedPercentage" id="Fact_61eee437429549c9bd6c895019eafb50" contextRef="c20210430_DebtInstrumentAxis_ConvertibleSeniorNotes0PercentMember" unitRef="U003" decimals="2" scale="-2" format="ixt:numdotdecimal">0</ix:nonFraction>%</span> Notes.
    The call spread cost us $<ix:nonFraction name="ions:CallSpread" id="Fact_45938d18fad44bc2bc671f89c0f3e5c1" contextRef="c20210401to20210430" unitRef="U001" decimals="-5" scale="6" format="ixt:numdotdecimal">46.9</ix:nonFraction> million, of which $<ix:nonFraction name="us-gaap:PaymentsForHedgeFinancingActivities" id="Fact_cc6d1f5569ac421088fb1ed8e274c5a3" contextRef="c20210401to20210430" unitRef="U001" decimals="-5" scale="6" format="ixt:numdotdecimal">136.7</ix:nonFraction>
    million was for the note hedge purchase, offset by $<ix:nonFraction name="us-gaap:ProceedsFromIssuanceOfWarrants" id="Fact_e9bc7b09d85741f78a67820a6c6ddf05" contextRef="c20210401to20210430" unitRef="U001" decimals="-5" scale="6" format="ixt:numdotdecimal">89.8</ix:nonFraction> million we received for selling the warrants. Similar to our <span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><ix:nonFraction name="us-gaap:DebtInstrumentInterestRateStatedPercentage" id="Fact_79e7642b983845adb2e3a947c74b5d8d" contextRef="c20211231_DebtInstrumentAxis_ConvertibleSeniorNotes0PercentMember" unitRef="U003" decimals="2" scale="-2" format="ixt:numdotdecimal">0</ix:nonFraction>%</span> Notes, our note hedges are subject to adjustment. Additionally, our note hedges
    are exercisable upon conversion of the <span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><ix:nonFraction name="us-gaap:DebtInstrumentInterestRateStatedPercentage" id="Fact_40bcd8d565f24236b2888eecc92d73e7" contextRef="c20211231_DebtInstrumentAxis_ConvertibleSeniorNotes0PercentMember" unitRef="U003" decimals="2" scale="-2" format="ixt:numdotdecimal">0</ix:nonFraction>%</span> Notes. The note
    hedges will expire upon maturity of the <span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><ix:nonFraction name="us-gaap:DebtInstrumentInterestRateStatedPercentage" id="Fact_f582debc52c04c5aada04ee857ff93c0" contextRef="c20211231_DebtInstrumentAxis_ConvertibleSeniorNotes0PercentMember" unitRef="U003" decimals="2" scale="-2" format="ixt:numdotdecimal">0</ix:nonFraction>%</span> Notes, or April
    2026. The note hedges and warrants are separate transactions and are not part of the terms of our <span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><ix:nonFraction name="us-gaap:DebtInstrumentInterestRateStatedPercentage" id="Fact_2534c4c5abfa48c090b1b6ca00700b67" contextRef="c20211231_DebtInstrumentAxis_ConvertibleSeniorNotes0PercentMember" unitRef="U003" decimals="2" scale="-2" format="ixt:numdotdecimal">0</ix:nonFraction>%</span> Notes. The holders of the <span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><ix:nonFraction name="us-gaap:DebtInstrumentInterestRateStatedPercentage" id="Fact_6f27c368e1a049d5b1d611151f012ac1" contextRef="c20211231_DebtInstrumentAxis_ConvertibleSeniorNotes0PercentMember" unitRef="U003" decimals="2" scale="-2" format="ixt:numdotdecimal">0</ix:nonFraction>%</span> Notes do not have any rights with respect to the note hedges and warrants.</div>
</ix:continuation>
  <ix:continuation id="Text_60d2e5dcb36e4dffa7326e0e2cb603a021" continuedAt="Text_60d2e5dcb36e4dffa7326e0e2cb603a022">
<div><br />
  </div>
</ix:continuation>
  <ix:continuation id="Text_60d2e5dcb36e4dffa7326e0e2cb603a022" continuedAt="Text_60d2e5dcb36e4dffa7326e0e2cb603a023">
<div style="display:none;"><br /></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We recorded the amount we paid for the note hedges and the amount we received for the warrants in additional paid-in
    capital in our consolidated balance sheet. See our Call Spread accounting policy in Note 1, <span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Organization and</span>&#160;<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Significant Accounting Policies</span>, in the Notes to the Consolidated Financial Statements. We reassess our ability to continue to classify the note hedges and warrants in
    shareholders&#8217; equity at each reporting period.</div>
</ix:continuation>
  <ix:continuation id="Text_60d2e5dcb36e4dffa7326e0e2cb603a023" continuedAt="Text_60d2e5dcb36e4dffa7326e0e2cb603a024">
<div><br />
  </div>
</ix:continuation>
  <ix:continuation id="Text_60d2e5dcb36e4dffa7326e0e2cb603a024" continuedAt="Text_60d2e5dcb36e4dffa7326e0e2cb603a025">
<div style="display:none;"><br /></div>
<div style="text-align: left; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;"><ix:nonFraction name="us-gaap:DebtInstrumentInterestRateStatedPercentage" id="Fact_24bd81e563b14654ae03c7e7d3dd5ad6" contextRef="c20211231_DebtInstrumentAxis_ConvertibleSeniorNotes0125PercentMember" unitRef="U003" decimals="5" scale="-2" format="ixt:numdotdecimal">0.125</ix:nonFraction> Percent
    Convertible Senior Notes and Call Spread</div>
</ix:continuation>
  <ix:continuation id="Text_60d2e5dcb36e4dffa7326e0e2cb603a025" continuedAt="Text_60d2e5dcb36e4dffa7326e0e2cb603a026">
<div><br />
  </div>
</ix:continuation>
  <ix:continuation id="Text_60d2e5dcb36e4dffa7326e0e2cb603a026" continuedAt="Text_60d2e5dcb36e4dffa7326e0e2cb603a027">
<div style="display:none;"><br /></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">In December 2019, we entered into privately negotiated exchange and/or subscription agreements with certain new investors
    and certain holders of our existing <ix:nonFraction name="us-gaap:DebtInstrumentInterestRateStatedPercentage" id="Fact_390bf7a33a0140eabae0128cec1f9749" contextRef="c20191231_DebtInstrumentAxis_ConvertibleSeniorNotes1PercentMember" unitRef="U003" decimals="2" scale="-2" format="ixt:numdotdecimal">1</ix:nonFraction>% Notes to exchange $<ix:nonFraction name="us-gaap:DebtInstrumentRepurchasedFaceAmount" id="Fact_e8aa8948c1904cd8994689a7c8ddf752" contextRef="c20191231_DebtInstrumentAxis_ConvertibleSeniorNotes1PercentMember" unitRef="U001" decimals="-5" scale="6" format="ixt:numdotdecimal">375.6</ix:nonFraction> million of our <ix:nonFraction name="us-gaap:DebtInstrumentInterestRateStatedPercentage" id="Fact_e64c55552c804597826a30d600879428" contextRef="c20191231_DebtInstrumentAxis_ConvertibleSeniorNotes1PercentMember" unitRef="U003" decimals="2" scale="-2" format="ixt:numdotdecimal">1</ix:nonFraction>% Notes for $<ix:nonFraction name="us-gaap:DebtInstrumentFaceAmount" id="Fact_9bc0a3bef6e84f3b911aebecd00ccdff" contextRef="c20191231_DebtInstrumentAxis_ConvertibleSeniorNotes0125PercentIssuedInExchangeFor1PercentNotesMember" unitRef="U001" decimals="-5" scale="6" format="ixt:numdotdecimal">439.3</ix:nonFraction> million of our <ix:nonFraction name="us-gaap:DebtInstrumentInterestRateStatedPercentage" id="Fact_7a5d3dee1a174c22a030641f3c611fca" contextRef="c20191231_DebtInstrumentAxis_ConvertibleSeniorNotes0125PercentMember" unitRef="U003" decimals="5" scale="-2" format="ixt:numdotdecimal">0.125</ix:nonFraction>% Notes, and to issue $<ix:nonFraction name="us-gaap:DebtInstrumentFaceAmount" id="Fact_8cabf126aaa24636a376009b8f6ee492" contextRef="c20191231_DebtInstrumentAxis_ConvertibleSeniorNotes0125PercentIssuedUnderSubscriptionAgreementsMember" unitRef="U001" decimals="-5" scale="6" format="ixt:numdotdecimal">109.5</ix:nonFraction> million of our <ix:nonFraction name="us-gaap:DebtInstrumentInterestRateStatedPercentage" id="Fact_8b16f56af9304784a81a5f232c31598c" contextRef="c20191231_DebtInstrumentAxis_ConvertibleSeniorNotes0125PercentMember" unitRef="U003" decimals="5" scale="-2" format="ixt:numdotdecimal">0.125</ix:nonFraction>% Notes.</div>
</ix:continuation>
  <ix:continuation id="Text_60d2e5dcb36e4dffa7326e0e2cb603a027" continuedAt="Text_60d2e5dcb36e4dffa7326e0e2cb603a028">
<div><br />
  </div>
</ix:continuation>
  <ix:continuation id="Text_60d2e5dcb36e4dffa7326e0e2cb603a028" continuedAt="Text_60d2e5dcb36e4dffa7326e0e2cb603a029"><ix:nonNumeric name="us-gaap:ConvertibleDebtTableTextBlock" id="Text_4c1b65a25fd04140ba02762f4e96676c" contextRef="c20210101to20211231_DebtInstrumentAxis_ConvertibleSeniorNotes0125PercentMember" escape="true" continuedAt="Text_b7bc16cb45034b1ea65593c1e7faae741">
<div style="display:none;"><br /></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">At December 31, 2021,
    we had the following <ix:nonFraction name="us-gaap:DebtInstrumentInterestRateStatedPercentage" id="Fact_3fb8f1d97321471d9e5726082a3b2fe9" contextRef="c20211231_DebtInstrumentAxis_ConvertibleSeniorNotes0125PercentMember" unitRef="U003" decimals="5" scale="-2" format="ixt:numdotdecimal">0.125</ix:nonFraction>% Notes outstanding with interest payable semi-annually (amounts in millions except interest rate and price per share
    data):</div>
</ix:nonNumeric></ix:continuation>
  <ix:continuation id="Text_60d2e5dcb36e4dffa7326e0e2cb603a029" continuedAt="Text_60d2e5dcb36e4dffa7326e0e2cb603a030"><ix:continuation id="Text_b7bc16cb45034b1ea65593c1e7faae741" continuedAt="Text_b7bc16cb45034b1ea65593c1e7faae742">
<div><br />
  </div>
</ix:continuation></ix:continuation>
  <ix:continuation id="Text_60d2e5dcb36e4dffa7326e0e2cb603a030" continuedAt="Text_60d2e5dcb36e4dffa7326e0e2cb603a031"><ix:continuation id="Text_b7bc16cb45034b1ea65593c1e7faae742">
<table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;" class="cfttable">


  <tr>

    <td valign="bottom" style="vertical-align: top; padding-bottom: 2px;">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: top; border-bottom: #000000 solid 2px;" colspan="2">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"><ix:nonFraction name="us-gaap:DebtInstrumentInterestRateStatedPercentage" id="Fact_ea9329672f5d405bbac1db8508656a61" contextRef="c20211231_DebtInstrumentAxis_ConvertibleSeniorNotes0125PercentMember" unitRef="U003" decimals="5" scale="-2" format="ixt:numdotdecimal">0.125</ix:nonFraction>%
            Notes</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: top; width: 88%; background-color: #CCEEFF;">
          <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Outstanding principal balance</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:DebtInstrumentCarryingAmount" id="Fact_35785824c816472383d5787344c63178" contextRef="c20211231_DebtInstrumentAxis_ConvertibleSeniorNotes0125PercentMember" unitRef="U001" decimals="-5" scale="6" format="ixt:numdotdecimal">548.8</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: top; width: 88%;">
          <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Unamortized debt issuance costs</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:DeferredFinanceCostsNet" id="Fact_d2ea11a1b6f84e8697249b6ca932f297" contextRef="c20211231_DebtInstrumentAxis_ConvertibleSeniorNotes0125PercentMember" unitRef="U001" decimals="-5" scale="6" format="ixt:numdotdecimal">6.5</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Maturity date</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: top; background-color: #CCEEFF;" colspan="2">
          <div style="text-align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="-sec-ix-hidden:Fact_ef7fbbee87c14676a78b2a22d99ec0ae">December 2024</span></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: top;">
          <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Interest rate</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: top;" colspan="2">
          <div style="text-align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:DebtInstrumentInterestRateStatedPercentage" id="Fact_580e22be451d4095aa3ef3da75a9dd68" contextRef="c20211231_DebtInstrumentAxis_ConvertibleSeniorNotes0125PercentMember" unitRef="U003" decimals="5" scale="-2" format="ixt:numdotdecimal">0.125</ix:nonFraction> percent</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Effective interest rate</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: top; background-color: #CCEEFF;" colspan="2">
          <div style="text-align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:DebtInstrumentInterestRateEffectivePercentage" id="Fact_78d08c4d9d5e4700b72f514bd6847c6d" contextRef="c20211231_DebtInstrumentAxis_ConvertibleSeniorNotes0125PercentMember" unitRef="U003" decimals="3" scale="-2" format="ixt:numdotdecimal">0.5</ix:nonFraction> percent</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: top; width: 88%;">
          <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Conversion price per share</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:DebtInstrumentConvertibleConversionPrice1" id="Fact_5c7bae2bbaec4a5ba152a59d30c5d294" contextRef="c20211231_DebtInstrumentAxis_ConvertibleSeniorNotes0125PercentMember" unitRef="U004" decimals="2" scale="0" format="ixt:numdotdecimal">83.28</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: top; width: 88%; background-color: #CCEEFF;">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Effective conversion price per share with call spread</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="ions:DebtInstrumentConvertibleConversionPriceIncludingCallSpread" id="Fact_206d570ed66045e1ae014614476e5a3b" contextRef="c20211231_DebtInstrumentAxis_ConvertibleSeniorNotes0125PercentMember" unitRef="U004" decimals="2" scale="0" format="ixt:numdotdecimal">123.38</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: top; width: 88%;">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Total shares of common stock subject to conversion</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="ions:DebtInstrumentConvertibleSharesSubjectToConversion" id="Fact_30011520ecb34844818fb103a47c4a87" contextRef="c20211231_DebtInstrumentAxis_ConvertibleSeniorNotes0125PercentMember" unitRef="U002" decimals="-5" scale="6" format="ixt:numdotdecimal">6.6</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>


</table>
</ix:continuation></ix:continuation>
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<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 12pt;"><br />
  </div>
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  <ix:continuation id="Text_60d2e5dcb36e4dffa7326e0e2cb603a032" continuedAt="Text_60d2e5dcb36e4dffa7326e0e2cb603a033">
<div style="display:none;"><br /></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">In conjunction with the issuance of our </span><ix:nonFraction name="us-gaap:DebtInstrumentInterestRateStatedPercentage" id="Fact_25e4b006c17f47a38e772a7e56867a80" contextRef="c20191231_DebtInstrumentAxis_ConvertibleSeniorNotes0125PercentMember" unitRef="U003" decimals="5" scale="-2" format="ixt:numdotdecimal">0.125</ix:nonFraction>%<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> Notes in December 2019, we entered into a call spread
      transaction, which was comprised of purchasing note hedges and selling warrants, to minimize the impact of potential economic dilution upon conversion of our </span><ix:nonFraction name="us-gaap:DebtInstrumentInterestRateStatedPercentage" id="Fact_a36dda5053e3435d8c7db676ef8e0a91" contextRef="c20191231_DebtInstrumentAxis_ConvertibleSeniorNotes0125PercentMember" unitRef="U003" decimals="5" scale="-2" format="ixt:numdotdecimal">0.125</ix:nonFraction>% Notes by increasing the effective conversion price on our <ix:nonFraction name="us-gaap:DebtInstrumentInterestRateStatedPercentage" id="Fact_dca379e197a94a36a36623bc7ac96f07" contextRef="c20191231_DebtInstrumentAxis_ConvertibleSeniorNotes0125PercentMember" unitRef="U003" decimals="5" scale="-2" format="ixt:numdotdecimal">0.125</ix:nonFraction>% Notes<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">. We increased our effective conversion price to $</span><ix:nonFraction name="ions:DebtInstrumentConvertibleConversionPriceIncludingCallSpread" id="Fact_cc1646117ceb4669a214b59d44df4271" contextRef="c20211231_DebtInstrumentAxis_ConvertibleSeniorNotes0125PercentMember" unitRef="U004" decimals="2" scale="0" format="ixt:numdotdecimal">123.38</ix:nonFraction><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> with the same number of underlying shares as our </span><ix:nonFraction name="us-gaap:DebtInstrumentInterestRateStatedPercentage" id="Fact_4e2d57bba7d14c0c94f9d189343d111f" contextRef="c20191231_DebtInstrumentAxis_ConvertibleSeniorNotes0125PercentMember" unitRef="U003" decimals="5" scale="-2" format="ixt:numdotdecimal">0.125</ix:nonFraction>%<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> Notes. The call spread cost us $</span><ix:nonFraction name="ions:CallSpread" id="Fact_6a72759a480a4c6e9f278b19fb85b311" contextRef="c20191201to20191231" unitRef="U001" decimals="-5" scale="6" format="ixt:numdotdecimal">52.6</ix:nonFraction><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> million, of which $</span><ix:nonFraction name="us-gaap:PaymentsForHedgeFinancingActivities" id="Fact_1764d8dd38464731ae51da974c6e8e2a" contextRef="c20191201to20191231" unitRef="U001" decimals="-5" scale="6" format="ixt:numdotdecimal">108.7</ix:nonFraction><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> million was for the note hedge purchase, offset by $</span><ix:nonFraction name="us-gaap:ProceedsFromIssuanceOfWarrants" id="Fact_527e30594188438fa02a6439bb9f2f66" contextRef="c20191201to20191231" unitRef="U001" decimals="-5" scale="6" format="ixt:numdotdecimal">56.1</ix:nonFraction><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> million we received for selling the warrants. Similar to our </span><ix:nonFraction name="us-gaap:DebtInstrumentInterestRateStatedPercentage" id="Fact_5c5a5f0f3f3a4b1ba4e03f69741bbc3c" contextRef="c20211231_DebtInstrumentAxis_ConvertibleSeniorNotes0125PercentMember" unitRef="U003" decimals="5" scale="-2" format="ixt:numdotdecimal">0.125</ix:nonFraction>%
    Notes<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">, our note hedges are subject to adjustment. Additionally, our note hedges are exercisable upon conversion of the </span><ix:nonFraction name="us-gaap:DebtInstrumentInterestRateStatedPercentage" id="Fact_5457d9bf4574451da648d1398eac8741" contextRef="c20211231_DebtInstrumentAxis_ConvertibleSeniorNotes0125PercentMember" unitRef="U003" decimals="5" scale="-2" format="ixt:numdotdecimal">0.125</ix:nonFraction>% Notes<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">. The note hedges will expire upon maturity of the
    </span><ix:nonFraction name="us-gaap:DebtInstrumentInterestRateStatedPercentage" id="Fact_84c8d61e60774934bdc9e59b05c3b3d7" contextRef="c20211231_DebtInstrumentAxis_ConvertibleSeniorNotes0125PercentMember" unitRef="U003" decimals="5" scale="-2" format="ixt:numdotdecimal">0.125</ix:nonFraction>% Notes<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">, or December 2024. The note
      hedges and warrants are separate transactions and are not part of the terms of our </span><ix:nonFraction name="us-gaap:DebtInstrumentInterestRateStatedPercentage" id="Fact_c912e09316644ad49b8fc72bbe37b748" contextRef="c20211231_DebtInstrumentAxis_ConvertibleSeniorNotes0125PercentMember" unitRef="U003" decimals="5" scale="-2" format="ixt:numdotdecimal">0.125</ix:nonFraction>% Notes<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">. The holders of the </span><ix:nonFraction name="us-gaap:DebtInstrumentInterestRateStatedPercentage" id="Fact_80b34cd6d40a4398bf2e8dea144d455b" contextRef="c20211231_DebtInstrumentAxis_ConvertibleSeniorNotes0125PercentMember" unitRef="U003" decimals="5" scale="-2" format="ixt:numdotdecimal">0.125</ix:nonFraction>% Notes<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> do not have any rights with respect to the note hedges and warrants.</span></div>
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<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We recorded the amount we paid for the note hedges and the amount we received for the warrants in additional paid-in
    capital in our consolidated balance sheet. See our Call Spread accounting policy in Note 1, <span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Organization and</span>&#160;<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Significant Accounting Policies</span>, in the Notes to the Consolidated Financial Statements. We reassess our ability to continue to classify the note hedges and warrants in
    shareholders&#8217; equity at each reporting period.</div>
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  <ix:continuation id="Text_60d2e5dcb36e4dffa7326e0e2cb603a035" continuedAt="Text_60d2e5dcb36e4dffa7326e0e2cb603a036">
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  </div>
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<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;"><ix:nonFraction name="us-gaap:DebtInstrumentInterestRateStatedPercentage" id="Fact_1a83f60c2b9d442898f06e130e8e59ae" contextRef="c20211231_DebtInstrumentAxis_ConvertibleSeniorNotes1PercentMember" unitRef="U003" decimals="2" scale="-2" format="ixt:numdotdecimal">1</ix:nonFraction> Percent
    Convertible Senior Notes</div>
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  <ix:continuation id="Text_60d2e5dcb36e4dffa7326e0e2cb603a038" continuedAt="Text_60d2e5dcb36e4dffa7326e0e2cb603a039">
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<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">In November 2014, we completed a $<ix:nonFraction name="us-gaap:DebtInstrumentFaceAmount" id="Fact_4c8aef4ea00a429cb229cd63cb7c85fe" contextRef="c20141130_DebtInstrumentAxis_ConvertibleSeniorNotes1PercentMember" unitRef="U001" decimals="-6" scale="6" format="ixt:numdotdecimal">500</ix:nonFraction> million offering of convertible senior notes, which matured in 2021 and beared interest at <ix:nonFraction name="us-gaap:DebtInstrumentInterestRateStatedPercentage" id="Fact_2c15262d336144828569852832845299" contextRef="c20141130_DebtInstrumentAxis_ConvertibleSeniorNotes1PercentMember" unitRef="U003" decimals="2" scale="-2" format="ixt:numdotdecimal">1</ix:nonFraction> percent with interest payable semi-annually. In December 2016, we issued an additional $<ix:nonFraction name="us-gaap:DebtInstrumentFaceAmount" id="Fact_5bd6eb182d7c4d1ca0730475259ea3d2" contextRef="c20161231_DebtInstrumentAxis_ConvertibleSeniorNotes1PercentMember" unitRef="U001" decimals="-5" scale="6" format="ixt:numdotdecimal">185.5</ix:nonFraction> million of <ix:nonFraction name="us-gaap:DebtInstrumentInterestRateStatedPercentage" id="Fact_54eef507c3af41a3ac1e48f2c859bd63" contextRef="c20161231_DebtInstrumentAxis_ConvertibleSeniorNotes1PercentMember" unitRef="U003" decimals="2" scale="-2" format="ixt:numdotdecimal">1</ix:nonFraction>% Notes in exchange for the redemption of a portion of our previously outstanding <ix:nonFraction name="us-gaap:DebtInstrumentInterestRateStatedPercentage" id="Fact_491309d8a59b4784bc6e485cdf32ad99" contextRef="c20161231_DebtInstrumentAxis_ConvertibleSeniorNotes275PercentMember" unitRef="U003" decimals="4" scale="-2" format="ixt:numdotdecimal">2.75</ix:nonFraction>% convertible senior notes, or <ix:nonFraction name="us-gaap:DebtInstrumentInterestRateStatedPercentage" id="Fact_f4db0185478f4aee8dbc5980167b5e49" contextRef="c20161231_DebtInstrumentAxis_ConvertibleSeniorNotes275PercentMember" unitRef="U003" decimals="4" scale="-2" format="ixt:numdotdecimal">2.75</ix:nonFraction>% Notes. In December 2019, we exchanged a
    portion of our <ix:nonFraction name="us-gaap:DebtInstrumentInterestRateStatedPercentage" id="Fact_db73c504dedf47879746b2bf5f038fc6" contextRef="c20191231_DebtInstrumentAxis_ConvertibleSeniorNotes1PercentMember" unitRef="U003" decimals="2" scale="-2" format="ixt:numdotdecimal">1</ix:nonFraction>% Notes for new <ix:nonFraction name="us-gaap:DebtInstrumentInterestRateStatedPercentage" id="Fact_cde951c5574446449a30c433f631a745" contextRef="c20191231_DebtInstrumentAxis_ConvertibleSeniorNotes0125PercentMember" unitRef="U003" decimals="5" scale="-2" format="ixt:numdotdecimal">0.125</ix:nonFraction>%
    Notes. As a result, the principal balance of <ix:nonFraction name="us-gaap:DebtInstrumentInterestRateStatedPercentage" id="Fact_4e90aed1e9144ff4a6f2c07ad15f3dde" contextRef="c20191231_DebtInstrumentAxis_ConvertibleSeniorNotes1PercentMember" unitRef="U003" decimals="2" scale="-2" format="ixt:numdotdecimal">1</ix:nonFraction>% Notes was $<ix:nonFraction name="us-gaap:DebtInstrumentCarryingAmount" id="Fact_ea45bf1a54a144b2a638ab6503918750" contextRef="c20191231_DebtInstrumentAxis_ConvertibleSeniorNotes1PercentMember" unitRef="U001" decimals="-5" scale="6" format="ixt:numdotdecimal">309.9</ix:nonFraction> million. Additionally, we recorded a $<ix:nonFraction name="us-gaap:GainsLossesOnExtinguishmentOfDebt" id="Fact_6c4f71b539af44548144f5762c61f770" contextRef="c20191201to20191231_DebtInstrumentAxis_ConvertibleSeniorNotes1PercentMember" unitRef="U001" decimals="-5" scale="6" sign="-" format="ixt:numdotdecimal">66.2</ix:nonFraction> million non-cash loss on the early
    retirement of debt, reflecting the early retirement of a significant portion of our <ix:nonFraction name="us-gaap:DebtInstrumentInterestRateStatedPercentage" id="Fact_56023e08380d42e5b6649579a0a3d570" contextRef="c20191231_DebtInstrumentAxis_ConvertibleSeniorNotes1PercentMember" unitRef="U003" decimals="2" scale="-2" format="ixt:numdotdecimal">1</ix:nonFraction>% Notes in December 2019. The non-cash loss on the early
    retirement of our debt is the difference between the amount paid to exchange our <ix:nonFraction name="us-gaap:DebtInstrumentInterestRateStatedPercentage" id="Fact_fdc16094955c493d99ab13a2243829d6" contextRef="c20191231_DebtInstrumentAxis_ConvertibleSeniorNotes1PercentMember" unitRef="U003" decimals="2" scale="-2" format="ixt:numdotdecimal">1</ix:nonFraction>% Notes and the net carrying balance of the liability at the
    time that we completed the debt exchange.</div>
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<div><ix:continuation id="Text_60d2e5dcb36e4dffa7326e0e2cb603a039" continuedAt="Text_60d2e5dcb36e4dffa7326e0e2cb603a040">
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  <ix:continuation id="Text_60d2e5dcb36e4dffa7326e0e2cb603a040" continuedAt="Text_60d2e5dcb36e4dffa7326e0e2cb603a041">
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<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">In April 2021, we repurchased $<ix:nonFraction name="us-gaap:DebtInstrumentRepurchasedFaceAmount" id="Fact_b9d8fff433b548408090d1b5165d94b1" contextRef="c20210430_DebtInstrumentAxis_ConvertibleSeniorNotes1PercentMember" unitRef="U001" decimals="-5" scale="6" format="ixt:numdotdecimal">247.9</ix:nonFraction> million in aggregate principal amount of our <ix:nonFraction name="us-gaap:DebtInstrumentInterestRateStatedPercentage" id="Fact_51335fbef4b14945ab8ef172fc66172e" contextRef="c20210430_DebtInstrumentAxis_ConvertibleSeniorNotes1PercentMember" unitRef="U003" decimals="2" scale="-2" format="ixt:numdotdecimal">1</ix:nonFraction>% Notes in privately negotiated
    transactions. As a result of the repurchase, we recognized an $<ix:nonFraction name="us-gaap:GainsLossesOnExtinguishmentOfDebt" id="Fact_97743d06e01540139ca378f1b42c7039" contextRef="c20210401to20210430_DebtInstrumentAxis_ConvertibleSeniorNotes1PercentMember" unitRef="U001" decimals="-5" scale="6" format="ixt:numdotdecimal">8.6</ix:nonFraction> million loss on early retirement of debt, reflecting the early retirement of a
    significant portion of our <ix:nonFraction name="us-gaap:DebtInstrumentInterestRateStatedPercentage" id="Fact_28a6988a6ac249c297d97a3ea2396ed6" contextRef="c20210430_DebtInstrumentAxis_ConvertibleSeniorNotes1PercentMember" unitRef="U003" decimals="2" scale="-2" format="ixt:numdotdecimal">1</ix:nonFraction>% Notes. The loss on the early retirement of our debt is the difference between the amount paid to retire our <ix:nonFraction name="us-gaap:DebtInstrumentInterestRateStatedPercentage" id="Fact_eb341c6d732e4e9ba9c2562c4061ace2" contextRef="c20210430_DebtInstrumentAxis_ConvertibleSeniorNotes1PercentMember" unitRef="U003" decimals="2" scale="-2" format="ixt:numdotdecimal">1</ix:nonFraction>% Notes and the net carrying balance of the liability at the time that we retired the debt. We paid the remaining principal balance of our <ix:nonFraction name="us-gaap:DebtInstrumentInterestRateStatedPercentage" id="Fact_26f53f48dcfd4c1fa29d6acfd423200a" contextRef="c20211130_DebtInstrumentAxis_ConvertibleSeniorNotes1PercentMember" unitRef="U003" decimals="2" scale="-2" format="ixt:numdotdecimal">1</ix:nonFraction>% Notes with $<ix:nonFraction name="us-gaap:RepaymentsOfConvertibleDebt" id="Fact_f7c4f5eea9b64de3b8c3a61d3c5f2fc8" contextRef="c20211101to20211130_DebtInstrumentAxis_ConvertibleSeniorNotes1PercentMember" unitRef="U001" decimals="-5" scale="6" format="ixt:numdotdecimal">62.0</ix:nonFraction> million of cash at maturity
    in November 2021.</div>
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<div><br />
  </div>
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<div style="display:none;"><br /></div>
<div style="text-align: left; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;">Other Terms of Convertible Senior Notes</div>
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<div><br />
  </div>
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<div style="display:none;"><br /></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">The <ix:nonFraction name="us-gaap:DebtInstrumentInterestRateStatedPercentage" id="Fact_3d8846636721485387ddd74cb4914415" contextRef="c20211231_DebtInstrumentAxis_ConvertibleSeniorNotes0PercentMember" unitRef="U003" decimals="2" scale="-2" format="ixt:numdotdecimal">0</ix:nonFraction>% and <ix:nonFraction name="us-gaap:DebtInstrumentInterestRateStatedPercentage" id="Fact_350d7b82e135444ab2263bd62ccd4d52" contextRef="c20211231_DebtInstrumentAxis_ConvertibleSeniorNotes0125PercentMember" unitRef="U003" decimals="5" scale="-2" format="ixt:numdotdecimal">0.125</ix:nonFraction>% Notes are convertible under certain conditions, at the option of the note holders. We can settle conversions of the notes, at our election, in cash,
    shares of our common stock or a combination of both. We may not redeem the notes prior to maturity, and we do not have to provide a sinking fund for them. Holders of the notes may require us to purchase some or all of their notes upon the occurrence of
    certain fundamental changes, as set forth in the indentures governing the notes, at a purchase price equal to <ix:nonFraction name="ions:DebtInstrumentConvertiblePercentageOfPrincipalAmountUsedAsPurchasePriceUponOccurrenceOfFundamentalChange" id="Fact_c14b63db0b8d48059f36330d90c36bbd" contextRef="c20210101to20211231_DebtInstrumentAxis_ConvertibleSeniorNotes0125PercentMember" unitRef="U003" decimals="2" scale="-2" format="ixt:numdotdecimal"><ix:nonFraction name="ions:DebtInstrumentConvertiblePercentageOfPrincipalAmountUsedAsPurchasePriceUponOccurrenceOfFundamentalChange" id="Fact_86737a03a6414937a8679fe3f5125795" contextRef="c20210101to20211231_DebtInstrumentAxis_ConvertibleSeniorNotes1PercentMember" unitRef="U003" decimals="2" scale="-2" format="ixt:numdotdecimal"><ix:nonFraction name="ions:DebtInstrumentConvertiblePercentageOfPrincipalAmountUsedAsPurchasePriceUponOccurrenceOfFundamentalChange" id="Fact_84ed437afebb4edca6d9db24e68d4621" contextRef="c20210101to20211231_DebtInstrumentAxis_ConvertibleSeniorNotes0PercentMember" unitRef="U003" decimals="2" scale="-2" format="ixt:numdotdecimal">100</ix:nonFraction></ix:nonFraction></ix:nonFraction> percent of the principal
    amount of the notes to be purchased, plus any accrued and unpaid interest. The <ix:nonFraction name="us-gaap:DebtInstrumentInterestRateStatedPercentage" id="Fact_e18598259d514d88a513bd7611cc2bf9" contextRef="c20211231_DebtInstrumentAxis_ConvertibleSeniorNotes1PercentMember" unitRef="U003" decimals="2" scale="-2" format="ixt:numdotdecimal">1</ix:nonFraction>% Notes were subject to similar terms.</div>
</ix:continuation>
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<div><br />
  </div>
</ix:continuation>
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<div style="display:none;"><br /></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Our total interest expense for our outstanding senior convertible notes for the years ended December 31, 2021, 2020 and 2019 included $<ix:nonFraction name="us-gaap:AmortizationOfFinancingCostsAndDiscounts" id="Fact_bdbef3ccc85649118ae89b354a641e27" contextRef="c20210101to20211231" unitRef="U001" decimals="-5" scale="6" format="ixt:numdotdecimal">4.9</ix:nonFraction> million, $<ix:nonFraction name="us-gaap:AmortizationOfFinancingCostsAndDiscounts" id="Fact_08ed41e893e1431f80a65f44ee96fab5" contextRef="c20200101to20201231" unitRef="U001" decimals="-5" scale="6" format="ixt:numdotdecimal">3.2</ix:nonFraction> million and $<ix:nonFraction name="us-gaap:AmortizationOfFinancingCostsAndDiscounts" id="Fact_cba46b1e3f554886934806f466f2faac" contextRef="c20190101to20191231" unitRef="U001" decimals="-5" scale="6" format="ixt:numdotdecimal">2.9</ix:nonFraction> million, respectively, of
    non-cash interest expense related to the amortization of debt issuance costs for our convertible notes.</div>
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<div><br />
  </div>
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<div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Financing Arrangements</div>
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<div><br />
  </div>
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<div style="display:none;"><br /></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic; font-weight: bold;">Research and Development and Manufacturing Facilities</div>
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<div><br />
  </div>
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<div style="display:none;"><br /></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">In July 2017, we purchased the building that houses our primary R&amp;D facility for $<ix:nonFraction name="us-gaap:PaymentsToAcquireBuildings" id="Fact_4a0c024b965c4f51b897f9cf5bc80424" contextRef="c20170701to20170731_PropertyPlantAndEquipmentByTypeAxis_PrimaryResearchAndDevelopmentFacilityMember" unitRef="U001" decimals="-5" scale="6" format="ixt:numdotdecimal">79.4</ix:nonFraction> million and our manufacturing facility for $<ix:nonFraction name="us-gaap:PaymentsToAcquireBuildings" id="Fact_06974c574f644e5baacbd3f8e2c599a6" contextRef="c20170701to20170731_PropertyPlantAndEquipmentByTypeAxis_ManufacturingFacilityMember" unitRef="U001" decimals="-5" scale="6" format="ixt:numdotdecimal">14.0</ix:nonFraction> million. We financed the purchase
    of these <ix:nonFraction name="ions:NumberOfPurchasedFacilitiesFinancedWithMortgageDebt" id="Fact_802514d6121f4f3ca8efa9133eb869cd" contextRef="c20170701to20170731" unitRef="U014" decimals="INF" scale="0" format="ixt-sec:numwordsen">two</ix:nonFraction> facilities with mortgage debt of $<ix:nonFraction name="us-gaap:DebtInstrumentFaceAmount" id="Fact_1c1b0d341f0d4a39b8dd7164eab2e39d" contextRef="c20170731_DebtInstrumentAxis_LongTermMortgageDebtMember" unitRef="U001" decimals="-5" scale="6" format="ixt:numdotdecimal">60.4</ix:nonFraction>
    million in total. Our primary R&amp;D facility mortgage has an interest rate of <ix:nonFraction name="us-gaap:DebtInstrumentInterestRateStatedPercentage" id="Fact_2e21e0a6347e447a8991607c0227050a" contextRef="c20170731_PropertyPlantAndEquipmentByTypeAxis_PrimaryResearchAndDevelopmentFacilityMember" unitRef="U003" decimals="4" scale="-2" format="ixt:numdotdecimal">3.88</ix:nonFraction> percent. Our manufacturing facility mortgage has an
    interest rate of <ix:nonFraction name="us-gaap:DebtInstrumentInterestRateStatedPercentage" id="Fact_b8df62c274f14f0499a84c79aa3dd4f9" contextRef="c20170731_PropertyPlantAndEquipmentByTypeAxis_ManufacturingFacilityMember" unitRef="U003" decimals="4" scale="-2" format="ixt:numdotdecimal">4.20</ix:nonFraction> percent. During the first <ix:nonNumeric name="ions:PeriodToMakeInterestOnlyPaymentsOnMortgageLoan" id="Fact_cec9dfdd051e4462bf766547d85be9b4" contextRef="c20210101to20211231_PropertyPlantAndEquipmentByTypeAxis_ManufacturingFacilityMember" format="ixt-sec:durwordsen"><ix:nonNumeric name="ions:PeriodToMakeInterestOnlyPaymentsOnMortgageLoan" id="Fact_885a5330a5d64c1ca25849873c2df457" contextRef="c20210101to20211231_PropertyPlantAndEquipmentByTypeAxis_PrimaryResearchAndDevelopmentFacilityMember" format="ixt-sec:durwordsen">five years</ix:nonNumeric></ix:nonNumeric> of both mortgages, we are only required to make interest payments. We will begin making principal payments in 2022. Both mortgages mature in August 2027.</div>
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<div><br />
  </div>
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  <ix:continuation id="Text_60d2e5dcb36e4dffa7326e0e2cb603a054" continuedAt="Text_60d2e5dcb36e4dffa7326e0e2cb603a055">
<div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Maturity Schedules</div>
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<div><br />
  </div>
</ix:continuation>
  <a id="_Hlk62200728"><!--Anchor--></a><ix:continuation id="Text_60d2e5dcb36e4dffa7326e0e2cb603a056" continuedAt="Text_60d2e5dcb36e4dffa7326e0e2cb603a057"><ix:nonNumeric name="srt:ContractualObligationFiscalYearMaturityScheduleTableTextBlock" id="Text_6dc2ca1985c5417f9414e27b1b36b062" contextRef="c20210101to20211231" escape="true" continuedAt="Text_8f5ea3d882d942b684d1ef727156bc3e1">
<div style="display:none;"><br /></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Annual debt and other obligation
    maturities, including fixed and determinable interest, at December 31, 2021 are as follows (in thousands):</div>
</ix:nonNumeric></ix:continuation>
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<div><br />
  </div>
</ix:continuation></ix:continuation>
  <ix:continuation id="Text_60d2e5dcb36e4dffa7326e0e2cb603a058"><ix:continuation id="Text_8f5ea3d882d942b684d1ef727156bc3e2">
<table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;" class="cfttable">


  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 88%; background-color: #CCEEFF;">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="text-indent: 0pt;">2022</span></div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:ContractualObligationDueInNextTwelveMonths" id="Fact_d2eb54062a6d4f188ef1dbae3b8653d3" contextRef="c20211231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">3,498</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 88%;">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="text-indent: 0pt;">2023</span></div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:ContractualObligationDueInSecondYear" id="Fact_c42e928b65cd45aa923675e567769ac7" contextRef="c20211231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">4,180</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 88%; background-color: #CCEEFF;">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="text-indent: 0pt;">2024</span></div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:ContractualObligationDueInThirdYear" id="Fact_6b7eb3455bef4825bec5934f0ca8a9f2" contextRef="c20211231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">4,180</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 88%;">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="text-indent: 0pt;">2025</span></div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:ContractualObligationDueInFourthYear" id="Fact_5163088d8dfb4bd8afb6a945c3e15b83" contextRef="c20211231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">1,184,820</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 88%; background-color: #CCEEFF;">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="text-indent: 0pt;">2026</span></div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:ContractualObligationDueInFifthYear" id="Fact_04194527fb664e52a3ac79595e34b654" contextRef="c20211231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">3,494</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 88%; padding-bottom: 2px;">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Thereafter</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:ContractualObligationDueAfterFifthYear" id="Fact_74f3f2a83bb64af5b0b4b21df7d35ef0" contextRef="c20211231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">57,439</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 88%; background-color: #CCEEFF;">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Subtotal</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:ContractualObligation" id="Fact_41f58f8c96774a38af7b7c1cc41eabb9" contextRef="c20211231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">1,257,611</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 88%;">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Less: current portion</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="ions:LongTermObligationsCurrent" id="Fact_bc879ac3c37f49de90a976632193e86e" contextRef="c20211231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">3,526</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 88%; background-color: #CCEEFF;">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Less: fixed and determinable interest</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:InterestPayableCurrentAndNoncurrent" id="Fact_ef9db53e88e14db9b13d2afa08b9cc23" contextRef="c20211231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">15,498</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 88%;">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Less: debt issuance costs</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:DeferredFinanceCostsNet" id="Fact_97e59891cc4a4a90baf9d56b32982707" contextRef="c20211231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">20,302</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 88%; background-color: #CCEEFF;">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Plus: lease liabilities</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:OperatingLeaseLiability" id="Fact_7ac353e428c24ea8bfa5e799cd084500" contextRef="c20211231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">22,058</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 88%; padding-bottom: 2px;">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Plus: other liabilities</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:OtherLiabilities" id="Fact_70cca2e07bbf4591982541c10c2b180d" contextRef="c20211231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">7,181</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 88%; padding-bottom: 4px; background-color: #CCEEFF;">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Total long-term debt</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="ions:LongTermObligationsNoncurrent" id="Fact_2e8033307b594b4f9b2e30ee6ba95bc3" contextRef="c20211231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">1,247,524</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>


</table>
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<div><ix:nonNumeric name="us-gaap:LesseeOperatingLeasesTextBlock" id="Text_816a383efe384026825a397c06709b4a" contextRef="c20210101to20211231" escape="true" continuedAt="Text_1c0b22067bfa445a9e38081331f76f6c1">
<div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Operating Leases</div>
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<div style="display:none;"><br /></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;">Carlsbad Leases</div>
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<div style="display:none;"><br /></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We lease a facility adjacent to our manufacturing facility that has laboratory and office space that we use to support our
    manufacturing facility. We lease this space under a non-cancelable operating lease. In May 2020, we exercised our option to extend our lease, extending our lease term from June 2021 to August 2026. We have <ix:nonFraction name="ions:LesseeLeasingArrangementsOperatingLeasesNumberOfOptionsToExtendLease" id="Fact_6447ecbf2d3b4dde91a4dfca391e39c1" contextRef="c20210101to20211231_GeographicDistributionAxis_CarlsbadFacilityMember" unitRef="U015" decimals="INF" scale="0" format="ixt-sec:numwordsen">one</ix:nonFraction> remaining option to extend the lease for an additional <ix:nonNumeric name="us-gaap:LesseeOperatingLeaseRenewalTerm" id="Fact_3fa1c2318c4d4b2f8088992fbf02bb6d" contextRef="c20211231_GeographicDistributionAxis_CarlsbadFacilityMember" format="ixt-sec:durwordsen">five-year</ix:nonNumeric>
    period.</div>
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  </div>
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<div style="display:none;"><br /></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We also lease additional office spaces in Carlsbad. We lease these spaces under non-cancelable operating leases with
    initial terms ending in 2023 with options to extend each of the leases for <ix:nonFraction name="ions:LesseeLeasingArrangementsOperatingLeasesNumberOfOptionsToExtendLease" id="Fact_cb77855b95994f0488becac7637cd2b1" contextRef="c20210101to20211231_GeographicDistributionAxis_CarlsbadOfficeSpacesMember" unitRef="U015" decimals="INF" scale="0" format="ixt-sec:numwordsen">one</ix:nonFraction>&#160;<ix:nonNumeric name="us-gaap:LesseeOperatingLeaseRenewalTerm" id="Fact_5cb70db62bdc4486992b4feba32be9c4" contextRef="c20211231_GeographicDistributionAxis_CarlsbadOfficeSpacesMember" format="ixt-sec:durwordsen">five-year</ix:nonNumeric> period.</div>
</ix:continuation></div>

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    <div class="DSPFPageFooter">
      <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">F-<span class="DSPFPageNumber">31</span></div>

    </div>

    <div style="page-break-after:always;" class="DSPFPageBreak">
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<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;">Boston Leases</div>
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<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We entered into an operating lease agreement for office space located in Boston, Massachusetts in the second quarter of
    2018. The lease commencement date was in August 2018 and we took occupancy in September 2018. We are leasing this space under a non-cancelable operating lease with an initial term ending after <ix:nonNumeric name="us-gaap:LesseeOperatingLeaseTermOfContract" id="Fact_1cf767bfa2604645b03665b44c8069bb" contextRef="c20211231_GeographicDistributionAxis_BostonOfficeSpaceMember" format="ixt-sec:durmonth">123</ix:nonNumeric> months and an option to extend the lease for an additional <ix:nonNumeric name="us-gaap:LesseeOperatingLeaseRenewalTerm" id="Fact_a817cf4e10ab4fdc88a9eaaa0d2f61a5" contextRef="c20211231_GeographicDistributionAxis_BostonOfficeSpaceMember" format="ixt-sec:durwordsen">five-year</ix:nonNumeric> term. Under
    the lease agreement, we received a <ix:nonNumeric name="ions:LesseeOperatingLeasePeriodOfFreeRent" id="Fact_ba6fa8c8bcc140258a36c6828c2ab217" contextRef="c20210101to20211231_GeographicDistributionAxis_BostonOfficeSpaceMember" format="ixt-sec:durwordsen">three-month</ix:nonNumeric> free rent period, which commenced on August 15, 2018, and a tenant improvement allowance up to $<ix:nonFraction name="ions:LesseeOperatingLeaseAllowanceForTenantImprovements" id="Fact_4d5ed2a157b248b29eab88a7bb6399b9" contextRef="c20211231_GeographicDistributionAxis_BostonOfficeSpaceMember" unitRef="U001" decimals="-5" scale="6" format="ixt:numdotdecimal">3.8</ix:nonFraction> million.</div>
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  </div>
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<div style="display:none;"><br /></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">In January 2022, we entered into a sublease agreement for our office space located in Boston, Massachusetts. The sublease commencement
    date was in January 2022 when the office space was ready for our tenant&#8217;s occupancy. We are subleasing this space under a non-cancelable operating sublease with a sublease term ending <ix:nonNumeric name="us-gaap:LessorOperatingLeaseTermOfContract" id="Fact_f3673b6f6d8a469cb3fc9b19fe6c9445" contextRef="c20220131_GeographicDistributionAxis_SubleasedOfficeSpaceInBostonMember_SubsequentEventTypeAxis_SubsequentEventMember" format="ixt-sec:durmonth">83</ix:nonNumeric> months following the sublease commencement date with no option to extend the sublease. Under the sublease agreement we provided a <ix:nonNumeric name="ions:LessorOperatingLeasePeriodOfFreeRent" id="Fact_bdb3d42dbeaf484494c12e827a769a24" contextRef="c20220101to20220131_GeographicDistributionAxis_SubleasedOfficeSpaceInBostonMember_SubsequentEventTypeAxis_SubsequentEventMember" format="ixt-sec:durwordsen">seven-month</ix:nonNumeric> free rent period, which commenced on January 6, 2022. We will receive lease payments over the sublease term totaling $<ix:nonFraction name="us-gaap:LessorOperatingLeasePaymentsToBeReceived" id="Fact_7c8de04d910848adb798d3e411c0825d" contextRef="c20220131_GeographicDistributionAxis_SubleasedOfficeSpaceInBostonMember_SubsequentEventTypeAxis_SubsequentEventMember" unitRef="U001" decimals="-5" scale="6" format="ixt:numdotdecimal">9.6</ix:nonFraction> million.</div>
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<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">In September 2021, we entered into an operating lease agreement for another office space located in Boston, Massachusetts. The lease
    commencement date was in November 2021 when the office space was ready for our occupancy. We are leasing this space under a non-cancelable operating lease with an initial term ending <ix:nonNumeric name="us-gaap:LesseeOperatingLeaseTermOfContract" id="Fact_f252e6bc1ca849dfb22869bd4a71369a" contextRef="c20211231_GeographicDistributionAxis_AnotherOfficeSpaceInBostonMember" format="ixt-sec:durmonth">91</ix:nonNumeric> months following the lease commencement date and an option to extend the lease for <span style="-sec-ix-hidden:Fact_75e2ca0ba9ea409188caefc97441d96a">an</span>
    additional <ix:nonNumeric name="us-gaap:LesseeOperatingLeaseRenewalTerm" id="Fact_0db31532f59e4b6483e94032872c2c44" contextRef="c20211231_GeographicDistributionAxis_AnotherOfficeSpaceInBostonMember" format="ixt-sec:durwordsen">five-year</ix:nonNumeric> term. Under the lease agreement, we will receive a <ix:nonNumeric name="ions:LesseeOperatingLeasePeriodOfFreeRent" id="Fact_99931a7181e04c71bbd9180a5f64f952" contextRef="c20210101to20211231_GeographicDistributionAxis_AnotherOfficeSpaceInBostonMember" format="ixt-sec:durwordsen">seven-month</ix:nonNumeric> free rent period, which commenced on November 1, 2021. Our lease payments over the initial term total $<ix:nonFraction name="us-gaap:LesseeOperatingLeaseLiabilityPaymentsDue" id="Fact_c350c485d2194852998ea1b496903ff5" contextRef="c20211231_GeographicDistributionAxis_AnotherOfficeSpaceInBostonMember" unitRef="U001" decimals="-5" scale="6" format="ixt:numdotdecimal">6.8</ix:nonFraction> million. We recognized a right-of-use lease asset and lease liability in the fourth quarter of 2021 upon the lease commencement date.</div>
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<div style="display:none;"><br /></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">When we determined our lease term for our operating lease right-of-use assets and lease liabilities for these leases, we
    did not include the extension options for these leases in the original lease term.</div>
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<div style="display:none;"><br /></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Amounts related to our operating leases were as follows (dollar amounts in millions):</div>
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<table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;" class="cfttable">


  <tr>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">

        </td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px; white-space: nowrap;" colspan="2">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">At December 31, 2021</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 88%; background-color: #CCEEFF;">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Right-of-use operating lease assets (1)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:OperatingLeaseRightOfUseAsset" id="Fact_23749203f9514c17a3eb9047effcbc3f" contextRef="c20211231" unitRef="U001" decimals="-5" scale="6" format="ixt:numdotdecimal">18.0</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

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    <td valign="bottom" style="vertical-align: bottom; width: 88%;">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Operating lease liabilities (2)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:OperatingLeaseLiability" id="Fact_0bcc1def02bf4a9fae57dfb5f4021412" contextRef="c20211231" unitRef="U001" decimals="-5" scale="6" format="ixt:numdotdecimal">22.1</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; background-color: #CCEEFF;">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Weighted average remaining lease term</div>
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    <td valign="bottom" style="vertical-align: bottom; background-color: #CCEEFF;" colspan="1">&#160;</td>

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    <td valign="bottom" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

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  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 88%;">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Weighted average discount rate</div>
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    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

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          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">%</div>
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  </tr>


</table>
</ix:continuation></ix:continuation>
  <ix:continuation id="Text_1c0b22067bfa445a9e38081331f76f6c21" continuedAt="Text_1c0b22067bfa445a9e38081331f76f6c22"><ix:continuation id="Text_a25367d78807432ca700840e140de1603" continuedAt="Text_a25367d78807432ca700840e140de1604">
<div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">________________</div>
</ix:continuation></ix:continuation>
  <ix:continuation id="Text_1c0b22067bfa445a9e38081331f76f6c22" continuedAt="Text_1c0b22067bfa445a9e38081331f76f6c23"><ix:continuation id="Text_a25367d78807432ca700840e140de1604" continuedAt="Text_a25367d78807432ca700840e140de1605">
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    <td style="width: 18pt; vertical-align: top; align: right; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(1)</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:footnote id="Foot_15f376e9d49947e4aed1aef14d199172" footnoteRole="http://www.xbrl.org/2003/role/footnote" xml:lang="en-US">Included in <span style="-sec-ix-hidden:Fact_f81ca57385a04657b8ecd0f06d505159">deposits and other assets</span> on our consolidated balance sheet.</ix:footnote></div>
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  </tr>


</table>
</ix:continuation></ix:continuation>
  <ix:continuation id="Text_1c0b22067bfa445a9e38081331f76f6c23" continuedAt="Text_1c0b22067bfa445a9e38081331f76f6c24"><ix:continuation id="Text_a25367d78807432ca700840e140de1605" continuedAt="Text_a25367d78807432ca700840e140de1606">
<div><br />
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</ix:continuation></ix:continuation>
  <ix:continuation id="Text_1c0b22067bfa445a9e38081331f76f6c24" continuedAt="Text_1c0b22067bfa445a9e38081331f76f6c25"><ix:continuation id="Text_a25367d78807432ca700840e140de1606">
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  <tr>

    <td style="width: 18pt; vertical-align: top; align: right; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(2)</td>

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          <div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:footnote id="Foot_e2e8d94790c647a9a64e7b8a949e611c" footnoteRole="http://www.xbrl.org/2003/role/footnote" xml:lang="en-US">Current portion of $<ix:nonFraction name="us-gaap:OperatingLeaseLiabilityCurrent" id="Fact_9b0c762d64a740078d7920512d9fd9e9" contextRef="c20211231" unitRef="U001" decimals="-5" scale="6" format="ixt:numdotdecimal">2.6</ix:nonFraction> million was included in <span style="-sec-ix-hidden:Fact_b2b58e46aca04158b3b03811dd0a9c0f">current portion of long-term obligations</span> on our consolidated balance sheet, with the difference included in <span style="-sec-ix-hidden:Fact_9c37cb3853f74a4f821bbe4ed37a06ba">long-term obligations</span>.</ix:footnote></div>
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  </tr>


</table>
</ix:continuation></ix:continuation>
  <ix:continuation id="Text_1c0b22067bfa445a9e38081331f76f6c25" continuedAt="Text_1c0b22067bfa445a9e38081331f76f6c26">
<div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 12pt;"><br />
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</ix:continuation>
  <ix:continuation id="Text_1c0b22067bfa445a9e38081331f76f6c26" continuedAt="Text_1c0b22067bfa445a9e38081331f76f6c27">
<div style="display:none;"><br /></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">During the years ended December 31, 2021, 2020, and 2019 we paid $<ix:nonFraction name="us-gaap:OperatingLeasePayments" id="Fact_826cead5743b4e90a9d8b807e97fe422" contextRef="c20210101to20211231" unitRef="U001" decimals="-5" scale="6" format="ixt:numdotdecimal">3.3</ix:nonFraction> million, $<ix:nonFraction name="us-gaap:OperatingLeasePayments" id="Fact_297fcce7f2e44b348fe63e7be360cf7c" contextRef="c20200101to20201231" unitRef="U001" decimals="-5" scale="6" format="ixt:numdotdecimal">3.8</ix:nonFraction> million and $<ix:nonFraction name="us-gaap:OperatingLeasePayments" id="Fact_50e928616e964a8c94f28d1e4409995c" contextRef="c20190101to20191231" unitRef="U001" decimals="-5" scale="6" format="ixt:numdotdecimal">3.9</ix:nonFraction> million of lease payments, which were included in
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</ix:continuation>
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<div><br />
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<div style="display:none;"><br /></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">As of December 31, 2021, the future payments for our operating lease liabilities are as follows (in thousands):</div>
</ix:nonNumeric></ix:continuation>
  <ix:continuation id="Text_1c0b22067bfa445a9e38081331f76f6c29" continuedAt="Text_1c0b22067bfa445a9e38081331f76f6c30"><ix:continuation id="Text_8b4f52cda887401d8508d9bd3bb4e1a81" continuedAt="Text_8b4f52cda887401d8508d9bd3bb4e1a82">
<div><br />
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</ix:continuation></ix:continuation>
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  <tr>

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    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" colspan="2">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Operating</span> <span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Leases</span></div>
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 88%; background-color: #CCEEFF;">
          <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Year ending December 31,</div>
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    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">$</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 88%;">
          <div style="text-align: justify; margin-left: 18.7pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">2022</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:LesseeOperatingLeaseLiabilityPaymentsDueNextTwelveMonths" id="Fact_9240bc8118ea402f85a2119c7486d19d" contextRef="c20211231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">4,075</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 88%; background-color: #CCEEFF;">
          <div style="text-align: justify; text-indent: -0.2pt; margin-left: 18.7pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="text-indent: 0pt;">2023</span></div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:LesseeOperatingLeaseLiabilityPaymentsDueYearTwo" id="Fact_4609f99ef9604c9aae3baed51a3c3fed" contextRef="c20211231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">4,314</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 88%;">
          <div style="text-align: justify; text-indent: -0.2pt; margin-left: 18.7pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="text-indent: 0pt;">2024</span></div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:LesseeOperatingLeaseLiabilityPaymentsDueYearThree" id="Fact_d11239309f5945a3891ef526d1491daa" contextRef="c20211231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">4,223</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 88%; background-color: #CCEEFF;">
          <div style="text-align: justify; margin-left: 18.7pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">2025</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:LesseeOperatingLeaseLiabilityPaymentsDueYearFour" id="Fact_43a6c7550e004272b7f9ca99a8ba22d8" contextRef="c20211231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">4,062</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 88%;">
          <div style="text-align: justify; margin-left: 18.7pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">2026</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:LesseeOperatingLeaseLiabilityPaymentsDueYearFive" id="Fact_74899d789ebf4c2ebccd545b74c63e21" contextRef="c20211231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">3,778</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 88%; padding-bottom: 2px; background-color: #CCEEFF;">
          <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Thereafter</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:LesseeOperatingLeaseLiabilityPaymentsDueAfterYearFive" id="Fact_3931369a624044a9b1905cb93b92544f" contextRef="c20211231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">7,035</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 88%;">
          <div style="text-align: left; margin-left: 18.7pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Total minimum lease payments</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 88%; background-color: #CCEEFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Less:</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 88%; padding-bottom: 2px;">
          <div style="text-align: left; margin-left: 18.7pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Imputed interest</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:LesseeOperatingLeaseLiabilityUndiscountedExcessAmount" id="Fact_7af8c05d1850481699607948c91a7946" contextRef="c20211231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">5,429</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 88%; padding-bottom: 4px; background-color: #CCEEFF;">
          <div style="text-align: left; margin-left: 36.7pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Total operating lease liabilities</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:OperatingLeaseLiability" id="Fact_5bc4a22d2bca49aca884201dc1170194" contextRef="c20211231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">22,058</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>


</table>
</ix:continuation></ix:continuation>
  <ix:continuation id="Text_1c0b22067bfa445a9e38081331f76f6c31" continuedAt="Text_1c0b22067bfa445a9e38081331f76f6c32">
<div style="display:none;"><br /></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 12pt;"><br />
  </div>
</ix:continuation>
  <ix:continuation id="Text_1c0b22067bfa445a9e38081331f76f6c32">
<div style="display:none;"><br /></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Rent expense was $<ix:nonFraction name="us-gaap:OperatingLeaseExpense" id="Fact_b625c294a3bd434f8c74620b51e1ea20" contextRef="c20210101to20211231" unitRef="U001" decimals="-5" scale="6" format="ixt:numdotdecimal">3.4</ix:nonFraction>
    million, $<ix:nonFraction name="us-gaap:OperatingLeaseExpense" id="Fact_37e7125f4da2437a81d1b7f1853e4554" contextRef="c20200101to20201231" unitRef="U001" decimals="-5" scale="6" format="ixt:numdotdecimal">3.7</ix:nonFraction> million and $<ix:nonFraction name="us-gaap:OperatingLeaseExpense" id="Fact_a6f37ce5e1654e67b6bfb04f2bfaa94b" contextRef="c20190101to20191231" unitRef="U001" decimals="-5" scale="6" format="ixt:numdotdecimal">3.6</ix:nonFraction> million
    for the years ended December 31, 2021, 2020
    and 2019, respectively. </div>
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<div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">4. Stockholders</span>&#8217;<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"> Equity</span></div>
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<div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Preferred Stock</div>
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<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We are authorized to issue up to <ix:nonFraction name="us-gaap:PreferredStockSharesAuthorized" id="Fact_cdf2c784100f453c85b910f7ffa74a1e" contextRef="c20211231_StatementClassOfStockAxis_PreferredStockMember" unitRef="U002" decimals="-6" scale="6" format="ixt:numdotdecimal">15</ix:nonFraction> million shares of &#8220;blank check&#8221; Preferred Stock. As of December 31, 2021, there
    were <ix:nonFraction name="us-gaap:PreferredStockSharesOutstanding" id="Fact_9e3c83d35b1a4ad9bb5804db20a70950" contextRef="c20211231_StatementClassOfStockAxis_PreferredStockMember" unitRef="U002" decimals="INF" scale="0" format="ixt-sec:numwordsen">no</ix:nonFraction> shares of Preferred Stock outstanding. We have designated Series C Junior Participating Preferred Stock but have <ix:nonFraction name="us-gaap:PreferredStockSharesOutstanding" id="Fact_56071bcb2d56480397a630e97def5c32" contextRef="c20211231_StatementClassOfStockAxis_SeriesCPreferredStockMember" unitRef="U002" decimals="INF" scale="0" format="ixt-sec:numwordsen"><ix:nonFraction name="us-gaap:PreferredStockSharesIssued" id="Fact_5fe1b66991274e8cbc8b7286eae05354" contextRef="c20211231_StatementClassOfStockAxis_SeriesCPreferredStockMember" unitRef="U002" decimals="INF" scale="0" format="ixt-sec:numwordsen">no</ix:nonFraction></ix:nonFraction> issued or outstanding shares as of December 31, 2021.</div>
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<div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Common Stock</div>
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<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">At December 31, 2021
    and 2020, we had <ix:nonFraction name="us-gaap:CommonStockSharesAuthorized" id="Fact_292edcba897f40209ed42c14feed0f2e" contextRef="c20201231_StatementClassOfStockAxis_CommonStockMember" unitRef="U002" decimals="-6" scale="6" format="ixt:numdotdecimal"><ix:nonFraction name="us-gaap:CommonStockSharesAuthorized" id="Fact_10c668f50b664401a30c1bb6a51edb5a" contextRef="c20211231_StatementClassOfStockAxis_CommonStockMember" unitRef="U002" decimals="-6" scale="6" format="ixt:numdotdecimal">300</ix:nonFraction></ix:nonFraction> million
    shares of common stock authorized, of which <ix:nonFraction name="us-gaap:CommonStockSharesOutstanding" id="Fact_6d69412111c94f649e3bc6185a645456" contextRef="c20211231_StatementClassOfStockAxis_CommonStockMember" unitRef="U002" decimals="-5" scale="6" format="ixt:numdotdecimal"><ix:nonFraction name="us-gaap:CommonStockSharesIssued" id="Fact_5f23b4a620974ffa9ac1338867c08a09" contextRef="c20211231_StatementClassOfStockAxis_CommonStockMember" unitRef="U002" decimals="-5" scale="6" format="ixt:numdotdecimal">141.2</ix:nonFraction></ix:nonFraction> million and <ix:nonFraction name="us-gaap:CommonStockSharesOutstanding" id="Fact_eba69077d17e4204b64b00ee384f8ab0" contextRef="c20201231_StatementClassOfStockAxis_CommonStockMember" unitRef="U002" decimals="-5" scale="6" format="ixt:numdotdecimal"><ix:nonFraction name="us-gaap:CommonStockSharesIssued" id="Fact_7461dbbf5e58485bbd613618075e0ee5" contextRef="c20201231_StatementClassOfStockAxis_CommonStockMember" unitRef="U002" decimals="-5" scale="6" format="ixt:numdotdecimal">140.4</ix:nonFraction></ix:nonFraction> million were issued and outstanding, respectively. As of December 31, 2021,
    total common shares reserved for future issuance were <ix:nonFraction name="us-gaap:CommonStockCapitalSharesReservedForFutureIssuance" id="Fact_47e88bfdb1664c48a2b1ff64f80389f5" contextRef="c20211231_StatementClassOfStockAxis_CommonStockMember" unitRef="U002" decimals="-5" scale="6" format="ixt:numdotdecimal">46.2</ix:nonFraction> million.</div>
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<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">During the years ended December 31, 2021, 2020 and 2019, we issued <ix:nonFraction name="us-gaap:StockIssuedDuringPeriodSharesShareBasedCompensationGross" id="Fact_0ee4b00a77834001bc604428d95159c5" contextRef="c20210101to20211231_StatementClassOfStockAxis_CommonStockMember" unitRef="U002" decimals="-5" scale="6" format="ixt:numdotdecimal">1.1</ix:nonFraction> million, <ix:nonFraction name="us-gaap:StockIssuedDuringPeriodSharesShareBasedCompensationGross" id="Fact_6d8eb059ce834187b603ca07d5abb207" contextRef="c20200101to20201231_StatementClassOfStockAxis_CommonStockMember" unitRef="U002" decimals="-5" scale="6" format="ixt:numdotdecimal">1.7</ix:nonFraction> million and <ix:nonFraction name="us-gaap:StockIssuedDuringPeriodSharesShareBasedCompensationGross" id="Fact_edd10ce23a74492e8176afb94a7abdb0" contextRef="c20190101to20191231_StatementClassOfStockAxis_CommonStockMember" unitRef="U002" decimals="-5" scale="6" format="ixt:numdotdecimal">3.1</ix:nonFraction> million shares of common stock, respectively, for stock option
    exercises, vesting of restricted stock units, and ESPP purchases. We received net proceeds from these transactions of $<ix:nonFraction name="us-gaap:ProceedsFromIssuanceOfSharesUnderIncentiveAndShareBasedCompensationPlansIncludingStockOptions" id="Fact_d6943984a2cd41b0a8cb3b1deb1f9fc2" contextRef="c20210101to20211231_StatementClassOfStockAxis_CommonStockMember" unitRef="U001" decimals="-5" scale="6" format="ixt:numdotdecimal">11.6</ix:nonFraction> million, $<ix:nonFraction name="us-gaap:ProceedsFromIssuanceOfSharesUnderIncentiveAndShareBasedCompensationPlansIncludingStockOptions" id="Fact_5fbad294b6304ae4a8a72a7d07384a09" contextRef="c20200101to20201231_StatementClassOfStockAxis_CommonStockMember" unitRef="U001" decimals="-5" scale="6" format="ixt:numdotdecimal">52.0</ix:nonFraction> million and $<ix:nonFraction name="us-gaap:ProceedsFromIssuanceOfSharesUnderIncentiveAndShareBasedCompensationPlansIncludingStockOptions" id="Fact_4af5fbc849034e59b7d2901adc45af29" contextRef="c20190101to20191231_StatementClassOfStockAxis_CommonStockMember" unitRef="U001" decimals="-5" scale="6" format="ixt:numdotdecimal">119.7</ix:nonFraction> million in 2021, 2020 and 2019, respectively.</div>
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<div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Share Repurchase Program</div>
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<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">In September 2019, our board of directors approved a share repurchase program of up to $<ix:nonFraction name="us-gaap:StockRepurchaseProgramAuthorizedAmount1" id="Fact_44310671d1664bfca3445b963a157027" contextRef="c20190930" unitRef="U001" decimals="-6" scale="6" format="ixt:numdotdecimal">125</ix:nonFraction> million of our common stock. In 2019, we repurchased <ix:nonFraction name="us-gaap:StockRepurchasedDuringPeriodShares" id="Fact_a0ec8c80989241c28567434e9da68f95" contextRef="c20190101to20191231" unitRef="U002" decimals="0" scale="0" format="ixt:numdotdecimal">535,000</ix:nonFraction>
    shares for $<ix:nonFraction name="us-gaap:PaymentsForRepurchaseOfCommonStock" id="Fact_b3c70b4e95ca4205b78bd5e2e50aeeab" contextRef="c20190101to20191231" unitRef="U001" decimals="-5" scale="6" format="ixt:numdotdecimal">34.4</ix:nonFraction> million. In the first quarter of 2020, we repurchased an additional <ix:nonFraction name="us-gaap:StockRepurchasedDuringPeriodShares" id="Fact_e459a3912815439c8077106b57fb5880" contextRef="c20200101to20200331" unitRef="U002" decimals="-5" scale="6" format="ixt:numdotdecimal">1.5</ix:nonFraction> million shares for $<ix:nonFraction name="us-gaap:PaymentsForRepurchaseOfCommonStock" id="Fact_2b769cf5ebe543ef91ba7139fec3a4d2" contextRef="c20200101to20200331" unitRef="U001" decimals="-5" scale="6" format="ixt:numdotdecimal">90.5</ix:nonFraction> million.</div>
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<div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Stock Plans</div>
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<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;">1989 Stock Option Plan</div>
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<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">In June 1989, our Board of Directors adopted, and the stockholders subsequently approved, a stock option plan that, as
    amended, provides for the issuance of non-qualified and incentive stock options for the purchase of up to <ix:nonFraction name="us-gaap:ShareBasedCompensationArrangementByShareBasedPaymentAwardNumberOfSharesAuthorized" id="Fact_2a82263b39a7474ba2b3298ff2f3a349" contextRef="c20211231_PlanNameAxis_StockOptionPlan1989Member" unitRef="U002" decimals="-5" scale="6" format="ixt:numdotdecimal">20.0</ix:nonFraction> million shares of common stock to
    our employees, directors, and consultants. The plan expires in January 2024. The 1989 Plan does not allow us to grant stock bonuses or restricted stock awards and prohibits us from repricing any options outstanding under the plan unless our
    stockholders approve the repricing. Options vest over a <ix:nonNumeric name="us-gaap:ShareBasedCompensationArrangementByShareBasedPaymentAwardAwardVestingPeriod1" id="Fact_300b6e73bf984f4ba7b411e09fd8ac0a" contextRef="c20210101to20211231_AwardTypeAxis_StockOptionMember_PlanNameAxis_StockOptionPlan1989Member" format="ixt-sec:durwordsen">four-year</ix:nonNumeric> period, with <ix:nonFraction name="us-gaap:SharebasedCompensationArrangementBySharebasedPaymentAwardAwardVestingRightsPercentage" id="Fact_f9de77fe0ed4406e89bc6cca403c951f" contextRef="c20210101to20211231_AwardTypeAxis_StockOptionMember_PlanNameAxis_StockOptionPlan1989Member_VestingAxis_ShareBasedCompensationAwardTrancheOneMember" unitRef="U003" decimals="2" scale="-2" format="ixt:numdotdecimal">25</ix:nonFraction>percent exercisable at the end of <ix:nonNumeric name="us-gaap:ShareBasedCompensationArrangementByShareBasedPaymentAwardAwardRequisiteServicePeriod1" id="Fact_8c42e3e31eb04afc9a1a6d089d774313" contextRef="c20210101to20211231_AwardTypeAxis_StockOptionMember_PlanNameAxis_StockOptionPlan1989Member_VestingAxis_ShareBasedCompensationAwardTrancheOneMember" format="ixt-sec:durwordsen">one year</ix:nonNumeric> from the date of the grant and the
    balance vesting ratably, on a monthly basis, thereafter and have a term of <ix:nonNumeric name="us-gaap:SharebasedCompensationArrangementBySharebasedPaymentAwardExpirationPeriod" id="Fact_7077ae6833184dee85f5278742d25b56" contextRef="c20210101to20211231_AwardTypeAxis_StockOptionMember_PlanNameAxis_StockOptionPlan1989Member" format="ixt-sec:durwordsen">seven years</ix:nonNumeric>. At December 31, 2021, a total of <ix:nonFraction name="us-gaap:ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsOutstandingNumber" id="Fact_add8de5b32ae49bb87473e4eddedffb6" contextRef="c20211231_PlanNameAxis_StockOptionPlan1989Member" unitRef="U002" decimals="-3" scale="3" format="ixt:numdotdecimal">28</ix:nonFraction> thousand options were outstanding, of which
    options to purchase <ix:nonFraction name="us-gaap:ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsExercisableNumber" id="Fact_803cbfb1dea74d34930f47cade7a9b19" contextRef="c20211231_PlanNameAxis_StockOptionPlan1989Member" unitRef="U002" decimals="-3" scale="3" format="ixt:numdotdecimal">28</ix:nonFraction> thousand shares were exercisable, and <ix:nonFraction name="us-gaap:ShareBasedCompensationArrangementByShareBasedPaymentAwardNumberOfSharesAvailableForGrant" id="Fact_8c931ba74e0d4e5c8d57ed4b294c4a22" contextRef="c20211231_PlanNameAxis_StockOptionPlan1989Member" unitRef="U002" decimals="-3" scale="3" format="ixt:numdotdecimal">49</ix:nonFraction> thousand shares were available for future grant under the 1989 Plan.</div>
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<div style="text-align: justify; text-indent: -18pt; margin-left: 54pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;">2011 Equity Incentive Plan</div>
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<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">In March 2011, our Board of Directors adopted, and the stockholders subsequently approved, a stock option plan that
    provides for the issuance of stock options, stock appreciation rights, restricted stock awards, restricted stock unit awards, and performance cash awards to our employees, directors, and consultants. In June 2015, May 2017 and June 2019, after
    receiving approval from our stockholders, we amended our 2011 Equity Incentive Plan, or<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> 2011 Plan,</span> to increase the total number of shares reserved for issuance. We
    increased the shares available under our 2011 Equity Incentive Plan from <ix:nonFraction name="us-gaap:ShareBasedCompensationArrangementByShareBasedPaymentAwardNumberOfSharesAuthorized" id="Fact_5882aa832aa646c6b635e3bfe41d5f81" contextRef="c20150531_PlanNameAxis_EquityIncentivePlan2011Member" unitRef="U002" decimals="-5" scale="6" format="ixt:numdotdecimal">5.5</ix:nonFraction> million to <ix:nonFraction name="us-gaap:ShareBasedCompensationArrangementByShareBasedPaymentAwardNumberOfSharesAuthorized" id="Fact_1f00ba80dcbf4591a6c03449d0ff3e6e" contextRef="c20150630_PlanNameAxis_EquityIncentivePlan2011Member" unitRef="U002" decimals="-5" scale="6" format="ixt:numdotdecimal">11.0</ix:nonFraction> million in June 2015, from <ix:nonFraction name="us-gaap:ShareBasedCompensationArrangementByShareBasedPaymentAwardNumberOfSharesAuthorized" id="Fact_b4182e47d22e4ab1b6c25c3beae739b7" contextRef="c20150630_PlanNameAxis_EquityIncentivePlan2011Member" unitRef="U002" decimals="-5" scale="6" format="ixt:numdotdecimal">11.0</ix:nonFraction> million to <ix:nonFraction name="us-gaap:ShareBasedCompensationArrangementByShareBasedPaymentAwardNumberOfSharesAuthorized" id="Fact_73b32b7412144ae2844353056c2328ce" contextRef="c20170531_PlanNameAxis_EquityIncentivePlan2011Member" unitRef="U002" decimals="-5" scale="6" format="ixt:numdotdecimal">16.0</ix:nonFraction> million in May 2017 and from <ix:nonFraction name="us-gaap:ShareBasedCompensationArrangementByShareBasedPaymentAwardNumberOfSharesAuthorized" id="Fact_67f1d774e8d34fbbbdcb82cbb830d91a" contextRef="c20170531_PlanNameAxis_EquityIncentivePlan2011Member" unitRef="U002" decimals="-5" scale="6" format="ixt:numdotdecimal">16.0</ix:nonFraction> million to <ix:nonFraction name="us-gaap:ShareBasedCompensationArrangementByShareBasedPaymentAwardNumberOfSharesAuthorized" id="Fact_dd1127c8a7ec4eedb63afb7ca6169e93" contextRef="c20190630_PlanNameAxis_EquityIncentivePlan2011Member" unitRef="U002" decimals="-5" scale="6" format="ixt:numdotdecimal">23.0</ix:nonFraction> million in June 2019. In the second quarter of 2021, after receiving approval from our stockholders, we amended our <span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">2011 Plan. The amendment increased the total number of shares of common stock authorized for issuance under the 2011 Plan from </span><ix:nonFraction name="us-gaap:ShareBasedCompensationArrangementByShareBasedPaymentAwardNumberOfSharesAuthorized" id="Fact_57cfec8e7dd44452863fefb2e13edfc5" contextRef="c20190630_PlanNameAxis_EquityIncentivePlan2011Member" unitRef="U002" decimals="-5" scale="6" format="ixt:numdotdecimal">23.0</ix:nonFraction><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> million to </span><ix:nonFraction name="us-gaap:ShareBasedCompensationArrangementByShareBasedPaymentAwardNumberOfSharesAuthorized" id="Fact_de84fcdda0694d5aa3e5b25edbac3ff6" contextRef="c20210630_PlanNameAxis_EquityIncentivePlan2011Member" unitRef="U002" decimals="-5" scale="6" format="ixt:numdotdecimal">29.7</ix:nonFraction><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> million and added a fungible share counting ratio whereby the share reserve will be reduced by </span><ix:nonFraction name="ions:IncreaseDecreaseInFungibleShareReserveForEachShareIssuedPursuantToFullValueAward" id="Fact_23f42a38660942f6be12a03f919b693c" contextRef="c20210630_PlanNameAxis_EquityIncentivePlan2011Member" unitRef="U002" decimals="1" sign="-" scale="0" format="ixt:numdotdecimal">1.7</ix:nonFraction><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> shares for each share of common stock issued pursuant to a full value award (i.e., RSU or PRSU) and increased by
    </span><ix:nonFraction name="ions:IncreaseDecreaseInFungibleShareReserveForEachShareReturningFromFullValueAward" id="Fact_4de4ba08df4c4468acb8a87fe4bb1be6" contextRef="c20210630_PlanNameAxis_EquityIncentivePlan2011Member" unitRef="U002" decimals="1" scale="0" format="ixt:numdotdecimal">1.7</ix:nonFraction><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> shares for each share of common stock returning from a
      full value award. </span>The plan expires in June 2031. The 2011 Plan does not allow us to reduce the exercise price of any outstanding stock options or stock appreciation rights or cancel any outstanding stock options or stock appreciation rights
    that have an exercise price or strike price greater than the current fair market value of the common stock in exchange for cash or other stock awards unless our stockholders approve such action. Currently we anticipate awarding only stock options, RSU
    and PRSU awards to our employees, directors and consultants. Options vest over a <ix:nonNumeric name="us-gaap:ShareBasedCompensationArrangementByShareBasedPaymentAwardAwardVestingPeriod1" id="Fact_763f3de6711b427ba6c4d7792811777d" contextRef="c20210101to20211231_AwardTypeAxis_StockOptionMember_PlanNameAxis_EquityIncentivePlan2011Member" format="ixt-sec:durwordsen">four-year</ix:nonNumeric> period, with <ix:nonFraction name="us-gaap:SharebasedCompensationArrangementBySharebasedPaymentAwardAwardVestingRightsPercentage" id="Fact_13d5cd5cb0eb4f0e964e186051bcf7a9" contextRef="c20210101to20211231_AwardTypeAxis_StockOptionMember_PlanNameAxis_EquityIncentivePlan2011Member_VestingAxis_ShareBasedCompensationAwardTrancheOneMember" unitRef="U003" decimals="2" scale="-2" format="ixt:numdotdecimal">25</ix:nonFraction> percent exercisable at the end of <ix:nonNumeric name="us-gaap:ShareBasedCompensationArrangementByShareBasedPaymentAwardAwardRequisiteServicePeriod1" id="Fact_3a3d9b453a064adea83801f87842c09c" contextRef="c20210101to20211231_AwardTypeAxis_StockOptionMember_PlanNameAxis_EquityIncentivePlan2011Member_VestingAxis_ShareBasedCompensationAwardTrancheOneMember" format="ixt-sec:durwordsen">one year</ix:nonNumeric> from the date of the grant
    and the balance vesting ratably, on a monthly basis, thereafter and have a term of <ix:nonNumeric name="us-gaap:SharebasedCompensationArrangementBySharebasedPaymentAwardExpirationPeriod" id="Fact_7cc41a014493404ba087ca86ab407ebe" contextRef="c20210101to20211231_AwardTypeAxis_StockOptionMember_PlanNameAxis_EquityIncentivePlan2011Member" format="ixt-sec:durwordsen">seven years</ix:nonNumeric>. Options granted after December 31, 2021 have a
    term of <ix:nonNumeric name="us-gaap:ShareBasedCompensationArrangementByShareBasedPaymentAwardAwardVestingPeriod1" id="Fact_c3a19253882c43ce8572c4be5c36bb38" contextRef="c20210101to20211231_AwardDateAxis_IssuedAfterDecember312021Member_AwardTypeAxis_StockOptionMember_PlanNameAxis_EquityIncentivePlan2011Member" format="ixt-sec:durwordsen">ten years</ix:nonNumeric>. We have granted restricted stock unit awards to our employees under the 2011 Plan which vest annually over a <ix:nonNumeric name="us-gaap:ShareBasedCompensationArrangementByShareBasedPaymentAwardAwardVestingPeriod1" id="Fact_323dc3ca223441ed8cae26677d80920d" contextRef="c20210101to20211231_AwardTypeAxis_RestrictedStockUnitsRSUMember_PlanNameAxis_EquityIncentivePlan2011Member" format="ixt-sec:durwordsen">four-year</ix:nonNumeric> period. At December 31, 2021, a
    total of <ix:nonFraction name="us-gaap:ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsOutstandingNumber" id="Fact_f6eb4ef69d9549b79f43b5ca7f3d3f65" contextRef="c20211231_PlanNameAxis_EquityIncentivePlan2011Member" unitRef="U002" decimals="-5" scale="6" format="ixt:numdotdecimal">12.8</ix:nonFraction> million options were outstanding, of which <ix:nonFraction name="us-gaap:ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsExercisableNumber" id="Fact_c37dd0f781d649a5bc97d2c87bbaeacf" contextRef="c20211231_PlanNameAxis_EquityIncentivePlan2011Member" unitRef="U002" decimals="-5" scale="6" format="ixt:numdotdecimal">8.3</ix:nonFraction> million were exercisable, <ix:nonFraction name="us-gaap:ShareBasedCompensationArrangementByShareBasedPaymentAwardNonOptionEquityInstrumentsOutstandingNumber" id="Fact_f19dff70c85e4b53ab5b44f7e4b872f2" contextRef="c20211231_AwardTypeAxis_RestrictedStockUnitsRSUMember_PlanNameAxis_EquityIncentivePlan2011Member" unitRef="U002" decimals="-5" scale="6" format="ixt:numdotdecimal">2.5</ix:nonFraction> million restricted stock unit awards were
    outstanding, and <ix:nonFraction name="us-gaap:ShareBasedCompensationArrangementByShareBasedPaymentAwardNumberOfSharesAvailableForGrant" id="Fact_f121d278af9942b4ba6d23912dbef6db" contextRef="c20211231_PlanNameAxis_EquityIncentivePlan2011Member" unitRef="U002" decimals="-5" scale="6" format="ixt:numdotdecimal">8.5</ix:nonFraction> million shares were available for future grant under the 2011 Plan.</div>
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<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Under the 2011 Plan, we may issue a stock award with additional acceleration of vesting and exercisability upon or after a
    change in control. In the absence of such provisions, no such acceleration will occur. The stock options and restricted stock unit awards we issued to Dr. Stanley T. Crooke in his former role as chief executive officer and certain stock options and
    restricted stock unit awards we issued to B. Lynne Parshall in her former role as chief operating officer have accelerated vesting upon a change of control, as defined in the 2011 Plan. In addition, we implemented a change of control and severance
    benefit plan that provides for change of control and severance benefits to our executive officers, including our chief executive officer and chief financial officer. If we terminate <ix:nonFraction name="ions:NumberOfExecutiveOfficersTerminatedBeforeChangeInControlWhenVestingWillAccelerateForExecutiveOfficers" id="Fact_8f959a059fb340fc9f6dfdc4cbdfc6d9" contextRef="c20210101to20211231_PlanNameAxis_EquityIncentivePlan2011Member" unitRef="U016" decimals="INF" scale="0" format="ixt-sec:numwordsen">one</ix:nonFraction> of our executive officers or if an executive officer resigns for good reason during the period that begins <ix:nonNumeric name="ions:PeriodBeforeChangeInControlWhenVestingWillAccelerateForExecutiveOfficers" id="Fact_5cf8f8a57af249d4a6cce115597f8861" contextRef="c20210101to20211231_PlanNameAxis_EquityIncentivePlan2011Member" format="ixt-sec:durwordsen">three months</ix:nonNumeric> before and ends <ix:nonNumeric name="ions:PeriodAfterChangeInControlWhenVestingWillAccelerateForExecutiveOfficers" id="Fact_4b4db5c64d7f42eca6f341535cd62db4" contextRef="c20210101to20211231_PlanNameAxis_EquityIncentivePlan2011Member" format="ixt-sec:durwordsen">twelve months</ix:nonNumeric> following a change in control of the
    company, the impacted executive officers&#8217; stock options and RSUs vesting will accelerate for options and RSUs outstanding as of the termination date.</div>
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<div style="text-align: justify; text-indent: -18pt; margin-left: 54pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;">2020 Equity Incentive Plan</div>
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<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">In connection with the Akcea Merger in October 2020, we
      assumed the unallocated portion of the available share reserve under the Akcea 2015 Equity Incentive Plan. In December 2020, we amended and restated the Akcea 2015 equity plan, including renaming the plan as the Ionis Pharmaceuticals, Inc. 2020
      Equity Incentive Plan, or 2020 Plan. The 2020 Plan provided for the issuance of up to </span><ix:nonFraction name="us-gaap:ShareBasedCompensationArrangementByShareBasedPaymentAwardNumberOfSharesAuthorized" id="Fact_c2fdd0b5f17c4a559deafa59528e79eb" contextRef="c20201231_PlanNameAxis_EquityIncentivePlan2020Member" unitRef="U002" decimals="-5" scale="6" format="ixt:numdotdecimal">2.6</ix:nonFraction><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> million shares of our Common Stock to our employees, directors and consultants who were employees of Akcea prior to the Akcea Merger. </span><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">In the second quarter of 2021, our Compensation Committee approved an amendment to the 2020 Plan. The amendment decreased the total number of shares of common stock authorized for issuance under the 2020 Plan from
      approximately </span><ix:nonFraction name="us-gaap:ShareBasedCompensationArrangementByShareBasedPaymentAwardNumberOfSharesAuthorized" id="Fact_b0e9739857ca4a9ca5aef49a60ac50e3" contextRef="c20201231_PlanNameAxis_EquityIncentivePlan2020Member" unitRef="U002" decimals="-5" scale="6" format="ixt:numdotdecimal">2.6</ix:nonFraction><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> million to </span><ix:nonFraction name="us-gaap:ShareBasedCompensationArrangementByShareBasedPaymentAwardNumberOfSharesAuthorized" id="Fact_c1bebf52134d402a8958171cfbc5c265" contextRef="c20210630_PlanNameAxis_EquityIncentivePlan2020Member" unitRef="U002" decimals="-5" scale="6" format="ixt:numdotdecimal">1.6</ix:nonFraction><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> million. We assumed the 2020 Plan in connection with Ionis&#8217;
      reacquisition of all of the outstanding shares of Akcea Therapeutics, Inc. as part of the Akcea Merger.</span></div>
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<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">The plan expires in December 2025. The 2020 Plan does not allow us to reduce the exercise price of any outstanding stock
    options or stock appreciation rights or cancel any outstanding stock options or stock appreciation rights that have an exercise price or strike price greater than the current fair market value of the common stock in exchange for cash or other stock
    awards unless our stockholders approve such action. Currently we anticipate awarding only stock options and RSU awards to our eligible employees, directors and consultants. Options vest over a <ix:nonNumeric name="us-gaap:ShareBasedCompensationArrangementByShareBasedPaymentAwardAwardVestingPeriod1" id="Fact_f1c93af494b04abea846be47da9b6f21" contextRef="c20210101to20211231_AwardTypeAxis_StockOptionMember_PlanNameAxis_EquityIncentivePlan2020Member" format="ixt-sec:durwordsen">four-year</ix:nonNumeric> period, with <ix:nonFraction name="us-gaap:SharebasedCompensationArrangementBySharebasedPaymentAwardAwardVestingRightsPercentage" id="Fact_bf4c2072cc4b4282835c60cb240d0d17" contextRef="c20210101to20211231_AwardTypeAxis_StockOptionMember_PlanNameAxis_EquityIncentivePlan2020Member_VestingAxis_ShareBasedCompensationAwardTrancheOneMember" unitRef="U003" decimals="2" scale="-2" format="ixt:numdotdecimal">25</ix:nonFraction> percent exercisable at the end of <ix:nonNumeric name="us-gaap:ShareBasedCompensationArrangementByShareBasedPaymentAwardAwardRequisiteServicePeriod1" id="Fact_6ad6746c60684d1cade6e5856104044e" contextRef="c20210101to20211231_AwardTypeAxis_StockOptionMember_PlanNameAxis_EquityIncentivePlan2020Member_VestingAxis_ShareBasedCompensationAwardTrancheOneMember" format="ixt-sec:durwordsen">one year</ix:nonNumeric> from the date of the grant and the balance vesting ratably, on a monthly basis, thereafter and have a term of <ix:nonNumeric name="us-gaap:SharebasedCompensationArrangementBySharebasedPaymentAwardExpirationPeriod" id="Fact_83e080be39814e6ba0c957ebe364dd77" contextRef="c20210101to20211231_AwardTypeAxis_StockOptionMember_PlanNameAxis_EquityIncentivePlan2020Member" format="ixt-sec:durwordsen">seven years</ix:nonNumeric>. Options granted after December 31, 2021 have a term of <ix:nonNumeric name="us-gaap:ShareBasedCompensationArrangementByShareBasedPaymentAwardAwardVestingPeriod1" id="Fact_8c17823f65d24056a081b6cf50f1e55f" contextRef="c20210101to20211231_AwardDateAxis_IssuedAfterDecember312021Member_AwardTypeAxis_StockOptionMember_PlanNameAxis_EquityIncentivePlan2020Member" format="ixt-sec:durwordsen">ten years</ix:nonNumeric>.
    We have granted restricted stock unit awards to our employees under the 2020 Plan which vest annually over a <ix:nonNumeric name="us-gaap:ShareBasedCompensationArrangementByShareBasedPaymentAwardAwardVestingPeriod1" id="Fact_3568607a84604758a037e6132fdacf7c" contextRef="c20210101to20211231_AwardTypeAxis_RestrictedStockUnitsRSUMember_PlanNameAxis_EquityIncentivePlan2020Member" format="ixt-sec:durwordsen">four-year</ix:nonNumeric> period. At December 31, 2021, a total of <ix:nonFraction name="us-gaap:ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsOutstandingNumber" id="Fact_7b23f3391b8648699d7f9d9bdfc98ad2" contextRef="c20211231_PlanNameAxis_EquityIncentivePlan2020Member" unitRef="U002" decimals="-5" scale="6" format="ixt:numdotdecimal">0.2</ix:nonFraction> million
    options were outstanding, of which <ix:nonFraction name="us-gaap:ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsExercisableNumber" id="Fact_4795c74284de4082b785b01a78026eb7" contextRef="c20211231_PlanNameAxis_EquityIncentivePlan2020Member" unitRef="U002" decimals="INF" scale="0" format="ixt-sec:numwordsen">none</ix:nonFraction> were exercisable, <ix:nonFraction name="us-gaap:ShareBasedCompensationArrangementByShareBasedPaymentAwardNonOptionEquityInstrumentsOutstandingNumber" id="Fact_998c6813ad25478d8df2ef4e673ad903" contextRef="c20211231_AwardTypeAxis_RestrictedStockUnitsRSUMember_PlanNameAxis_EquityIncentivePlan2020Member" unitRef="U002" decimals="-5" scale="6" format="ixt:numdotdecimal">0.1</ix:nonFraction> million restricted stock unit awards were outstanding, and <ix:nonFraction name="us-gaap:ShareBasedCompensationArrangementByShareBasedPaymentAwardNumberOfSharesAvailableForGrant" id="Fact_445e0eb67023409bac8ed8d6e705c2d6" contextRef="c20211231_PlanNameAxis_EquityIncentivePlan2020Member" unitRef="U002" decimals="-5" scale="6" format="ixt:numdotdecimal">1.3</ix:nonFraction> million shares were
    available for future grant under the 2020 Plan.</div>
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<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Under the 2020 Plan, we may issue a stock award with additional acceleration of vesting and exercisability upon or after a
    change in control. In the absence of such provisions, no such acceleration will occur.</div>
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<div style="text-align: left; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;">Corporate Transactions and Change in Control under 2011 and 2020 Plans</div>
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<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">In the event of certain significant corporate transactions, our Board of Directors has the discretion to take one or more
    of the following actions with respect to outstanding stock awards under the 2011 and 2020 Plans:</div>
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          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">arrange for assumption, continuation, or substitution of a stock award by a surviving or acquiring entity (or its parent company);</div>
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          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">arrange for the assignment of any reacquisition or repurchase rights applicable to any shares of our common stock issued pursuant to a stock award to the
            surviving or acquiring corporation (or its parent company);</div>
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    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">accelerate the vesting and exercisability of a stock award followed by the termination of the stock award;</div>
        </td>

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</table>
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    <td style="width: 36pt;"></td>

    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">arrange for the lapse of any reacquisition or repurchase rights applicable to any shares of our common stock issued pursuant to a stock award;</div>
        </td>

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</table>
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    <td style="width: 36pt;"></td>

    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">cancel or arrange for the cancellation of a stock award, to the extent not vested or not exercised prior to the effective date of the corporate
            transaction, in exchange for cash consideration, if any, as the Board, in its sole discretion, may consider appropriate; and</div>
        </td>

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</table>
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    <td style="width: 36pt;"></td>

    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">arrange for the surrender of a stock award in exchange for a payment equal to the excess of (a) the value of the property the holder of the stock award
            would have received upon the exercise of the stock award, over (b) any exercise price payable by such holder in connection with such exercise.</div>
        </td>

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</table>
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<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;">2002 Non-Employee Directors&#8217; Stock Option Plan</div>
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<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">In September 2001, our Board of Directors adopted, and the stockholders subsequently approved, an amendment and
    restatement of the 1992 Non-Employee Directors&#8217; Stock Option Plan, which provides for the issuance of non-qualified stock options and restricted stock units to our non-employee directors. The name of the resulting plan is the 2002 Non-Employee
    Directors&#8217; Stock Option Plan, or the 2002 Plan. In June 2015, after receiving approval from our stockholders, we amended our 2002 Plan to increase the total number of shares reserved for issuance from <ix:nonFraction name="us-gaap:ShareBasedCompensationArrangementByShareBasedPaymentAwardNumberOfSharesAuthorized" id="Fact_0e9dea3a9bb44f258d4a6a1eeffbb1b0" contextRef="c20150531_PlanNameAxis_NonemployeeDirectorsStockOptionPlan2002Member" unitRef="U002" decimals="-5" scale="6" format="ixt:numdotdecimal">1.2</ix:nonFraction> million to <ix:nonFraction name="us-gaap:ShareBasedCompensationArrangementByShareBasedPaymentAwardNumberOfSharesAuthorized" id="Fact_e55c20e37dc6464eb74bde99a3d220dc" contextRef="c20150630_PlanNameAxis_NonemployeeDirectorsStockOptionPlan2002Member" unitRef="U002" decimals="-5" scale="6" format="ixt:numdotdecimal">2.0</ix:nonFraction> million. In June 2020, after receiving approval from our
    stockholders, we further amended our 2002 Plan. <span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">The amendments included:</span></div>
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    <td style="width: 36pt;"></td>

    <td style="width: 18pt; vertical-align: top; align: right; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">An increase to the total number of shares reserved for issuance under the
              plan from </span><ix:nonFraction name="us-gaap:ShareBasedCompensationArrangementByShareBasedPaymentAwardNumberOfSharesAuthorized" id="Fact_fda3670487384cb49c8eb41d6d8f4665" contextRef="c20150630_PlanNameAxis_NonemployeeDirectorsStockOptionPlan2002Member" unitRef="U002" decimals="-5" scale="6" format="ixt:numdotdecimal">2.0</ix:nonFraction><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> million to </span><ix:nonFraction name="us-gaap:ShareBasedCompensationArrangementByShareBasedPaymentAwardNumberOfSharesAuthorized" id="Fact_8b16c9fcbd8a4de6a3ff40e97438a3a8" contextRef="c20200630_PlanNameAxis_NonemployeeDirectorsStockOptionPlan2002Member" unitRef="U002" decimals="-5" scale="6" format="ixt:numdotdecimal">2.8</ix:nonFraction><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> million shares;</span></div>
        </td>

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    <td style="width: 36pt;"></td>

    <td style="width: 18pt; vertical-align: top; align: right; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">A reduction to the amount of the automatic awards under the plan;</div>
        </td>

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</table>
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    <td style="width: 36pt;"></td>

    <td style="width: 18pt; vertical-align: top; align: right; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">A revision to the vesting schedule of new awards granted; and</div>
        </td>

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    <td style="width: 36pt;"></td>

    <td style="width: 18pt; vertical-align: top; align: right; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;">An extension of the term of the plan.</div>
        </td>

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</table>
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<div style="display:none;"><br /></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Options under this plan expire <ix:nonNumeric name="us-gaap:SharebasedCompensationArrangementBySharebasedPaymentAwardExpirationPeriod" id="Fact_e6b00753880241348e596a82fa22bab2" contextRef="c20210101to20211231_AwardTypeAxis_StockOptionMember_PlanNameAxis_NonemployeeDirectorsStockOptionPlan2002Member" format="ixt-sec:durwordsen">10 years</ix:nonNumeric> from the date of grant. At December 31, 2021, a total of <ix:nonFraction name="us-gaap:ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsOutstandingNumber" id="Fact_28beff5bd3d14e0c9936c3a0e4bfd184" contextRef="c20211231_PlanNameAxis_NonemployeeDirectorsStockOptionPlan2002Member" unitRef="U002" decimals="-5" scale="6" format="ixt:numdotdecimal">1.0</ix:nonFraction> million options were outstanding, of which <ix:nonFraction name="us-gaap:ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsExercisableNumber" id="Fact_5c3c554e640546a481c2968b37014870" contextRef="c20211231_PlanNameAxis_NonemployeeDirectorsStockOptionPlan2002Member" unitRef="U002" decimals="-5" scale="6" format="ixt:numdotdecimal">0.8</ix:nonFraction>
    million were exercisable, <ix:nonFraction name="us-gaap:ShareBasedCompensationArrangementByShareBasedPaymentAwardNonOptionEquityInstrumentsOutstandingNumber" id="Fact_d025b834777346cfa313dfb503dafd03" contextRef="c20211231_AwardTypeAxis_RestrictedStockUnitsRSUMember_PlanNameAxis_NonemployeeDirectorsStockOptionPlan2002Member" unitRef="U002" decimals="-5" scale="6" format="ixt:numdotdecimal">0.1</ix:nonFraction> million restricted stock unit awards were outstanding, and <ix:nonFraction name="us-gaap:ShareBasedCompensationArrangementByShareBasedPaymentAwardNumberOfSharesAvailableForGrant" id="Fact_03da27efb55141628520731fb9e70ab8" contextRef="c20211231_PlanNameAxis_NonemployeeDirectorsStockOptionPlan2002Member" unitRef="U002" decimals="-5" scale="6" format="ixt:numdotdecimal">0.7</ix:nonFraction> million shares were available for future grant under the 2002 Plan.</div>
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<div style="text-align: justify; text-indent: -18pt; margin-left: 54pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;">Employee Stock Purchase Plan</div>
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<div><br />
  </div>
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<div style="display:none;"><br /></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">In June 2009, our Board of Directors adopted, and the stockholders subsequently approved, the amendment and restatement of
    the ESPP and we reserved an additional <ix:nonFraction name="us-gaap:ShareBasedCompensationArrangementByShareBasedPaymentAwardNumberOfAdditionalSharesAuthorized" id="Fact_3b40f4cda8e040fdba6be624573711c9" contextRef="c20090601to20090630_PlanNameAxis_EmployeeStockPurchasePlanMember" unitRef="U002" decimals="0" scale="0" format="ixt:numdotdecimal">150,000</ix:nonFraction> shares of common stock for issuance thereunder. In each of the subsequent years until 2019, we
    reserved an additional <ix:nonFraction name="us-gaap:ShareBasedCompensationArrangementByShareBasedPaymentAwardNumberOfAdditionalSharesAuthorized" id="Fact_627f300828104f14b873bf05eda50f67" contextRef="c20210101to20211231_PlanNameAxis_EmployeeStockPurchasePlanMember" unitRef="U002" decimals="0" scale="0" format="ixt:numdotdecimal">150,000</ix:nonFraction> shares of common stock for the ESPP resulting in a total of <ix:nonFraction name="us-gaap:ShareBasedCompensationArrangementByShareBasedPaymentAwardNumberOfSharesAuthorized" id="Fact_e19efe7ddb5143df982e961a832ee9c5" contextRef="c20211231_PlanNameAxis_EmployeeStockPurchasePlanMember" unitRef="U002" decimals="-5" scale="6" format="ixt:numdotdecimal">3.2</ix:nonFraction> million shares authorized under the plan as of December 31, 2021. The ESPP
    permits full-time employees to purchase common stock through payroll deductions (which cannot exceed <ix:nonFraction name="us-gaap:ShareBasedCompensationArrangementByShareBasedPaymentAwardMaximumEmployeeSubscriptionRate" id="Fact_ad7d5d970b7445cb891d0cfb579417b5" contextRef="c20211231_PlanNameAxis_EmployeeStockPurchasePlanMember" unitRef="U003" decimals="2" scale="-2" format="ixt:numdotdecimal">10</ix:nonFraction>percent of each employee&#8217;s compensation)
    at the lower of <ix:nonFraction name="us-gaap:SharebasedCompensationArrangementBySharebasedPaymentAwardPurchasePriceOfCommonStockPercent" id="Fact_f1124fb149ea4ba28036505d69fad8f3" contextRef="c20210101to20211231_PlanNameAxis_EmployeeStockPurchasePlanMember" unitRef="U003" decimals="2" scale="-2" format="ixt:numdotdecimal">85</ix:nonFraction>percent of fair market value at the beginning of the purchase period or the end of each purchase period. Under the amended
    and restated ESPP, employees must hold the stock they purchase for a minimum of <ix:nonNumeric name="ions:ShareBasedCompensationArrangementByShareBasedPaymentAwardHoldingPeriod" id="Fact_f085e44a32534bbd8486ce10fc828657" contextRef="c20210101to20211231_PlanNameAxis_EmployeeStockPurchasePlanMember" format="ixt-sec:durwordsen">six months</ix:nonNumeric> from the date of purchase. During 2021, employees purchased and we issued to employees <ix:nonFraction name="us-gaap:StockIssuedDuringPeriodSharesEmployeeStockPurchasePlans" id="Fact_36267c2abcb644b69eb45aceda22f69b" contextRef="c20210101to20211231_PlanNameAxis_EmployeeStockPurchasePlanMember" unitRef="U002" decimals="-4" scale="6" format="ixt:numdotdecimal">0.07</ix:nonFraction>
    million shares under the ESPP at a weighted average price of $<ix:nonFraction name="ions:EmployeeStockPurchasePlanWeightedAverageSalesPriceOfSharesPurchased" id="Fact_2c284719dc094a59851d962ad33aacae" contextRef="c20210101to20211231_PlanNameAxis_EmployeeStockPurchasePlanMember" unitRef="U004" decimals="2" scale="0" format="ixt:numdotdecimal">39.26</ix:nonFraction> per share. At December 31, 2021, there were <ix:nonFraction name="ions:EmployeeStockPurchasePlanSharesAvailableForPurchase" id="Fact_9bcf03b844ab41c1a8fbd64333e01f0e" contextRef="c20211231_PlanNameAxis_EmployeeStockPurchasePlanMember" unitRef="U002" decimals="-5" scale="6" format="ixt:numdotdecimal">0.6</ix:nonFraction> million shares available for purchase under the
    ESPP.</div>
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<div><br />
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<div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Stock Option Activity</div>
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<div><br />
  </div>
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<div style="display:none;"><br /></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">The following table summarizes the stock option activity under our stock plans for the year ended December 31, 2021 (in thousands, except per share and contractual life data):</div>
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<div><br />
  </div>
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  <tr>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">

        </td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px; white-space: nowrap;" colspan="2">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Number</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">of Shares</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px; white-space: nowrap;" colspan="2">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Weighted</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Average Exercise</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Price Per Share</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px; white-space: nowrap;" colspan="2">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Average</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Remaining</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Contractual Term</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">(Years)</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px; white-space: nowrap;" colspan="2">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Aggregate</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Intrinsic</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Value</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; background-color: #CCEEFF;">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="text-indent: 0pt;">Outstanding at December 31, 2020</span></div>
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    <td valign="bottom" style="vertical-align: bottom; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsOutstandingNumber" id="Fact_de361e6a303f48689eff997a4c7a9e18" contextRef="c20201231_AwardTypeAxis_StockOptionMember" unitRef="U002" decimals="-3" scale="3" format="ixt:numdotdecimal">12,439</ix:nonFraction></div>
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsOutstandingWeightedAverageExercisePrice" id="Fact_013443363d8b4eb7aa061c464dc7a3dd" contextRef="c20201231_AwardTypeAxis_StockOptionMember" unitRef="U004" decimals="2" scale="0" format="ixt:numdotdecimal">54.11</ix:nonFraction></div>
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; background-color: #CCEEFF;" colspan="2">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; background-color: #CCEEFF;" colspan="2">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom;">
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        </td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsGrantsInPeriodGross" id="Fact_c363e628c500466b86c02f00df87e45d" contextRef="c20210101to20211231_AwardTypeAxis_StockOptionMember" unitRef="U002" decimals="-3" scale="3" format="ixt:numdotdecimal">3,382</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:ShareBasedCompensationArrangementsByShareBasedPaymentAwardOptionsGrantsInPeriodWeightedAverageExercisePrice" id="Fact_147bf3d775c544d39301adb1493fa05e" contextRef="c20210101to20211231_AwardTypeAxis_StockOptionMember" unitRef="U004" decimals="2" scale="0" format="ixt:numdotdecimal">53.07</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="2">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="2">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; background-color: #CCEEFF;">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 18pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Exercised</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:StockIssuedDuringPeriodSharesStockOptionsExercised" id="Fact_65fe49e661654c6fadd66c3158cb37e5" contextRef="c20210101to20211231_AwardTypeAxis_StockOptionMember" unitRef="U002" decimals="-3" scale="3" format="ixt:numdotdecimal">219</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:ShareBasedCompensationArrangementsByShareBasedPaymentAwardOptionsExercisesInPeriodWeightedAverageExercisePrice" id="Fact_645eac997a48446a8364fedf6f9b00a2" contextRef="c20210101to20211231_AwardTypeAxis_StockOptionMember" unitRef="U004" decimals="2" scale="0" format="ixt:numdotdecimal">38.69</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; background-color: #CCEEFF;" colspan="2">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; background-color: #CCEEFF;" colspan="2">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 18pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Cancelled/forfeited/expired</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; border-bottom: #000000 solid 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; border-bottom: #000000 solid 2px;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsForfeituresAndExpirationsInPeriod" id="Fact_d7093d8852d44af280644f5b3f4724f8" contextRef="c20210101to20211231_AwardTypeAxis_StockOptionMember" unitRef="U002" decimals="-3" scale="3" format="ixt:numdotdecimal">1,513</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; padding-bottom: 2px;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:ShareBasedCompensationArrangementsByShareBasedPaymentAwardOptionsForfeituresInPeriodWeightedAverageExercisePrice" id="Fact_b2d99eaaf66c4310b3826984e917430d" contextRef="c20210101to20211231_AwardTypeAxis_StockOptionMember" unitRef="U004" decimals="2" scale="0" format="ixt:numdotdecimal">54.65</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="2">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="2">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 52%; padding-bottom: 4px; background-color: #CCEEFF;">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="text-indent: 0pt;">Outstanding at December 31, 2021</span></div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsOutstandingNumber" id="Fact_ac7cb8c9588948168b54c219f469e752" contextRef="c20211231_AwardTypeAxis_StockOptionMember" unitRef="U002" decimals="-3" scale="3" format="ixt:numdotdecimal">14,089</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsOutstandingWeightedAverageExercisePrice" id="Fact_3a779dec16434ab39ded18c995252583" contextRef="c20211231_AwardTypeAxis_StockOptionMember" unitRef="U004" decimals="2" scale="0" format="ixt:numdotdecimal">54.04</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonNumeric name="us-gaap:SharebasedCompensationArrangementBySharebasedPaymentAwardOptionsOutstandingWeightedAverageRemainingContractualTerm2" id="Fact_8a97634ee0de48ab9bba7815890a31ce" contextRef="c20210101to20211231_AwardTypeAxis_StockOptionMember" format="ixt-sec:duryear">3.89</ix:nonNumeric></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsOutstandingIntrinsicValue" id="Fact_c25c76c1a9f94691b856964b458fadef" contextRef="c20211231_AwardTypeAxis_StockOptionMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">1,131</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 52%; padding-bottom: 4px;">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="text-indent: 0pt;">Exercisable at December 31, 2021</span></div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsExercisableNumber" id="Fact_f87605af70314ee88af627c71f1097ba" contextRef="c20211231_AwardTypeAxis_StockOptionMember" unitRef="U002" decimals="-3" scale="3" format="ixt:numdotdecimal">9,175</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsExercisableWeightedAverageExercisePrice" id="Fact_385eca89102d4e9587c5000cc39964b4" contextRef="c20211231_AwardTypeAxis_StockOptionMember" unitRef="U004" decimals="2" scale="0" format="ixt:numdotdecimal">53.65</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonNumeric name="us-gaap:SharebasedCompensationArrangementBySharebasedPaymentAwardOptionsExercisableWeightedAverageRemainingContractualTerm1" id="Fact_7314f310e53045fd9d6e985a8a4eb55d" contextRef="c20210101to20211231_AwardTypeAxis_StockOptionMember" format="ixt-sec:duryear">2.94</ix:nonNumeric></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:SharebasedCompensationArrangementBySharebasedPaymentAwardOptionsExercisableIntrinsicValue1" id="Fact_bb850db7a9184d57b61549c6a8eeacca" contextRef="c20211231_AwardTypeAxis_StockOptionMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">1,067</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>


</table>
</ix:continuation></ix:continuation>
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<div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 12pt;"><br />
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</ix:continuation>
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<div style="display:none;"><br /></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">The weighted-average estimated fair values of options granted were $<ix:nonFraction name="us-gaap:ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsGrantsInPeriodWeightedAverageGrantDateFairValue" id="Fact_bd436c790ccc47e68cd7e2153d0e63dd" contextRef="c20210101to20211231_AwardTypeAxis_StockOptionMember" unitRef="U004" decimals="2" scale="0" format="ixt:numdotdecimal">24.35</ix:nonFraction>, $<ix:nonFraction name="us-gaap:ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsGrantsInPeriodWeightedAverageGrantDateFairValue" id="Fact_4dd2a593ab554175bbb0a93d55390a88" contextRef="c20200101to20201231_AwardTypeAxis_StockOptionMember" unitRef="U004" decimals="2" scale="0" format="ixt:numdotdecimal">29.43</ix:nonFraction> and $<ix:nonFraction name="us-gaap:ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsGrantsInPeriodWeightedAverageGrantDateFairValue" id="Fact_a3befa246b7c4d03aced2b483085120f" contextRef="c20190101to20191231_AwardTypeAxis_StockOptionMember" unitRef="U004" decimals="2" scale="0" format="ixt:numdotdecimal">28.76</ix:nonFraction> for the years ended December 31, 2021, 2020 and 2019, respectively. The total intrinsic value of options
    exercised during the years ended December 31, 2021, 2020 and 2019 were $<ix:nonFraction name="us-gaap:ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsExercisesInPeriodTotalIntrinsicValue" id="Fact_1218d40eea68418bb4f00f1ad78f4cff" contextRef="c20210101to20211231_AwardTypeAxis_StockOptionMember" unitRef="U001" decimals="-5" scale="6" format="ixt:numdotdecimal">2.5</ix:nonFraction> million, $<ix:nonFraction name="us-gaap:ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsExercisesInPeriodTotalIntrinsicValue" id="Fact_bde2c92764604d8497b0668d13fb888b" contextRef="c20200101to20201231_AwardTypeAxis_StockOptionMember" unitRef="U001" decimals="-5" scale="6" format="ixt:numdotdecimal">15.5</ix:nonFraction> million and $<ix:nonFraction name="us-gaap:ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsExercisesInPeriodTotalIntrinsicValue" id="Fact_8cc0e16daa8e4b2382fc554cc98ddf99" contextRef="c20190101to20191231_AwardTypeAxis_StockOptionMember" unitRef="U001" decimals="-5" scale="6" format="ixt:numdotdecimal">83.8</ix:nonFraction> million, respectively, which we determined as of the date of exercise. The amount of cash received from the exercise of stock options was $<ix:nonFraction name="us-gaap:ProceedsFromStockOptionsExercised" id="Fact_83423df31a3f436fab220d64f20b3ada" contextRef="c20210101to20211231_AwardTypeAxis_StockOptionMember" unitRef="U001" decimals="-5" scale="6" format="ixt:numdotdecimal">8.5</ix:nonFraction> million, $<ix:nonFraction name="us-gaap:ProceedsFromStockOptionsExercised" id="Fact_9199ba163c904e0aaa3d539cccdda650" contextRef="c20200101to20201231_AwardTypeAxis_StockOptionMember" unitRef="U001" decimals="-5" scale="6" format="ixt:numdotdecimal">43.7</ix:nonFraction> million and $<ix:nonFraction name="us-gaap:ProceedsFromStockOptionsExercised" id="Fact_6cc972e2025849d8a6820145ab793c87" contextRef="c20190101to20191231_AwardTypeAxis_StockOptionMember" unitRef="U001" decimals="-5" scale="6" format="ixt:numdotdecimal">105.9</ix:nonFraction> million for the years ended December 31, 2021, 2020 and 2019, respectively. For the year
    ended December 31, 2021, the weighted-average fair value of options exercised was $<ix:nonFraction name="ions:ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsExercisesInPeriodWeightedAverageFairValue" id="Fact_2b17593a26f3421991429bedce8b1c41" contextRef="c20210101to20211231_AwardTypeAxis_StockOptionMember" unitRef="U004" decimals="2" scale="0" format="ixt:numdotdecimal">50.13</ix:nonFraction>. As of December 31, 2021, total unrecognized compensation cost related to
    non-vested stock options was $<ix:nonFraction name="us-gaap:EmployeeServiceShareBasedCompensationNonvestedAwardsTotalCompensationCostNotYetRecognizedStockOptions" id="Fact_72c37b7b47114b45a9abf8d6722faa52" contextRef="c20211231_AwardTypeAxis_StockOptionMember" unitRef="U001" decimals="-5" scale="6" format="ixt:numdotdecimal">49.6</ix:nonFraction> million. We expect to recognize this cost over a weighted average period of <ix:nonNumeric name="us-gaap:EmployeeServiceShareBasedCompensationNonvestedAwardsTotalCompensationCostNotYetRecognizedPeriodForRecognition1" id="Fact_b3913cf410e541fe90a6f1003271ba18" contextRef="c20210101to20211231_AwardTypeAxis_StockOptionMember" format="ixt-sec:duryear">1.1</ix:nonNumeric> years. We will adjust the total unrecognized compensation cost for future changes in estimated forfeitures.</div>
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<div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Restricted Stock Unit Activity</div>
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<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">The following table summarizes the RSU activity for the year ended December 31, 2021 (in thousands, except per share data):</div>
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          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Weighted Average</div>
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    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
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    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
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          <div style="text-align: justify; text-indent: -9pt; margin-left: 18pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Granted</div>
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    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
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    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
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    <td valign="bottom" style="vertical-align: bottom; width: 76%; background-color: #CCEEFF;">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 18pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Vested</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
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    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

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    <td valign="bottom" style="vertical-align: bottom; width: 76%; padding-bottom: 2px;">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 18pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Cancelled/forfeited</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:ShareBasedCompensationArrangementByShareBasedPaymentAwardEquityInstrumentsOtherThanOptionsForfeituresWeightedAverageGrantDateFairValue" id="Fact_d3684b8ecd434d79a0c627293baaf219" contextRef="c20210101to20211231_AwardTypeAxis_RestrictedStockUnitsRSUMember" unitRef="U004" decimals="2" scale="0" format="ixt:numdotdecimal">59.24</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 76%; padding-bottom: 4px; background-color: #CCEEFF;">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="text-indent: 0pt;">Non-vested at December 31, 2021</span></div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:ShareBasedCompensationArrangementByShareBasedPaymentAwardEquityInstrumentsOtherThanOptionsNonvestedNumber" id="Fact_28559434ff5b402683a66fe056752875" contextRef="c20211231_AwardTypeAxis_RestrictedStockUnitsRSUMember" unitRef="U002" decimals="-3" scale="3" format="ixt:numdotdecimal">2,677</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:ShareBasedCompensationArrangementByShareBasedPaymentAwardEquityInstrumentsOtherThanOptionsNonvestedWeightedAverageGrantDateFairValue" id="Fact_5d0497b5899240c48adeef1f11e34ed4" contextRef="c20211231_AwardTypeAxis_RestrictedStockUnitsRSUMember" unitRef="U004" decimals="2" scale="0" format="ixt:numdotdecimal">58.51</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>


</table>
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<div style="display:none;"><br /></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">For the years ended December 31, 2021, 2020 and 2019, the weighted-average grant date fair value of RSUs granted was $<ix:nonFraction name="us-gaap:ShareBasedCompensationArrangementByShareBasedPaymentAwardEquityInstrumentsOtherThanOptionsGrantsInPeriodWeightedAverageGrantDateFairValue" id="Fact_6c1a06db93094900a762b6eb164c546f" contextRef="c20210101to20211231_AwardTypeAxis_RestrictedStockUnitsRSUMember" unitRef="U004" decimals="2">57.69</ix:nonFraction>, $<ix:nonFraction name="us-gaap:ShareBasedCompensationArrangementByShareBasedPaymentAwardEquityInstrumentsOtherThanOptionsGrantsInPeriodWeightedAverageGrantDateFairValue" id="Fact_43f43b5a78cc4be1918b46bdde39a8d8" contextRef="c20200101to20201231_AwardTypeAxis_RestrictedStockUnitsRSUMember" unitRef="U004" decimals="2" scale="0" format="ixt:numdotdecimal">60.86</ix:nonFraction> and $<ix:nonFraction name="us-gaap:ShareBasedCompensationArrangementByShareBasedPaymentAwardEquityInstrumentsOtherThanOptionsGrantsInPeriodWeightedAverageGrantDateFairValue" id="Fact_57cca4b8f1044664988a96c292d978d1" contextRef="c20190101to20191231_AwardTypeAxis_RestrictedStockUnitsRSUMember" unitRef="U004" decimals="2" scale="0" format="ixt:numdotdecimal">60.23</ix:nonFraction> per RSU, respectively. As of
    December 31, 2021, total unrecognized compensation cost related to RSUs was $<ix:nonFraction name="us-gaap:EmployeeServiceShareBasedCompensationNonvestedAwardsTotalCompensationCostNotYetRecognizedShareBasedAwardsOtherThanOptions" id="Fact_87ca3f2ec59f473aaf7df5ff01d27232" contextRef="c20211231_AwardTypeAxis_RestrictedStockUnitsRSUMember" unitRef="U001" decimals="-5" scale="6" format="ixt:numdotdecimal">57.0</ix:nonFraction> million. We expect to recognize this cost over a weighted average period of <ix:nonNumeric name="us-gaap:EmployeeServiceShareBasedCompensationNonvestedAwardsTotalCompensationCostNotYetRecognizedPeriodForRecognition1" id="Fact_18e1a1c706d54df78d64da3820fb50b9" contextRef="c20210101to20211231_AwardTypeAxis_RestrictedStockUnitsRSUMember" format="ixt-sec:duryear">1.2</ix:nonNumeric>
    years. We will adjust the total unrecognized compensation cost for future changes in estimated forfeitures.</div>
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<div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Stock-based Compensation Expense and Valuation Information</div>
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<div><br />
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<div style="display:none;"><br /></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">The following table summarizes stock-based compensation expense for the years ended December 31, 2021, 2020 and 2019 (in thousands):</div>
</ix:nonNumeric></ix:continuation>
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<div><br />
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    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;" colspan="1">&#160;</td>

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          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Year Ended December 31,</div>
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

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  <tr>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;" colspan="1">&#160;</td>

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    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;" colspan="1">&#160;</td>

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          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2020</div>
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;" colspan="1">&#160;</td>

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          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2019</div>
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

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  <tr>

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    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
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    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

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  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 64%;">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Research, development and patent</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:AllocatedShareBasedCompensationExpense" id="Fact_082a856e25ff4c6c87bb43e07011a3a0" contextRef="c20210101to20211231_IncomeStatementLocationAxis_ResearchDevelopmentAndPatentMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">87,522</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:AllocatedShareBasedCompensationExpense" id="Fact_fbf019d0d38c4d20951785656bdfb76e" contextRef="c20200101to20201231_IncomeStatementLocationAxis_ResearchDevelopmentAndPatentMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">115,584</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:AllocatedShareBasedCompensationExpense" id="Fact_590dd7d3580e4ce79e0bd853a27c60e2" contextRef="c20190101to20191231_IncomeStatementLocationAxis_ResearchDevelopmentAndPatentMember" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">95,348</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #CCEEFF;">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Selling, general and administrative</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 4px;">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Total</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:AllocatedShareBasedCompensationExpense" id="Fact_e526ced9a8ee48df88cdbb0fe414de86" contextRef="c20210101to20211231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">120,678</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:AllocatedShareBasedCompensationExpense" id="Fact_e09ed4e35f1149ffade548f4d1e3dd6a" contextRef="c20200101to20201231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">230,117</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:AllocatedShareBasedCompensationExpense" id="Fact_14e48c9e15754897b6ddb6e8ce984ffb" contextRef="c20190101to20191231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">146,574</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>


</table>
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<div style="text-align: justify; font-family: 'Times New Roman', Times, serif; font-size: 12pt;"><br />
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<div style="display:none;"><br /></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">In October 2020, as part of the Akcea Merger, Akcea&#8217;s outstanding equity awards vested under Akcea&#8217;s Plan. As a result, in
    the fourth quarter of 2020, we recognized all unrecognized stock-based compensation ($<ix:nonFraction name="us-gaap:EmployeeServiceShareBasedCompensationNonvestedAwardsTotalCompensationCostNotYetRecognizedShareBasedAwardsOtherThanOptions" id="Fact_d16c0cc8629a4c07b114768b69b0edb5" contextRef="c20201031_ConsolidatedEntitiesAxis_AkceaTherapeuticsIncMember" unitRef="U001" decimals="-5" scale="6" format="ixt:numdotdecimal">59.3</ix:nonFraction> million) under Akcea&#8217;s Plan. See Note 7, <span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Akcea Merger</span>, in the Notes to the Consolidated Financial Statements for further details.</div>
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<div><br />
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  <ix:continuation id="Text_4d04ad75e3004626afb6a236247ded6386" continuedAt="Text_4d04ad75e3004626afb6a236247ded6387">
<div style="display:none;"><br /></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">In the third quarter of 2019, </span><ix:nonFraction name="ions:NumberOfExecutiveOfficersTerminatingEmployment" id="Fact_5ae968a2633a430684e974cc63021deb" contextRef="c20190701to20190930_ConsolidatedEntitiesAxis_AkceaTherapeuticsIncMember" unitRef="U016" decimals="INF" scale="0" format="ixt-sec:numwordsen">three</ix:nonFraction><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> Akcea executive officers terminated their employment and entered into
      separation agreements with Akcea. As a result, in the third quarter of 2019, Akcea reversed $</span><ix:nonFraction name="us-gaap:AllocatedShareBasedCompensationExpense" id="Fact_911c01da068b45da87f911f97ac956aa" contextRef="c20190701to20190930_ConsolidatedEntitiesAxis_AkceaTherapeuticsIncMember" unitRef="U001" decimals="-5" scale="6" sign="-" format="ixt:numdotdecimal">19.1</ix:nonFraction><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> million of stock-based compensation expense it had previously recognized related to the executive officers&#8217; stock options and RSUs that were no longer going to vest.</span></div>
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<div style="text-align: justify; text-indent: -18pt; margin-left: 54pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;">Determining Fair Value</div>
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  </div>
</ix:continuation>
  <ix:continuation id="Text_4d04ad75e3004626afb6a236247ded6390" continuedAt="Text_4d04ad75e3004626afb6a236247ded6391">
<div style="display:none;"><br /></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Valuation.</span> We
    measure stock-based compensation expense for equity-classified awards, principally related to stock options, RSUs, PRSUs and stock purchase rights under the ESPP at the grant date, based on the estimated fair value of the award and we recognize the
    expense over the employee&#8217;s requisite service period. We value RSUs based on the market price of our common stock on the date of grant. See Note 1, <span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Organization
      and Significant Accounting Policies</span>, in the Notes to the Consolidated Financial Statements for further details on how we determine the fair value of PRSUs.</div>
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<div style="display:none;"><br /></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We use the Black-Scholes model to estimate the fair value of stock options granted and stock purchase rights under our
    ESPP. The expected term of stock options granted represents the period of time that we expect them to be outstanding. We estimate the expected term of stock options granted based on actual and projected exercise patterns. We recognize compensation
    expense for stock options granted, RSUs, PRSUs and stock purchase rights under the ESPP using the accelerated multiple-option approach. Under the accelerated multiple-option approach (also known as the graded-vesting method), we recognize compensation
    expense over the requisite service period for each separately vesting tranche of the award as though the award were in substance multiple awards, which results in the expense being front-loaded over the vesting period.</div>
</ix:continuation></div>

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    <div class="DSPFPageFooter">
      <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">F-<span class="DSPFPageNumber">36</span></div>

    </div>

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<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">For the years ended December 31, 2021, 2020 and 2019, we used the following weighted-average assumptions in our Black-Scholes calculations:</div>
</ix:continuation>
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<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;">Ionis Employee Stock Options:</div>
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    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;" colspan="1">&#160;</td>

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    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;" colspan="1">&#160;</td>

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    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

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    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

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    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
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    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

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    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

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    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

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  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Volatility</div>
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    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
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    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">%</div>
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    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
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  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom;">
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        </td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="2">
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="1">&#160;</td>

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    <td valign="bottom" style="text-align: left; vertical-align: bottom; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="2">
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; white-space: nowrap;" colspan="1">&#160;</td>

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<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;">Ionis Board of Director Stock Options:</div>
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  <tr>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">

        </td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" colspan="10">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Year Ended December 31,</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" colspan="2">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2021</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" colspan="2">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2020</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;" colspan="1">&#160;</td>

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    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

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    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

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    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
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    <td valign="bottom" style="vertical-align: bottom; width: 64%;">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Dividend yield</div>
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    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
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    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
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          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">%</div>
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    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
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    <td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;">
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    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
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          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">%</div>
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    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">%</div>
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    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
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  <tr>

    <td valign="bottom" style="vertical-align: bottom;">
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    <td valign="bottom" style="vertical-align: bottom;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="2">
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="2">
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="2">
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; white-space: nowrap;" colspan="1">&#160;</td>

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    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;" colspan="1">&#160;</td>

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          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Year Ended December 31,</div>
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  <tr>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;" colspan="1">&#160;</td>

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    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" colspan="2">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2020</div>
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" colspan="2">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2019</div>
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  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Risk-free interest rate</div>
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    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
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    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
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    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
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  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 64%;">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Dividend yield</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">%</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:ShareBasedCompensationArrangementByShareBasedPaymentAwardFairValueAssumptionsExpectedDividendRate" id="Fact_0eb7e7fbc4304fdf9099a8b950d12dde" contextRef="c20200101to20201231_AwardTypeAxis_EmployeeStockMember" unitRef="U003" decimals="3" scale="-2" format="ixt:numdotdecimal">0.0</ix:nonFraction></div>
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          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">%</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">%</div>
        </td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Volatility</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">%</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">%</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">%</div>
        </td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom;">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Expected life</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="2">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="2">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="2">
          <div style="text-align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonNumeric name="us-gaap:SharebasedCompensationArrangementBySharebasedPaymentAwardFairValueAssumptionsExpectedTerm1" id="Fact_b50f67a3f15a4f28a7f815371d6feb14" contextRef="c20190101to20191231_AwardTypeAxis_EmployeeStockMember" format="ixt-sec:durwordsen">6 months</ix:nonNumeric></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>


</table>
</ix:continuation></ix:continuation>
  <ix:continuation id="Text_4d04ad75e3004626afb6a236247ded63107" continuedAt="Text_4d04ad75e3004626afb6a236247ded63108">
<div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 12pt;"><br />
  </div>
</ix:continuation>
  <ix:continuation id="Text_4d04ad75e3004626afb6a236247ded63108" continuedAt="Text_4d04ad75e3004626afb6a236247ded63109">
<div style="display:none;"><br /></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Risk-Free Interest Rate.</span>
    We base the risk-free interest rate assumption on observed interest rates appropriate for the term of our stock option plans or ESPP.</div>
</ix:continuation>
  <ix:continuation id="Text_4d04ad75e3004626afb6a236247ded63109" continuedAt="Text_4d04ad75e3004626afb6a236247ded63110">
<div><br />
  </div>
</ix:continuation>
  <ix:continuation id="Text_4d04ad75e3004626afb6a236247ded63110" continuedAt="Text_4d04ad75e3004626afb6a236247ded63111">
<div style="display:none;"><br /></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Dividend Yield.</span> We
    base the dividend yield assumption on our history and expectation of dividend payouts. We have not paid dividends in the past and do not expect to in the future.</div>
</ix:continuation>
  <ix:continuation id="Text_4d04ad75e3004626afb6a236247ded63111" continuedAt="Text_4d04ad75e3004626afb6a236247ded63112">
<div><br />
  </div>
</ix:continuation>
  <ix:continuation id="Text_4d04ad75e3004626afb6a236247ded63112" continuedAt="Text_4d04ad75e3004626afb6a236247ded63113">
<div style="display:none;"><br /></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Volatility.</span> We use
    an average of the historical stock price volatility of our stock for the Black-Scholes model. We computed the historical stock volatility based on the expected term of the awards.</div>
</ix:continuation>
  <ix:continuation id="Text_4d04ad75e3004626afb6a236247ded63113" continuedAt="Text_4d04ad75e3004626afb6a236247ded63114">
<div><br />
  </div>
</ix:continuation>
  <ix:continuation id="Text_4d04ad75e3004626afb6a236247ded63114" continuedAt="Text_4d04ad75e3004626afb6a236247ded63115">
<div style="display:none;"><br /></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Expected Life. </span>The
    expected term of stock options we have granted represents the period of time that we expect them to be outstanding. We estimated the expected term of options we have granted based on actual and projected exercise patterns.</div>
</ix:continuation>
  <ix:continuation id="Text_4d04ad75e3004626afb6a236247ded63115" continuedAt="Text_4d04ad75e3004626afb6a236247ded63116">
<div><br />
  </div>
</ix:continuation>
  <ix:continuation id="Text_4d04ad75e3004626afb6a236247ded63116">
<div style="display:none;"><br /></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Forfeitures.</span> We
    reduce stock-based compensation expense for estimated forfeitures. We estimate forfeitures at the time of grant and revise, if necessary, in subsequent periods if actual forfeitures differ from those estimates. We estimate forfeitures based on
    historical experience. </div>
</ix:continuation></div>

  <div><br />
  </div>
<div><ix:nonNumeric name="us-gaap:IncomeTaxDisclosureTextBlock" id="Text_6df02471ad074e68b7de0becddf8a447" contextRef="c20210101to20211231" escape="true" continuedAt="Text_719e67a58bcc4bb6a3750a77d49120191">
<div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">5. Income Taxes</div>
</ix:nonNumeric>

  <ix:continuation id="Text_719e67a58bcc4bb6a3750a77d49120191" continuedAt="Text_719e67a58bcc4bb6a3750a77d49120192">
<div><br />
  </div>
</ix:continuation>
  <ix:continuation id="Text_719e67a58bcc4bb6a3750a77d49120192" continuedAt="Text_719e67a58bcc4bb6a3750a77d49120193"><ix:nonNumeric name="us-gaap:ScheduleOfIncomeBeforeIncomeTaxDomesticAndForeignTableTextBlock" id="Text_7281bd0eb54443b994694c659a6a8f66" contextRef="c20210101to20211231" escape="true" continuedAt="Text_6bfc54f258a94e23a76518c02f5892e41">
<div style="display:none;"><br /></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Income (loss) before income taxes is comprised of (in thousands):</div>
</ix:nonNumeric></ix:continuation>
  <ix:continuation id="Text_719e67a58bcc4bb6a3750a77d49120193" continuedAt="Text_719e67a58bcc4bb6a3750a77d49120194"><ix:continuation id="Text_6bfc54f258a94e23a76518c02f5892e41" continuedAt="Text_6bfc54f258a94e23a76518c02f5892e42">
<div><br />
  </div>
</ix:continuation></ix:continuation>
  <ix:continuation id="Text_719e67a58bcc4bb6a3750a77d49120194" continuedAt="Text_719e67a58bcc4bb6a3750a77d49120195"><ix:continuation id="Text_6bfc54f258a94e23a76518c02f5892e42">
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  <tr>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">

        </td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" colspan="10">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Year Ended December 31,</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" colspan="2">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2021</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" colspan="2">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2020</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" colspan="2">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2019</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom;">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="2">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="2">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">(as revised*)</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="2">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">(as revised*)</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom;">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="2">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="2">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="2">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">United States</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:IncomeLossFromContinuingOperationsBeforeIncomeTaxesDomestic" id="Fact_1154d9477ea5403c89bcaba61b591e79" contextRef="c20210101to20211231" unitRef="U001" decimals="-3" scale="3" sign="-" format="ixt:numdotdecimal">29,966</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:IncomeLossFromContinuingOperationsBeforeIncomeTaxesDomestic" id="Fact_74d3abad4f744e0aa68801acc3a6ed6b" contextRef="c20200101to20201231" unitRef="U001" decimals="-3" scale="3" sign="-" format="ixt:numdotdecimal">137,222</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:IncomeLossFromContinuingOperationsBeforeIncomeTaxesDomestic" id="Fact_8977ca2c8272434794efd8259c5f22b7" contextRef="c20190101to20191231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">336,277</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 2px;">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Foreign</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:IncomeLossFromContinuingOperationsBeforeIncomeTaxesForeign" id="Fact_70ca994a31be49619caefe5e71de1587" contextRef="c20210101to20211231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">818</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:IncomeLossFromContinuingOperationsBeforeIncomeTaxesForeign" id="Fact_8425f2adaf6948cdb4db61cdf7def1fc" contextRef="c20200101to20201231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">2,670</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 4px; background-color: #CCEEFF;">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Income (loss) before income taxes</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:IncomeLossFromContinuingOperationsBeforeIncomeTaxesExtraordinaryItemsNoncontrollingInterest" id="Fact_317564d38d3f4684aaa47f65a5d386e8" contextRef="c20210101to20211231" unitRef="U001" decimals="-3" scale="3" sign="-" format="ixt:numdotdecimal">29,148</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:IncomeLossFromContinuingOperationsBeforeIncomeTaxesExtraordinaryItemsNoncontrollingInterest" id="Fact_9fd05fd89e164623ad7d51c758cf30c6" contextRef="c20200101to20201231" unitRef="U001" decimals="-3" scale="3" sign="-" format="ixt:numdotdecimal">134,552</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:IncomeLossFromContinuingOperationsBeforeIncomeTaxesExtraordinaryItemsNoncontrollingInterest" id="Fact_225bd758b4d047a9b56b2a1266e8768e" contextRef="c20190101to20191231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">338,766</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>


</table>
</ix:continuation></ix:continuation>
  <ix:continuation id="Text_719e67a58bcc4bb6a3750a77d49120195" continuedAt="Text_719e67a58bcc4bb6a3750a77d49120196">
<div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 12pt;"><br />
  </div>
</ix:continuation></div>

  <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" class="DSPFPageBreakArea">
    <div class="DSPFPageFooter">
      <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">F-<span class="DSPFPageNumber">37</span></div>

    </div>

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      <hr style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;" /></div>


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<div><ix:continuation id="Text_719e67a58bcc4bb6a3750a77d49120196" continuedAt="Text_719e67a58bcc4bb6a3750a77d49120197"><ix:nonNumeric name="us-gaap:ScheduleOfComponentsOfIncomeTaxExpenseBenefitTableTextBlock" id="Text_d123dff19b9e4823b03cc17efdea0755" contextRef="c20210101to20211231" escape="true" continuedAt="Text_04a0d590e1a342dc9d08431d06de007d1">
<div style="display:none;"><br /></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Our income tax expense (benefit) was as follows (in thousands):</div>
</ix:nonNumeric></ix:continuation>

  <ix:continuation id="Text_719e67a58bcc4bb6a3750a77d49120197" continuedAt="Text_719e67a58bcc4bb6a3750a77d49120198"><ix:continuation id="Text_04a0d590e1a342dc9d08431d06de007d1" continuedAt="Text_04a0d590e1a342dc9d08431d06de007d2">
<div><br />
  </div>
</ix:continuation></ix:continuation>
  <ix:continuation id="Text_719e67a58bcc4bb6a3750a77d49120198" continuedAt="Text_719e67a58bcc4bb6a3750a77d49120199"><ix:continuation id="Text_04a0d590e1a342dc9d08431d06de007d2">
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    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">

        </td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" colspan="10">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Year Ended December 31,</div>
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" colspan="2">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2021</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" colspan="2">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2020</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" colspan="2">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2019</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom;">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="2">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="2">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">(as revised*)</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="2">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">(as revised*)</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom;">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="2">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="2">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="2">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom;">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Current:</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="2">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="2">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="2">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Federal</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:CurrentFederalTaxExpenseBenefit" id="Fact_f7d1c022ad9f48ddaa94094db5e10a09" contextRef="c20210101to20211231" unitRef="U001" decimals="-3" scale="3" sign="-" format="ixt:numdotdecimal">200</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:CurrentFederalTaxExpenseBenefit" id="Fact_3b8dd023e1f647b8a3ac8d6daa73c20c" contextRef="c20200101to20201231" unitRef="U001" decimals="-3" scale="3" sign="-" format="ixt:numdotdecimal">837</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:CurrentFederalTaxExpenseBenefit" id="Fact_7390edee7ebc486d8f38622d5c52bcc1" contextRef="c20190101to20191231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">35,861</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 64%;">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">State</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:CurrentStateAndLocalTaxExpenseBenefit" id="Fact_29cdf46cccf847508b045e7ee750b157" contextRef="c20210101to20211231" unitRef="U001" decimals="-3" scale="3" sign="-" format="ixt:numdotdecimal">690</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:CurrentStateAndLocalTaxExpenseBenefit" id="Fact_18598915ff304ad69c4f603530fa17ba" contextRef="c20200101to20201231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">3,782</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:CurrentStateAndLocalTaxExpenseBenefit" id="Fact_b16b487bd08b4f16b0833b9f760c9124" contextRef="c20190101to20191231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">14,329</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #CCEEFF;">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Foreign</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:CurrentForeignTaxExpenseBenefit" id="Fact_ca5d84cba52a406991333d46438a92be" contextRef="c20210101to20211231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">339</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:CurrentForeignTaxExpenseBenefit" id="Fact_7ac2061535c24653b193dc9c25179163" contextRef="c20200101to20201231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">518</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:CurrentForeignTaxExpenseBenefit" id="Fact_94c31631758a4c52bc819107405e16bf" contextRef="c20190101to20191231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">413</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 64%;">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Total current income tax expense (benefit)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:CurrentIncomeTaxExpenseBenefit" id="Fact_273269185dee42eb91195045f6449fc7" contextRef="c20210101to20211231" unitRef="U001" decimals="-3" scale="3" sign="-" format="ixt:numdotdecimal">551</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
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    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

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    <td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

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  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 64%;">
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    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

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  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Federal</div>
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    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 2px;">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">State</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #CCEEFF;">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Total deferred income tax benefit</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:DeferredIncomeTaxExpenseBenefit" id="Fact_be2ed18e2072458bba8c88d0a45981b5" contextRef="c20210101to20211231" unitRef="U001" decimals="-3" scale="3" format="ixt:zerodash">&#8212;</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:DeferredIncomeTaxExpenseBenefit" id="Fact_499db25413694d1996ce63465160cf19" contextRef="c20200101to20201231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">341,728</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:DeferredIncomeTaxExpenseBenefit" id="Fact_b02665644bb848b5b79ed1b9b7aba937" contextRef="c20190101to20191231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">904</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 4px;">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Total income tax expense (benefit)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:IncomeTaxExpenseBenefit" id="Fact_39aa3556afa54b90a94840a97eb5b995" contextRef="c20210101to20211231" unitRef="U001" decimals="-3" scale="3" sign="-" format="ixt:numdotdecimal">551</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:IncomeTaxExpenseBenefit" id="Fact_d3a17d5cbd604f2eaffbec171dab238a" contextRef="c20200101to20201231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">345,191</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:IncomeTaxExpenseBenefit" id="Fact_72e6d39ff1da4d90b52e886f5e5ff672" contextRef="c20190101to20191231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">51,507</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" colspan="1">&#160;</td>

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</ix:continuation></ix:continuation>
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<div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 12pt;"><br />
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</ix:continuation>
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<div style="display:none;"><br /></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Our expense (benefit) for income taxes differs from the amount computed by applying the U.S. federal
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</ix:nonNumeric></ix:continuation>
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<div><br />
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</ix:continuation></ix:continuation>
  <ix:continuation id="Text_719e67a58bcc4bb6a3750a77d491201912" continuedAt="Text_719e67a58bcc4bb6a3750a77d491201913"><ix:continuation id="Text_337f270c197241aa8bd2d796529e2ff72">
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    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">

        </td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" colspan="22">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Year Ended December 31,</div>
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

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  <tr>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" colspan="6">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2021</div>
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" colspan="6">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2020</div>
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" colspan="6">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2019</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom;">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="6">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="6">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">(as revised*)</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="6">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">(as revised*)</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom;">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="6">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="6">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="6">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; background-color: #CCEEFF;">
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    <td valign="bottom" style="vertical-align: bottom; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF;" colspan="1">
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    <td valign="bottom" style="vertical-align: bottom; text-align: right; background-color: #CCEEFF;" colspan="1">
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
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    <td valign="bottom" style="vertical-align: bottom; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; background-color: #CCEEFF;" colspan="2">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
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    <td valign="bottom" style="vertical-align: bottom; text-align: right; background-color: #CCEEFF;" colspan="1">
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
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    <td valign="bottom" style="vertical-align: bottom; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; background-color: #CCEEFF;" colspan="2">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; background-color: #CCEEFF;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; background-color: #CCEEFF;" colspan="2">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom;">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="2">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="2">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="2">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 28%; background-color: #CCEEFF;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Statutory rate</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
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        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">%</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">%</div>
        </td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 28%;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">State income tax net of federal benefit</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)%</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">%</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">%</div>
        </td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 28%; background-color: #CCEEFF;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Foreign</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)%</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">%</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
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    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
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  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 28%;">
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    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">
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    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">
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        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)%</div>
        </td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 28%; background-color: #CCEEFF;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Loss on debt transactions</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)%</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">%</div>
        </td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 28%;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Impact from outside basis differences</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)%</div>
        </td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 28%; background-color: #CCEEFF;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Tax credits</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">%</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">%</div>
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    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
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    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
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  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 28%;">
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    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">
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    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">
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    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">
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    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">
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    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">
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  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 28%; background-color: #CCEEFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Tax rate change</div>
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    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
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    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
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    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
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    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">%</div>
        </td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 28%;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Non-deductible compensation</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)%</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)%</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">%</div>
        </td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 28%; background-color: #CCEEFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Other non-deductible items</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)%</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
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    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
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  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 28%;">
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    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">
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    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)%</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)%</div>
        </td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 28%; background-color: #CCEEFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Foreign-derived intangible income benefit</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="ions:EffectiveIncomeTaxRateReconciliationForeignDerivedIntangibleIncomeBenefitAmount" id="Fact_282ef35eb1654b2f8cb0e93c44ba382f" contextRef="c20200101to20201231" unitRef="U001" decimals="-3" scale="3" format="ixt:zerodash">&#8212;</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="ions:EffectiveIncomeTaxRateReconciliationForeignDerivedIntangibleIncomeBenefitPercent" id="Fact_09164a15a1544ccf853826dd0b3550ba" contextRef="c20200101to20201231" unitRef="U003" decimals="3" scale="-2" format="ixt:zerodash">&#8212;</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)%</div>
        </td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 28%;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Impacts from Akcea Merger</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">%</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 28%; padding-bottom: 2px; background-color: #CCEEFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Other</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:EffectiveIncomeTaxRateReconciliationOtherAdjustments" id="Fact_d4daf54210844f62bbb1a04059ef74aa" contextRef="c20210101to20211231" unitRef="U003" decimals="3" scale="-2" format="ixt:numdotdecimal">5.1</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">%</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">%</div>
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    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)%</div>
        </td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 28%; padding-bottom: 4px;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Effective rate</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">%</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:IncomeTaxExpenseBenefit" id="Fact_9706d35248bb454c8a3a3c80240bc33f" contextRef="c20200101to20201231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">345,191</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" colspan="1">
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)%</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:IncomeTaxExpenseBenefit" id="Fact_05f18d362e2441e2a636fa371d9e87f0" contextRef="c20190101to20191231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">51,507</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" colspan="1">
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">%</div>
        </td>

  </tr>


</table>
</ix:continuation></ix:continuation>
  <ix:continuation id="Text_719e67a58bcc4bb6a3750a77d491201913" continuedAt="Text_719e67a58bcc4bb6a3750a77d491201914">
<div style="display:none;"><br /></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 12pt;"><br />
  </div>
</ix:continuation>
  <ix:continuation id="Text_719e67a58bcc4bb6a3750a77d491201914" continuedAt="Text_719e67a58bcc4bb6a3750a77d491201915">
<div style="display:none;"><br /></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Deferred income taxes reflect the net tax effects of temporary differences between the carrying amounts of assets and
    liabilities for financial reporting purposes and the amounts used for income tax purposes.</div>
</ix:continuation></div>

  <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" class="DSPFPageBreakArea">
    <div class="DSPFPageFooter">
      <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">F-<span class="DSPFPageNumber">38</span></div>

    </div>

    <div style="page-break-after:always;" class="DSPFPageBreak">
      <hr style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;" /></div>


  </div>
<div><ix:continuation id="Text_719e67a58bcc4bb6a3750a77d491201915" continuedAt="Text_719e67a58bcc4bb6a3750a77d491201916">
<div><br />
  </div>
</ix:continuation>

  <ix:continuation id="Text_719e67a58bcc4bb6a3750a77d491201916" continuedAt="Text_719e67a58bcc4bb6a3750a77d491201917"><ix:nonNumeric name="us-gaap:ScheduleOfDeferredTaxAssetsAndLiabilitiesTableTextBlock" id="Text_bc622eca11e84c0c8cebdfd099e985df" contextRef="c20210101to20211231" escape="true" continuedAt="Text_f1358d2849ec4a4fbad33223ff0de4c31">
<div style="display:none;"><br /></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Significant components of our deferred tax assets and liabilities as of December 31, 2021 and 2020 are as follows (in thousands):</div>
</ix:nonNumeric></ix:continuation>
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<div><br />
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</ix:continuation></ix:continuation>
  <ix:continuation id="Text_719e67a58bcc4bb6a3750a77d491201918" continuedAt="Text_719e67a58bcc4bb6a3750a77d491201919"><ix:continuation id="Text_f1358d2849ec4a4fbad33223ff0de4c32" continuedAt="Text_f1358d2849ec4a4fbad33223ff0de4c33">
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  <tr>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">

        </td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" colspan="6">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Year Ended December 31,</div>
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" colspan="2">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2021</div>
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" colspan="2">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2020</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom;">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="2">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="2">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">(as revised*)</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom;">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="2">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="2">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom;">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Deferred Tax Assets:</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="2">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom;" colspan="2">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 76%; background-color: #CCEEFF;">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Net operating loss carryovers</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:DeferredTaxAssetsOperatingLossCarryforwards" id="Fact_f6113dec90244be7a15feeec0e7f99b3" contextRef="c20211231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">85,600</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:DeferredTaxAssetsOperatingLossCarryforwards" id="Fact_de531fc8054a467eb0d8ebe192e75809" contextRef="c20201231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">83,681</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 76%;">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Tax credits</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 76%; background-color: #CCEEFF;">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Deferred revenue</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:DeferredTaxAssetsDeferredIncome" id="Fact_3161a0571c2d40cfa484d6df3f0587b3" contextRef="c20211231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">104,330</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:DeferredTaxAssetsDeferredIncome" id="Fact_8e7b04eb5d41408cb9a2aae8c76b704c" contextRef="c20201231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">124,452</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 76%;">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Stock-based compensation</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 76%; background-color: #CCEEFF;">
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    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 76%;">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Convertible debt</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="ions:DeferredTaxAssetsFinancingArrangements" id="Fact_d5e56b516fd44b23a7d77df2c87dd193" contextRef="c20211231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">45,681</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="ions:DeferredTaxAssetsFinancingArrangements" id="Fact_56e973c6c9d8438697c10963c3e2b910" contextRef="c20201231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">22,395</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 76%; background-color: #CCEEFF;">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Interest expense limitation</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="ions:DeferredTaxAssetsInterestExpenseLimitation" id="Fact_c83b54345a1c4b8780d8a7e7358c64bd" contextRef="c20211231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">6,996</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="ions:DeferredTaxAssetsInterestExpenseLimitation" id="Fact_c3b08cb12f234f2481debf0a48e48ad6" contextRef="c20201231" unitRef="U001" decimals="-3" scale="3" format="ixt:zerodash">&#8212;</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 76%; padding-bottom: 2px;">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Other</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:DeferredTaxAssetsOther" id="Fact_68255c3bd980428f8ac1596cf0f40278" contextRef="c20211231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">15,048</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:DeferredTaxAssetsOther" id="Fact_8fd4dba767ea4fb1ad2e077d22dd1144" contextRef="c20201231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">13,402</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 76%; background-color: #CCEEFF;">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Total deferred tax assets</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:DeferredTaxAssetsGross" id="Fact_db490d6be6234997ab204f135fae4219" contextRef="c20211231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">706,346</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:DeferredTaxAssetsGross" id="Fact_0e07da67ce43444f913fc9c18171c638" contextRef="c20201231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">668,174</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 76%;">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 76%; background-color: #CCEEFF;">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Deferred Tax Liabilities:</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 76%;">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Fixed assets</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:DeferredTaxLiabilitiesPropertyPlantAndEquipment" id="Fact_e25b4841ea8643daaead657546cec52e" contextRef="c20211231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">3,303</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:DeferredTaxLiabilitiesPropertyPlantAndEquipment" id="Fact_9878485dcb08467684a2d157588eeafd" contextRef="c20201231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">3,611</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 76%; padding-bottom: 2px; background-color: #CCEEFF;">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Other</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:DeferredTaxLiabilitiesOther" id="Fact_1b5703c2c4764515a3e8ad2afeea59cf" contextRef="c20211231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">5,270</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:DeferredTaxLiabilitiesOther" id="Fact_1b2f279a0c764ac6861cf53127c15459" contextRef="c20201231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">5,808</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 76%;">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Net deferred tax asset</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="ions:DeferredTaxAssetsLiabilitiesNetBeforeValuationAllowance" id="Fact_2aed2e8242ea4d2a953befcd5fd869ee" contextRef="c20211231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">697,773</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="ions:DeferredTaxAssetsLiabilitiesNetBeforeValuationAllowance" id="Fact_079ce9450c7a4660ba7391c5cb7a50dc" contextRef="c20201231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">658,755</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 76%; padding-bottom: 2px; background-color: #CCEEFF;">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Valuation allowance</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:DeferredTaxAssetsValuationAllowance" id="Fact_972868dc5873412980ceca72fd836c11" contextRef="c20211231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">697,773</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:DeferredTaxAssetsValuationAllowance" id="Fact_2c9b12b4481545a7ba60367cdb421919" contextRef="c20201231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">658,755</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 76%; padding-bottom: 4px;">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Total net deferred tax assets and liabilities</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:DeferredTaxAssetsLiabilitiesNet" id="Fact_57658da53796431d95347a5ae91df615" contextRef="c20211231" unitRef="U001" decimals="-3" scale="3" format="ixt:zerodash">&#8212;</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:DeferredTaxAssetsLiabilitiesNet" id="Fact_b0ad9b5a1bcf4171839877e1f6c48962" contextRef="c20201231" unitRef="U001" decimals="-3" scale="3" format="ixt:zerodash">&#8212;</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>


</table>
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<div><br />
  </div>
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<table cellspacing="0" cellpadding="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">


  <tr>

    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">*</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We revised our 2020 and 2019 amounts to reflect the simplified convertible instruments accounting guidance, which we adopted retrospectively. Refer to
            Note 1, <span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Organization and Significant Accounting Policies</span>, for further information.</div>
        </td>

  </tr>


</table>
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<div style="display:none;"><br /></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We evaluate our deferred tax assets regularly to determine whether adjustments to the valuation allowance are appropriate
    due to changes in facts or circumstances, such as changes in expected future pre-tax earnings, tax law, interactions with taxing authorities and developments in case law. In making this evaluation, we rely on our recent history of pre-tax earnings. Our
    material assumptions are our forecasts of future pre-tax earnings and the nature and timing of future deductions and income represented by the deferred tax assets and liabilities, all of which involve the exercise of significant judgment. Although we
    believe our estimates are reasonable, we are required to use significant judgment in determining the appropriate amount of valuation allowance recorded against our deferred tax assets.</div>
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<div style="display:none;"><br /></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Ionis and Akcea filed separate U.S. federal income tax returns from the date of Akcea&#8217;s IPO in 2017 through October 12,
    2020, the date on which we completed the Akcea Merger. As a result of the Akcea Merger, Ionis and Akcea now file a consolidated U.S. federal income tax return, and we now assess our U.S. federal and state valuation allowance requirements on a
    consolidated basis.</div>
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  </div>
</ix:continuation>
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<div style="display:none;"><br /></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We assessed our valuation allowance requirements and recorded a valuation allowance of $<ix:nonFraction name="us-gaap:ValuationAllowancesAndReservesPeriodIncreaseDecrease" id="Fact_a89e5292a1d2448488579c61e3ad1c88" contextRef="c20201001to20201231" unitRef="U001" decimals="-6" scale="6" format="ixt:numdotdecimal">341</ix:nonFraction> million against all of Ionis&#8217; U.S. federal net deferred tax assets in the fourth quarter of 2020, due to uncertainties related to our ability to realize
    the tax benefits associated with these assets. We based this determination largely on Akcea rejoining the Ionis consolidated U.S. federal tax group in the fourth quarter of 2020. Due to Akcea&#8217;s historical and projected financial statement losses, and
    the expected negative impact this will have on Ionis&#8217; consolidated taxable income, we are uncertain if we will generate sufficient consolidated pre-tax income in future periods to realize the Ionis deferred tax benefits. We also expect that Ionis&#8217;
    pre-tax income in future periods will be lower due to significant investments in research and development associated with our pipeline of wholly owned medicines. We now maintain a valuation allowance against all our consolidated U.S. federal and state
    net deferred tax assets.</div>
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  </div>
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<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Our valuation allowance increased by $<ix:nonFraction name="us-gaap:ValuationAllowancesAndReservesPeriodIncreaseDecrease" id="Fact_66c86cbe348d4776a343b6ddac2f20fe" contextRef="c20210101to20211231" unitRef="U001" decimals="-6" scale="6" format="ixt:numdotdecimal">39</ix:nonFraction> million from December 31, 2020 to December 31, 2021. The increase was primarily related to increases in our deferred tax assets for tax credits and convertible debt offset against a decrease in our
    deferred tax asset for deferred revenue.</div>
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  </div>
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<div style="display:none;"><br /></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">At December 31, 2021,
    we had federal and state, primarily California, tax net operating loss carryforwards of $<ix:nonFraction name="us-gaap:OperatingLossCarryforwards" id="Fact_d9f8be4484bf4eb29dfdbd375c201523" contextRef="c20211231_IncomeTaxAuthorityNameAxis_InternalRevenueServiceIRSMember" unitRef="U001" decimals="-5" scale="6" format="ixt:numdotdecimal">271.5</ix:nonFraction> million and $<ix:nonFraction name="us-gaap:OperatingLossCarryforwards" id="Fact_ad3cae48e06445f7aefbd80a218590f4" contextRef="c20211231_IncomeTaxAuthorityNameAxis_CaliforniaFranchiseTaxBoardMember" unitRef="U001" decimals="-5" scale="6" format="ixt:numdotdecimal">333.8</ix:nonFraction> million, respectively. Our federal tax loss carryforwards are available indefinitely. Our California tax loss carryforwards will begin to expire in 2031. At December 31, 2021, we also had federal and California research and development tax credit carryforwards of $<ix:nonFraction name="us-gaap:TaxCreditCarryforwardAmount" id="Fact_895e697c597d405a96e760deb75e2c01" contextRef="c20211231_IncomeTaxAuthorityNameAxis_InternalRevenueServiceIRSMember_TaxCreditCarryforwardAxis_ResearchMember" unitRef="U001" decimals="-5" scale="6" format="ixt:numdotdecimal">225.5</ix:nonFraction> million and $<ix:nonFraction name="us-gaap:TaxCreditCarryforwardAmount" id="Fact_8191e961253a4f2faaff06f7920ca14f" contextRef="c20211231_IncomeTaxAuthorityNameAxis_CaliforniaFranchiseTaxBoardMember_TaxCreditCarryforwardAxis_ResearchMember" unitRef="U001" decimals="-5" scale="6" format="ixt:numdotdecimal">99.7</ix:nonFraction> million, respectively. Our federal research and development tax
    credit carryforwards will begin to expire in 2034. Our California research and development tax credit carryforwards are available indefinitely.</div>
</ix:continuation></div>

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    <div class="DSPFPageFooter">
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<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Utilization of the net operating loss and tax credit carryforwards may be subject to an annual limitation due to the ownership change
    limitations provided by the Internal Revenue Code of 1986, as amended, and similar state provisions. The annual limitation may result in the expiration of net operating losses and credits before utilization.</div>
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<div style="display:none;"><br /></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We analyze filing positions in all U.S. federal, state and foreign jurisdictions where we file income tax returns, and all open tax years
    in these jurisdictions to determine if we have any uncertain tax positions on any of our income tax returns. We recognize the impact of an uncertain tax position on an income tax return at the largest amount that the relevant taxing authority is
    more-likely-than not to sustain upon audit. We do not recognize uncertain income tax positions if they have less than 50 percent likelihood of the applicable tax authority sustaining our position.</div>
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  <ix:continuation id="Text_719e67a58bcc4bb6a3750a77d491201936" continuedAt="Text_719e67a58bcc4bb6a3750a77d491201937"><ix:nonNumeric name="us-gaap:ScheduleOfUnrecognizedTaxBenefitsRollForwardTableTextBlock" id="Text_12d4365f69d7416c8040c6997595919c" contextRef="c20210101to20211231" escape="true" continuedAt="Text_9fc49456b13f447685285600ceb56c1e1">
<div style="display:none;"><br /></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">The following table summarizes our gross unrecognized tax benefits <span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">(in thousands):</span></div>
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  </div>
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<table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;" class="cfttable">


  <tr>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">

        </td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" colspan="10">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Year Ended December 31,</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" colspan="2">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2021</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" colspan="2">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2020</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" colspan="2">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2019</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Beginning balance of unrecognized tax benefits</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:UnrecognizedTaxBenefits" id="Fact_6f5ba375963f47a19fbb04fed7232165" contextRef="c20201231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">54,163</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:UnrecognizedTaxBenefits" id="Fact_0f12ba3f88584d21bf0b87b613d47847" contextRef="c20191231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">69,784</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:UnrecognizedTaxBenefits" id="Fact_67e334d942db4ea29c0cbe3ffcea2715" contextRef="c20181231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">68,301</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 64%;">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Decrease for prior period tax positions</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:UnrecognizedTaxBenefitsDecreasesResultingFromPriorPeriodTaxPositions" id="Fact_3f06e5d0f5b747c280280e9fcf69a448" contextRef="c20210101to20211231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">695</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:UnrecognizedTaxBenefitsDecreasesResultingFromPriorPeriodTaxPositions" id="Fact_39287cd4b49c44a4a617144fa53df1bf" contextRef="c20200101to20201231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">24,154</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:UnrecognizedTaxBenefitsDecreasesResultingFromPriorPeriodTaxPositions" id="Fact_0bb19795798b4cca8d22978a26340bd0" contextRef="c20190101to20191231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">867</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Increase for prior period tax positions</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
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    <td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 2px;">
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        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:UnrecognizedTaxBenefitsIncreasesResultingFromCurrentPeriodTaxPositions" id="Fact_809af95107674a60b9a6aa50165e5ba7" contextRef="c20190101to20191231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">1,614</ix:nonFraction></div>
        </td>

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    <td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 4px; background-color: #CCEEFF;">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Ending balance of unrecognized tax benefits</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" colspan="1">&#160;</td>

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          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:UnrecognizedTaxBenefits" id="Fact_c2747640a25a483791181f56caf8bc45" contextRef="c20211231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">55,085</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:UnrecognizedTaxBenefits" id="Fact_58382ea6463045ef8f7cefb3fdbf3dd7" contextRef="c20201231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">54,163</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:UnrecognizedTaxBenefits" id="Fact_ed1574437d194d92b955e24fdec9efce" contextRef="c20191231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">69,784</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>


</table>
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<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Included in the balance of unrecognized tax benefits at December 31, 2021, 2020 and 2019 was $<ix:nonFraction name="us-gaap:UnrecognizedTaxBenefitsThatWouldImpactEffectiveTaxRate" id="Fact_552285171ef248dfab36d0ee9948271e" contextRef="c20211231" unitRef="U001" decimals="-5" scale="6" format="ixt:numdotdecimal">6.2</ix:nonFraction> million, $<ix:nonFraction name="us-gaap:UnrecognizedTaxBenefitsThatWouldImpactEffectiveTaxRate" id="Fact_609bbfafde0b4ea9bce0bad6399c9eb6" contextRef="c20201231" unitRef="U001" decimals="-5" scale="6" format="ixt:numdotdecimal">6.4</ix:nonFraction> million and $<ix:nonFraction name="us-gaap:UnrecognizedTaxBenefitsThatWouldImpactEffectiveTaxRate" id="Fact_49d7f6eb2570409abc1312c432abdfe0" contextRef="c20191231" unitRef="U001" decimals="-5" scale="6" format="ixt:numdotdecimal">0.4</ix:nonFraction> million respectively, that if we recognized, could impact our effective tax rate, subject to our remaining valuation allowance.</div>
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<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We do not foresee any material changes to our gross unrecognized tax benefits within the next twelve months.</div>
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<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We recognize interest and/or penalties related to income tax matters in income tax expense. During the year ended December
    31, 2021 and 2020, we recognized $<ix:nonFraction name="us-gaap:UnrecognizedTaxBenefitsIncomeTaxPenaltiesAndInterestExpense" id="Fact_5d817f0050924f7f82257fc7b70a23d7" contextRef="c20210101to20211231" unitRef="U001" decimals="-5" scale="6" format="ixt:numdotdecimal">0.5</ix:nonFraction>
    million and $<ix:nonFraction name="us-gaap:UnrecognizedTaxBenefitsIncomeTaxPenaltiesAndInterestExpense" id="Fact_2955ef1a6fab40d7ab1c8f70571532db" contextRef="c20200101to20201231" unitRef="U001" decimals="-5" scale="6" format="ixt:numdotdecimal">0.3</ix:nonFraction> million, respectively, of accrued interest and penalties related to gross unrecognized tax benefits. We did <ix:nonFraction name="us-gaap:UnrecognizedTaxBenefitsIncomeTaxPenaltiesAndInterestExpense" id="Fact_2321538f28f84622993d01cd1e04e2c0" contextRef="c20190101to20191231" unitRef="U001" decimals="-6" scale="6" format="ixt-sec:numwordsen">no</ix:nonFraction>t record any accrued interest and penalties for the years ended December 31, 2019.</div>
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<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We are subject to taxation in the U.S. and various state and foreign jurisdictions. Our tax years for 1999 through 2020
    are subject to examination by the U.S. federal, state and foreign tax authorities.</div>
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<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">We do not provide for a U.S. income tax
      liability and foreign withholding taxes on undistributed foreign earnings of our foreign subsidiaries as we consider those earnings to be permanently reinvested. It is not practicable for us to calculate the amount of unrecognized deferred tax
      liabilities associated with these earnings</span>.</div>
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<div><ix:nonNumeric name="us-gaap:CollaborativeArrangementDisclosureTextBlock" id="Text_80c8d3faa85543f28cd974b1bfe28318" contextRef="c20210101to20211231" escape="true" continuedAt="Text_94d04d6648bd4eb79b4d365680e182fc1">
<div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">6. Collaborative Arrangements and Licensing Agreements</div>
</ix:nonNumeric>

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<div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Strategic Partnership</div>
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<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;">Biogen</div>
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<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We have several strategic collaborations with Biogen focused on using antisense technology to advance the treatment of
    neurological disorders. These collaborations combine our expertise in creating antisense medicines with Biogen&#8217;s expertise in developing therapies for neurological disorders. We developed and licensed to Biogen SPINRAZA, our approved medicine to treat
    people with spinal muscular atrophy, or SMA. We and Biogen are currently developing <ix:nonFraction name="ions:NumberOfMedicinesBeingDeveloped" id="Fact_7af8e6ccc5734a52b212b2cb39251c85" contextRef="c20211231_TypeOfArrangementAxis_BiogenCollaborationsMember" unitRef="U017" decimals="INF" scale="0" format="ixt-sec:numwordsen">nine</ix:nonFraction> investigational medicines to treat neurodegenerative
    diseases under these collaborations, including medicines in development to treat people with ALS, SMA, AS, Alzheimer&#8217;s disease<sub>&#160;</sub>and Parkinson&#8217;s disease. In addition to these medicines, our collaborations with Biogen include a substantial
    research pipeline that addresses a broad range of neurological diseases. From inception through December 2021, we have received more than $<ix:nonFraction name="ions:CumulativePaymentsReceived" id="Fact_06e533557dd645a0a293de69cd61db32" contextRef="c20211231_RangeAxis_MinimumMember_TypeOfArrangementAxis_BiogenCollaborationsMember" unitRef="U001" decimals="-8" scale="9" format="ixt:numdotdecimal">3.1</ix:nonFraction> billion from our Biogen collaborations.</div>
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<div style="text-align: left; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic; font-weight: bold;">Spinal Muscular Atrophy Collaborations</div>
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<div style="text-align: left; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;">SPINRAZA</div>
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<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">In January 2012, we entered into a
      collaboration agreement with Biogen to develop and commercialize SPINRAZA, an RNA-targeted therapy for the treatment of SMA.</span>&#160;<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">From inception through
      December 2021, we earned more than $</span><ix:nonFraction name="ions:CumulativeRevenueFromContractWithCustomerExcludingAssessedTax" id="Fact_80c48219eb9e4393b8569e87d9780e38" contextRef="c20211231_RangeAxis_MinimumMember_TypeOfArrangementAxis_BiogenCollaborationSpinrazaMember" unitRef="U001" decimals="-8" scale="9" format="ixt:numdotdecimal">1.6</ix:nonFraction><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">
      billion in total revenue under our SPINRAZA collaboration, including nearly $</span><ix:nonFraction name="ions:CumulativeRevenueFromContractWithCustomerExcludingAssessedTax" id="Fact_6cef645a43bf4562909cf1040246fa31" contextRef="c20211231_ProductOrServiceAxis_SpinrazaRoyaltiesMember_RangeAxis_MaximumMember_TypeOfArrangementAxis_BiogenCollaborationSpinrazaMember" unitRef="U001" decimals="-8" scale="9" format="ixt:numdotdecimal">1.2</ix:nonFraction><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> billion in revenue from SPINRAZA royalties and more than $</span><ix:nonFraction name="ions:CumulativeRevenueFromContractWithCustomerExcludingAssessedTax" id="Fact_4f6bdc7d5939403c952ca9aeb8c58deb" contextRef="c20211231_ProductOrServiceAxis_ResearchAndDevelopmentRevenueUnderCollaborativeAgreementsMember_RangeAxis_MinimumMember_TypeOfArrangementAxis_BiogenCollaborationSpinrazaMember" unitRef="U001" decimals="-6" scale="6" format="ixt:numdotdecimal">435</ix:nonFraction><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> million in R&amp;D revenue. We are receiving tiered royalties ranging from </span><ix:nonFraction name="ions:RoyaltyPercentageReceivedOnNetSalesOfMedicine" id="Fact_61c6432e61694a50bab0c763baf066d7" contextRef="c20210101to20211231_RangeAxis_MinimumMember_TypeOfArrangementAxis_BiogenCollaborationSpinrazaMember" unitRef="U003" decimals="2" scale="-2" format="ixt:numdotdecimal">11</ix:nonFraction> percent<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> to </span><ix:nonFraction name="ions:RoyaltyPercentageReceivedOnNetSalesOfMedicine" id="Fact_1823d09bb3e44264ad0c1a26037d2ae5" contextRef="c20210101to20211231_RangeAxis_MaximumMember_TypeOfArrangementAxis_BiogenCollaborationSpinrazaMember" unitRef="U003" decimals="2" scale="-2" format="ixt:numdotdecimal">15</ix:nonFraction> percent<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> on net sales of SPINRAZA. We have exclusively in-licensed patents related to SPINRAZA from Cold Spring Harbor Laboratory and the University of Massachusetts. We pay Cold Spring Harbor
      Laboratory and the University of Massachusetts a low single digit royalty on net sales of SPINRAZA. Biogen is responsible for all global development, regulatory and commercialization activities and costs for SPINRAZA. We completed our performance
      obligations under our collaboration in 2016</span>.</div>
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<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;">New antisense medicines for the treatment of SMA</div>
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<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">In December 2017, we entered into a
      collaboration agreement with Biogen to </span>identify <span style="background-color: #FBFBFB; font-size: 10pt; font-family: 'Times New Roman', Times, serif;">new antisense medicines for the treatment of SMA</span><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">. </span><span style="background-color: #FBFBFB; font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">Biogen has the option to license therapies arising out of
      this collaboration following the completion of preclinical studies. Upon licensing, Biogen </span><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">will be responsible for global development, regulatory and
      commercialization activities and costs for such therapies</span><span style="background-color: #FBFBFB; font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">. Under the collaboration agreement, we received a </span>$<ix:nonFraction name="ions:UpfrontPaymentReceived" id="Fact_d0f059efca0b4cb78eead790f4fa19ae" contextRef="c20171001to20171231_TypeOfArrangementAxis_BiogenCollaborationNewAntisenseMedicinesForTreatmentOfSmaMember" unitRef="U001" decimals="-6" scale="6" format="ixt:numdotdecimal">25</ix:nonFraction> million<span style="background-color: #FBFBFB; font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> upfront payment in the </span><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">fourth</span><span style="background-color: #FBFBFB; font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> quarter of </span><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">2017</span><span style="background-color: #FBFBFB; font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">. </span><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">In December 2021, we earned a $</span><ix:nonFraction name="us-gaap:RevenueFromContractWithCustomerExcludingAssessedTax" id="Fact_7948382269be4b958cfc743393d71711" contextRef="c20211201to20211231_ProductOrServiceAxis_Ion306Member_TypeOfArrangementAxis_BiogenCollaborationNewAntisenseMedicinesForTreatmentOfSmaMember" unitRef="U001" decimals="-6" scale="6" format="ixt:numdotdecimal">60</ix:nonFraction><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> million license fee payment when Biogen exercised its option to license ION306. </span><span style="background-color: #FBFBFB; font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">We will receive development and regulatory milestone payments from Biogen if new medicines advance towards marketing approval. </span><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">In total over the term of our collaboration, we are eligible to receive up to $</span><ix:nonFraction name="ions:MaximumAmountOfPaymentsReceivableForLicenseFeesMilestonePaymentsAndOtherPayments" id="Fact_8fa42de141e3407c99bbfa2f29113c53" contextRef="c20211231_TypeOfArrangementAxis_BiogenCollaborationNewAntisenseMedicinesForTreatmentOfSmaMember" unitRef="U001" decimals="-8" scale="9" format="ixt:numdotdecimal">1.2</ix:nonFraction><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> billion in license fees, milestone payments and other payments, including up to $</span><ix:nonFraction name="ions:MaximumAmountOfPaymentsReceivableForDevelopmentCommercializationAndSalesMilestones" id="Fact_3e6911040e1d45c0b915ba4b62552c08" contextRef="c20211231_ProductOrServiceAxis_Ion306Member_TypeOfArrangementAxis_BiogenCollaborationNewAntisenseMedicinesForTreatmentOfSmaMember" unitRef="U001" decimals="-6" scale="6" format="ixt:numdotdecimal">555</ix:nonFraction><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> million in payments if Biogen advances ION306, which includes up to $</span><ix:nonFraction name="ions:MaximumAmountOfPaymentsReceivableForDevelopmentMilestones" id="Fact_1777f9042b9e450888607262dedee914" contextRef="c20211231_ProductOrServiceAxis_Ion306Member_TypeOfArrangementAxis_BiogenCollaborationNewAntisenseMedicinesForTreatmentOfSmaMember" unitRef="U001" decimals="-6" scale="6" format="ixt:numdotdecimal">45</ix:nonFraction><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> million for the achievement of development milestones, up to $</span><ix:nonFraction name="ions:MaximumAmountOfPaymentsReceivableForRegulatoryMilestones" id="Fact_596b7561419e42bab887182782ab4cf3" contextRef="c20211231_ProductOrServiceAxis_Ion306Member_TypeOfArrangementAxis_BiogenCollaborationNewAntisenseMedicinesForTreatmentOfSmaMember" unitRef="U001" decimals="-6" scale="6" format="ixt:numdotdecimal">110</ix:nonFraction><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> million for the achievement of regulatory milestones and up
      to $</span><ix:nonFraction name="ions:MaximumAmountOfPaymentsReceivableForSalesMilestones" id="Fact_693f93823cdd4834932fe11e90d4dbbc" contextRef="c20211231_ProductOrServiceAxis_Ion306Member_TypeOfArrangementAxis_BiogenCollaborationNewAntisenseMedicinesForTreatmentOfSmaMember" unitRef="U001" decimals="-6" scale="6" format="ixt:numdotdecimal">400</ix:nonFraction><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> million for the achievement of
      sales milestones. In addition, we are eligible to receive tiered royalties </span><span style="background-color: #FBFBFB; font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">from the mid-teens to </span><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">mid-</span><ix:nonFraction name="ions:RoyaltyPercentageReceivedOnNetSalesOfMedicine" id="Fact_febbc9e4755e4074b3a325f2dacf1e28" contextRef="c20210101to20211231_TypeOfArrangementAxis_BiogenCollaborationNewAntisenseMedicinesForTreatmentOfSmaMember" unitRef="U003" decimals="2" scale="-2" format="ixt:numdotdecimal">20</ix:nonFraction> percent<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> range </span><span style="background-color: #FBFBFB; font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">on net sales.</span><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> We will achieve the next payment of up to $</span><ix:nonFraction name="ions:NextPotentialPayment" id="Fact_7d01c2380f624d1fb49986067438d3ed" contextRef="c20211231_TypeOfArrangementAxis_BiogenCollaborationNewAntisenseMedicinesForTreatmentOfSmaMember" unitRef="U001" decimals="-6" scale="6" format="ixt:numdotdecimal">45</ix:nonFraction><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> millionfor the initiation of a Phase 3 trial under this collaboration. </span></div>
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<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">At the commencement of this collaboration, we identified <ix:nonFraction name="ions:RevenueFromContractWithCustomerNumberOfSeparatePerformanceObligations" id="Fact_d072d638eb714ba6a26876ea2bbbb72a" contextRef="c20171231_TypeOfArrangementAxis_BiogenCollaborationNewAntisenseMedicinesForTreatmentOfSmaMember" unitRef="U006" decimals="INF" scale="0" format="ixt-sec:numwordsen">one</ix:nonFraction> performance obligation, which was to perform R&amp;D services for Biogen. We determined the transaction price to be the $<ix:nonFraction name="ions:RevenueFromContractWithCustomerTransactionPrice" id="Fact_e3683f7ee88940418d4cb28dad798342" contextRef="c20171231_TypeOfArrangementAxis_BiogenCollaborationNewAntisenseMedicinesForTreatmentOfSmaMember" unitRef="U001" decimals="-6" scale="6">25</ix:nonFraction> million upfront payment we received when we entered into the collaboration. We allocated the transaction price to our single performance obligation. In the fourth quarter of 2019, we
    completed our R&amp;D services performance obligation under this collaboration. We recognized revenue as we performed services based on our effort to satisfy our performance obligation relative to the total effort expected to satisfy our performance
    obligation. We completed our performance obligation earlier than we previously estimated, as a result, we recognized $<ix:nonFraction name="us-gaap:RevenueFromContractWithCustomerExcludingAssessedTax" id="Fact_4edfbf91e3db4c149d8f7c6de6cfd7f2" contextRef="c20191001to20191231_TypeOfArrangementAxis_BiogenCollaborationNewAntisenseMedicinesForTreatmentOfSmaMember" unitRef="U001" decimals="-5" scale="6" format="ixt:numdotdecimal">8.3</ix:nonFraction> million of additional
    revenue in the fourth quarter of 2019.</div>
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<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">In the fourth quarter of 2021, we identified another performance obligation upon Biogen&#8217;s license of ION306 because the license we granted
    to Biogen is distinct from our other performance obligations. We recognized the $<ix:nonFraction name="us-gaap:RevenueFromContractWithCustomerExcludingAssessedTax" id="Fact_96726e695ad843d9931f094dadfb35e4" contextRef="c20211201to20211231_ProductOrServiceAxis_Ion306Member_TypeOfArrangementAxis_BiogenCollaborationNewAntisenseMedicinesForTreatmentOfSmaMember" unitRef="U001" decimals="-6" scale="6" format="ixt:numdotdecimal">60</ix:nonFraction> million license fee for ION306 as revenue at that time
    because Biogen had full use of the license without any continuing involvement from us. Additionally, we did not have any further performance obligations related to the license after we delivered it to Biogen. Biogen is solely responsible for the costs
    and expenses related to the development, manufacturing and potential future commercialization of ION306 following the option exercise. We do not have any remaining performance obligations under this collaboration.</div>
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<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic; font-weight: bold;">Neurology Collaborations</div>
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<div style="text-align: left; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;">2018 Strategic Neurology</div>
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<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">In April 2018, we and Biogen entered into a
      strategic collaboration to develop novel antisense medicines for a broad range of neurological diseases and entered into a SPA. As part of the collaboration, Biogen gained exclusive rights to the use of our antisense technology to develop therapies
      for these diseases for </span><ix:nonNumeric name="ions:TermOfCollaborationAgreement" id="Fact_3d01100b8b54487eb5650d892b0313da" contextRef="c20210101to20211231_TypeOfArrangementAxis_BiogenCollaboration2018StrategicNeurologyMember" format="ixt-sec:duryear">10</ix:nonNumeric><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> years. We are
      responsible for the identification of antisense drug candidates based on selected medicines</span>. Biogen is responsible for conducting IND-enabling toxicology studies for the selected medicine. <span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">Biogen will have the option to license the selected medicine </span>after it completes the IND-enabling toxicology study. <span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">If Biogen exercises its option to license a medicine, it will assume global development, regulatory and commercialization responsibilities and costs for that medicine.</span></div>
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<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="background-color: #FBFBFB; font-size: 10pt; font-family: 'Times New Roman', Times, serif;">In the </span>second<span style="background-color: #FBFBFB; font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> quarter of </span>2018<span style="background-color: #FBFBFB; font-size: 10pt; font-family: 'Times New Roman', Times, serif;">, we received </span>$<ix:nonFraction name="ions:UpfrontPaymentReceivedIncludingPurchaseOfStock" id="Fact_976237d61b074e5e9b91af22b9df351f" contextRef="c20180401to20180630_TypeOfArrangementAxis_BiogenCollaboration2018StrategicNeurologyMember" unitRef="U001" decimals="-9" scale="9" format="ixt:numdotdecimal">1</ix:nonFraction> billion from Biogen, comprised of $<ix:nonFraction name="us-gaap:ProceedsFromIssuanceOfCommonStock" id="Fact_271dd8aced544c41be19b5a818ba4058" contextRef="c20180401to20180630_TypeOfArrangementAxis_BiogenCollaboration2018StrategicNeurologyMember" unitRef="U001" decimals="-6" scale="6" format="ixt:numdotdecimal">625</ix:nonFraction> million
    to purchase our stock at an approximately <ix:nonFraction name="ions:PercentageCashPremiumPaidOnSharesPurchased" id="Fact_c96d0cb6c7e643c7b9c75b57384aa601" contextRef="c20180401to20180630_TypeOfArrangementAxis_BiogenCollaboration2018StrategicNeurologyMember" unitRef="U003" decimals="2" scale="-2" format="ixt:numdotdecimal">25</ix:nonFraction> percent cash premium and $<ix:nonFraction name="ions:UpfrontPaymentReceived" id="Fact_755b026d1fee41558d1dc2c5b62ee556" contextRef="c20180401to20180630_TypeOfArrangementAxis_BiogenCollaboration2018StrategicNeurologyMember" unitRef="U001" decimals="-6" scale="6" format="ixt:numdotdecimal">375</ix:nonFraction> million in an upfront payment. <span style="background-color: #FBFBFB; font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We are eligible to receive up to $</span><ix:nonFraction name="ions:MaximumAmountOfPaymentsReceivablePerMedicineForMilestonePayments" id="Fact_62648637171d42169a691df96b84fa12" contextRef="c20211231_TypeOfArrangementAxis_BiogenCollaboration2018StrategicNeurologyMember" unitRef="U001" decimals="-6" scale="6" format="ixt:numdotdecimal">270</ix:nonFraction><span style="background-color: #FBFBFB; font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> million in milestone payments for each medicine
      that achieves marketing approval. </span>In addition, we are eligible to receive tiered royalties <span style="background-color: #FBFBFB; font-size: 10pt; font-family: 'Times New Roman', Times, serif;">up to the </span><ix:nonFraction name="ions:RoyaltyPercentageReceivedOnNetSalesOfMedicine" id="Fact_210a08ece63647968230838a5127deb6" contextRef="c20210101to20211231_TypeOfArrangementAxis_BiogenCollaboration2018StrategicNeurologyMember" unitRef="U003" decimals="2" scale="-2" format="ixt:numdotdecimal">20</ix:nonFraction> percent range <span style="background-color: #FBFBFB; font-size: 10pt; font-family: 'Times New Roman', Times, serif;">on net sales.</span>&#160;<span style="background-color: #FBFBFB; font-size: 10pt; font-family: 'Times New Roman', Times, serif;">W</span>e are currently advancing <ix:nonFraction name="ions:NumberOfProgramsBeingAdvanced" id="Fact_bcc6f527b7724a709204e78caa6a12c2" contextRef="c20211231_TypeOfArrangementAxis_BiogenCollaboration2018StrategicNeurologyMember" unitRef="U018" decimals="INF" scale="0" format="ixt-sec:numwordsen">nine</ix:nonFraction>
    programs under this collaboration and from inception through December 2021, we have received nearly $<ix:nonFraction name="ions:CumulativePaymentsReceived" id="Fact_da56d1dc03c24e66a27cff951a361cbb" contextRef="c20211231_RangeAxis_MaximumMember_TypeOfArrangementAxis_BiogenCollaboration2018StrategicNeurologyMember" unitRef="U001" decimals="-8" scale="9" format="ixt:numdotdecimal">1.1</ix:nonFraction> billion in payments under this
    collaboration. We will achieve the next payment of $<ix:nonFraction name="ions:NextPotentialPayment" id="Fact_2ccf74adb28c46398e26d42924be60cb" contextRef="c20211231_TypeOfArrangementAxis_BiogenCollaboration2018StrategicNeurologyMember" unitRef="U001" decimals="-5" scale="6" format="ixt:numdotdecimal">7.5</ix:nonFraction> million if Biogen designates or advances another program<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">under this collaboration. </span></div>
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<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">At the commencement of this collaboration, </span>we
    identified <ix:nonFraction name="ions:RevenueFromContractWithCustomerNumberOfSeparatePerformanceObligations" id="Fact_5e47f934a68347d89f25d91842517b61" contextRef="c20180430_TypeOfArrangementAxis_BiogenCollaboration2018StrategicNeurologyMember" unitRef="U006" decimals="INF" scale="0" format="ixt-sec:numwordsen">one</ix:nonFraction> performance obligation, which was to perform R&amp;D services for Biogen.<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> We determined our transaction price to be $</span><ix:nonFraction name="ions:RevenueFromContractWithCustomerTransactionPrice" id="Fact_295623a84e6d476bb91ebff3bfed5858" contextRef="c20180430_TypeOfArrangementAxis_BiogenCollaboration2018StrategicNeurologyMember" unitRef="U001" decimals="-6" scale="6" format="ixt:numdotdecimal">552</ix:nonFraction><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> million, comprised of $</span><ix:nonFraction name="ions:UpfrontPaymentReceived" id="Fact_141e7593cbf740c7a6acd7c7ace28ee3" contextRef="c20180401to20180630_TypeOfArrangementAxis_BiogenCollaboration2018StrategicNeurologyMember" unitRef="U001" decimals="-6" scale="6" format="ixt:numdotdecimal">375</ix:nonFraction><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> million from the upfront payment and $</span><ix:nonFraction name="ions:PremiumPaidOnSharesPurchased" id="Fact_90cf8273bd7a479187f0efa5fa9c8263" contextRef="c20180401to20180630_TypeOfArrangementAxis_BiogenCollaboration2018StrategicNeurologyMember" unitRef="U001" decimals="-6" scale="6" format="ixt:numdotdecimal">177</ix:nonFraction><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> million for the premium paid by Biogen for its purchase of our common stock.</span> We determined the fair value of the premium we received by using the stated premium in the SPA and applying a lack of marketability
    discount. We included a lack of marketability discount in our valuation of the premium because Biogen received restricted shares of our common stock. We allocated the transaction price to our single performance obligation.</div>
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<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">From inception through December 2021, we have included $<ix:nonFraction name="ions:CumulativePaymentsIncludedInTransactionPriceForPerformanceObligation" id="Fact_20ba18c7432f48b692b7d780c2e643aa" contextRef="c20211231_TypeOfArrangementAxis_BiogenCollaboration2018StrategicNeurologyMember" unitRef="U001" decimals="-6" scale="6" format="ixt:numdotdecimal">616</ix:nonFraction> million <span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">in payments in the transaction price for our R&amp;D services performance obligation
      under this collaboration, including $</span><ix:nonFraction name="ions:MilestonePaymentsAchievedAndIncludedInTransactionPriceForPerformanceObligation" id="Fact_3f7c210dad714493961c539d0e6cfc20" contextRef="c20210101to20211231_TypeOfArrangementAxis_BiogenCollaboration2018StrategicNeurologyMember" unitRef="U001" decimals="-6" scale="6" format="ixt:numdotdecimal">23</ix:nonFraction><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">
      million of milestone payments we achieved in 2021 and $</span><ix:nonFraction name="ions:MilestonePaymentsAchievedAndIncludedInTransactionPriceForPerformanceObligation" id="Fact_c3f14a3ed4c14ef2b91a6574e6cdd6e4" contextRef="c20200101to20201231_TypeOfArrangementAxis_BiogenCollaboration2018StrategicNeurologyMember" unitRef="U001" decimals="-6" scale="6" format="ixt:numdotdecimal">11</ix:nonFraction><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> million of milestone payments we achieved in 2020. These milestone payments did not create new performance obligations because they are part of our original R&amp;D services performance obligation. Therefore, we included these
      amounts in our transaction price for our R&amp;D services performance obligation in the period we achieved the milestone payment. We are recognizing revenue for our R&amp;D services performance obligation as we perform services based on our effort to
      satisfy our performance obligation relative to our total effort expected to satisfy our performance obligation. We currently estimate we will satisfy our performance obligation at the end of the contractual term in June 2028.</span></div>
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<div style="text-align: left; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;">2013 Strategic Neurology</div>
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<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">In September 2013, we and Biogen entered into a long-term strategic relationship focused on applying antisense technology
    to advance the treatment of neurodegenerative diseases. As part of the collaboration, Biogen gained exclusive rights to the use of our antisense technology to develop therapies for neurological diseases and has the option to license medicines resulting
    from this collaboration. We will usually be responsible for drug discovery and early development of antisense medicines and Biogen has the option to license antisense medicines after Phase 2 proof-of-concept. In October 2016, we expanded our
    collaboration to include additional research activities we will perform. If Biogen exercises its option to license a medicine, it will assume global development, regulatory and commercialization responsibilities and costs for that medicine. We are
    currently advancing <ix:nonFraction name="ions:NumberOfMedicinesCurrentlyBeingAdvanced" id="Fact_eb09908f5c9a48cc93d43f56069f13ca" contextRef="c20211231_TypeOfArrangementAxis_BiogenCollaboration2013StrategicNeurologyMember" unitRef="U017" decimals="INF" scale="0" format="ixt-sec:numwordsen">six</ix:nonFraction> investigational medicines in development under this collaboration, including <span style="-sec-ix-hidden:Fact_864d03b225ca4f548971b12e6b3ad3d0">a</span> medicine for Parkinson&#8217;s disease (ION859), <ix:nonFraction name="ions:NumberOfMedicinesCurrentlyBeingAdvanced" id="Fact_996f95d3d4dd49e39ee68fd344ce391e" contextRef="c20211231_ProductOrServiceAxis_MedicinesForAmyotrophicLateralSclerosisMember_TypeOfArrangementAxis_BiogenCollaboration2013StrategicNeurologyMember" unitRef="U017" decimals="INF" scale="0" format="ixt-sec:numwordsen">three</ix:nonFraction> medicines for ALS
    (tofersen, IONIS-C9<sub>Rx</sub> and ION541), <span style="-sec-ix-hidden:Fact_7b05dc571fcb46f8bbbe0db51a44d460">a</span> medicine for multiple system atrophy (ION464) and <span style="-sec-ix-hidden:Fact_33617a5e2de04e8688f1a06dd038ea29">a</span> medicine for an undisclosed target. In the fourth quarter of 2018, Biogen exercised its option to license our most advanced ALS medicine, tofersen, our medicine in Phase 3
    development for SOD1 ALS. As a result, Biogen is now responsible for global development, regulatory and commercialization activities and costs for tofersen.</div>
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<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Under the terms of the agreement, we received an upfront payment of $<ix:nonFraction name="ions:UpfrontPaymentReceived" id="Fact_df6e4e7a86a541f1926d3e828e7efea5" contextRef="c20130901to20130930_TypeOfArrangementAxis_BiogenCollaboration2013StrategicNeurologyMember" unitRef="U001" decimals="-6" scale="6" format="ixt:numdotdecimal">100</ix:nonFraction> million and are eligible to receive milestone payments, license fees and royalty payments for all medicines developed under this collaboration, with the specific amounts dependent upon the
    modality of the molecule advanced by Biogen. For each antisense molecule that is chosen for drug discovery and development under this collaboration, we are eligible to receive up to approximately $<ix:nonFraction name="ions:MaximumAmountOfPaymentsReceivablePerProgramForLicenseFeesAndSubstantiveMilestonePayments" id="Fact_e29891c91d1a456e9cb73201cb58d5f4" contextRef="c20211231_ProductOrServiceAxis_AntisenseMoleculeMember_TypeOfArrangementAxis_BiogenCollaboration2013StrategicNeurologyMember" unitRef="U001" decimals="-6" scale="6" format="ixt:numdotdecimal">260</ix:nonFraction> million in a license fee and milestone payments per program. The $<ix:nonFraction name="ions:MaximumAmountOfPaymentsReceivablePerProgramForLicenseFeesAndSubstantiveMilestonePayments" id="Fact_0dfbd8128b624f969b95f7ef71d4d44f" contextRef="c20211231_ProductOrServiceAxis_AntisenseMoleculeMember_TypeOfArrangementAxis_BiogenCollaboration2013StrategicNeurologyMember" unitRef="U001" decimals="-6" scale="6" format="ixt:numdotdecimal">260</ix:nonFraction> million per
    program consists of approximately $<ix:nonFraction name="ions:MaximumAmountOfPaymentsReceivablePerProgramForDevelopmentMilestones" id="Fact_245f4587f74e4be8b4a2a97ac77ea0f6" contextRef="c20211231_ProductOrServiceAxis_AntisenseMoleculeMember_TypeOfArrangementAxis_BiogenCollaboration2013StrategicNeurologyMember" unitRef="U001" decimals="-6" scale="6" format="ixt:numdotdecimal">60</ix:nonFraction> million in development milestones, including amounts related to the cost of clinical trials, and up to $<ix:nonFraction name="ions:MaximumAmountOfPaymentsReceivablePerProgramForRegulatoryMilestones" id="Fact_c1d1f25511534235862a7aa4449afd2d" contextRef="c20211231_ProductOrServiceAxis_AntisenseMoleculeMember_TypeOfArrangementAxis_BiogenCollaboration2013StrategicNeurologyMember" unitRef="U001" decimals="-6" scale="6" format="ixt:numdotdecimal">130</ix:nonFraction> million in milestone payments if Biogen achieves pre-specified regulatory milestones. In addition, we are eligible to receive tiered royalties up to the
    mid-teens on net sales from any antisense medicines developed under this collaboration. From inception through December 2021, we have received over $<ix:nonFraction name="ions:CumulativePaymentsReceived" id="Fact_43252364b31243cf9fe665618b7d0d4d" contextRef="c20211231_RangeAxis_MinimumMember_TypeOfArrangementAxis_BiogenCollaboration2013StrategicNeurologyMember" unitRef="U001" decimals="-6" scale="6" format="ixt:numdotdecimal">280</ix:nonFraction>
    million in upfront fees, milestone payments and other payments under this collaboration. We will achieve the next payment of up to $<ix:nonFraction name="ions:NextPotentialPayment" id="Fact_531e5e06da924c38a4eddf832276baff" contextRef="c20211231_TypeOfArrangementAxis_BiogenCollaboration2013StrategicNeurologyMember" unitRef="U001" decimals="-6" scale="6" format="ixt:numdotdecimal">70</ix:nonFraction> million if
    Biogen licenses a medicine under this collaboration.</div>
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<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">At the commencement of our 2013 strategic neurology collaboration, we identified <ix:nonFraction name="ions:RevenueFromContractWithCustomerNumberOfSeparatePerformanceObligations" id="Fact_5f22f24c59d44580af822992d7804572" contextRef="c20130930_TypeOfArrangementAxis_BiogenCollaboration2013StrategicNeurologyMember" unitRef="U006" decimals="INF" scale="0" format="ixt-sec:numwordsen">one</ix:nonFraction> performance obligation, which was to perform R&amp;D services for Biogen. At inception, we determined the transaction price to be the $<ix:nonFraction name="ions:RevenueFromContractWithCustomerTransactionPrice" id="Fact_bcce97a700fa470ea25912768f89b9f3" contextRef="c20130930_TypeOfArrangementAxis_BiogenCollaboration2013StrategicNeurologyMember" unitRef="U001" decimals="-6" scale="6" format="ixt:numdotdecimal">100</ix:nonFraction> million upfront payment we received and allocated it to our single performance obligation. As we achieve milestone payments for our R&amp;D services, we
    include these amounts in our transaction price for our R&amp;D services performance obligation. We recognized revenue for our R&amp;D services performance obligation based on our effort to satisfy our performance obligation relative to our total effort
    expected to satisfy our performance obligation<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">. </span>In the third quarter of 2019, we updated our estimate of the total effort we expect to expend to
    satisfy our performance obligation. As a result, we recorded a cumulative catch up adjustment of $<ix:nonFraction name="us-gaap:RevenueFromContractWithCustomerExcludingAssessedTax" id="Fact_b62f5dd4cf444635b5e8c1a45181319c" contextRef="c20190701to20190930_TypeOfArrangementAxis_BiogenCollaboration2013StrategicNeurologyMember" unitRef="U001" decimals="-5" scale="6" sign="-" format="ixt:numdotdecimal">16.5</ix:nonFraction> million to decrease revenue in the third
    quarter of 2019. During 2020, we completed our remaining<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> research and development services and recognized the remaining revenue related to this performance
      obligation. </span>From inception through the completion of our R&amp;D services performance obligation in 2020, we included $<ix:nonFraction name="ions:CumulativePaymentsIncludedInTransactionPriceForPerformanceObligation" id="Fact_8e6bac473c9a4873a7bb0e87fa0b76df" contextRef="c20201231_ProductOrServiceAxis_ResearchAndDevelopmentRevenueUnderCollaborativeAgreementsMember_TypeOfArrangementAxis_BiogenCollaboration2013StrategicNeurologyMember" unitRef="U001" decimals="-6" scale="6" format="ixt:numdotdecimal">145</ix:nonFraction> million in
    total payments in the transaction price for our R&amp;D services performance obligation.</div>
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      generated additional payments that we concluded were not part of our R&amp;D services performance obligation. We recognized each of these payments in full in the respective quarter we generated the payment because we did not have any performance
      obligations for the respective payment. For example, in the second quarter of 2021, we earned a </span>$<ix:nonFraction name="us-gaap:RevenueFromContractWithCustomerExcludingAssessedTax" id="Fact_ba45cef284724211a7df8091311affbd" contextRef="c20210401to20210630_ProductOrServiceAxis_Ion541Member_TypeOfArrangementAxis_BiogenCollaboration2013StrategicNeurologyMember" unitRef="U001" decimals="-6" scale="6" format="ixt:numdotdecimal">10</ix:nonFraction>&#160;<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">million milestone payment when Biogen advanced ION541, which we recognized in full because we did not have any performance obligations related to this milestone payment.</span></div>
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<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;">2012 Neurology</div>
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<div style="text-align: justify; text-indent: 35.3pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">In December 2012, we and Biogen entered into a collaboration agreement to develop and commercialize novel antisense
    medicines to treat neurodegenerative diseases. We are responsible for the development of each of the medicines through the completion of the initial Phase 2 clinical study for such medicine. Biogen has the option to license a medicine from each of the
    programs through the completion of the first Phase 2 study for each program. Under this collaboration, we are currently advancing IONIS-MAPT<sub>Rx</sub> for Alzheimer&#8217;s disease and ION582 for AS. If Biogen exercises its option to license a medicine,
    it will assume global development, regulatory and commercialization responsibilities and costs for that medicine. In the fourth quarter of 2019, Biogen exercised its option to license IONIS-MAPT<sub>Rx</sub>. We are responsible for completing the Phase
    1/2 in study patients with mild AD and a <ix:nonNumeric name="ions:TermOfExtensionStudy" id="Fact_c9487a6f142a4d15bf3c0d28e9000ec3" contextRef="c20210101to20211231_ProductOrServiceAxis_IonisMaptMember_TypeOfArrangementAxis_BiogenCollaboration2012NeurologyMember" format="ixt-sec:durwordsen">one-year</ix:nonNumeric> long-term extension study. Biogen will have responsibility for global development, regulatory
    and commercialization activities and costs for IONIS-MAPT<sub>Rx</sub>.</div>
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<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">Under the terms of the agreement, we received
      an upfront payment of $</span><ix:nonFraction name="ions:UpfrontPaymentReceived" id="Fact_96e0bfc66c13486cb77a67ff0bc02893" contextRef="c20121201to20121231_TypeOfArrangementAxis_BiogenCollaboration2012NeurologyMember" unitRef="U001" decimals="-6" scale="6" format="ixt:numdotdecimal">30</ix:nonFraction><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> million. Over the
      term of the collaboration, we are eligible to receive up to $</span><ix:nonFraction name="ions:MaximumAmountOfPaymentsReceivablePerProgramForLicenseFeesAndSubstantiveMilestonePayments" id="Fact_ca3ece52a6764f27b53aa658420e1e3c" contextRef="c20211231_TypeOfArrangementAxis_BiogenCollaboration2012NeurologyMember" unitRef="U001" decimals="-6" scale="6" format="ixt:numdotdecimal">210</ix:nonFraction><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> million in a license fee and milestone payments per program, plus a mark-up on the cost estimate of the Phase 1 and 2 studies. The $</span><ix:nonFraction name="ions:MaximumAmountOfPaymentsReceivablePerProgramForLicenseFeesAndSubstantiveMilestonePayments" id="Fact_0bbe193efceb411386581d3674a65290" contextRef="c20211231_TypeOfArrangementAxis_BiogenCollaboration2012NeurologyMember" unitRef="U001" decimals="-6" scale="6" format="ixt:numdotdecimal">210</ix:nonFraction><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> million per program consists of up to $</span><ix:nonFraction name="ions:MaximumAmountOfPaymentsReceivablePerProgramForDevelopmentMilestones" id="Fact_75f24e61b9f94c949ecc39419626d788" contextRef="c20211231_TypeOfArrangementAxis_BiogenCollaboration2012NeurologyMember" unitRef="U001" decimals="-6" scale="6" format="ixt:numdotdecimal">10</ix:nonFraction><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> million in development milestone payments, plus a mark-up on the cost estimate of the Phase 1 and
      2 studies and up to $</span><ix:nonFraction name="ions:MaximumAmountOfPaymentsReceivablePerProgramForRegulatoryMilestones" id="Fact_12ca19bdf13e48ffb87ff55a87528661" contextRef="c20211231_TypeOfArrangementAxis_BiogenCollaboration2012NeurologyMember" unitRef="U001" decimals="-6" scale="6" format="ixt:numdotdecimal">130</ix:nonFraction><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> million in
      milestone payments if Biogen achieves pre-specified regulatory milestones. In addition, we are eligible to receive tiered royalties up to the mid-teens on net sales of any medicines resulting from each of the </span><ix:nonFraction name="ions:NumberOfProgramsUnderWhichMedicinesAreToBeDevelopedAndCommercialized" id="Fact_a9dc5fc90fff488ab419c13f5bd3df17" contextRef="c20121231_TypeOfArrangementAxis_BiogenCollaboration2012NeurologyMember" unitRef="U018" decimals="INF" scale="0" format="ixt-sec:numwordsen">three</ix:nonFraction><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> programs. From inception through December 2021, we have
      received $</span><ix:nonFraction name="ions:CumulativePaymentsReceived" id="Fact_7a4c67230f974ba9bfd049a2c63e615a" contextRef="c20211231_TypeOfArrangementAxis_BiogenCollaboration2012NeurologyMember" unitRef="U001" decimals="-6" scale="6" format="ixt:numdotdecimal">155</ix:nonFraction><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> million in payments under
      this collaboration, including $</span><ix:nonFraction name="ions:MilestonePaymentsAchievedAndIncludedInTransactionPriceForPerformanceObligation" id="Fact_172663d8cbda44468f24f9516f1ec7aa" contextRef="c20200101to20201231_ProductOrServiceAxis_IonisMaptMember_TypeOfArrangementAxis_BiogenCollaboration2012NeurologyMember" unitRef="U001" decimals="-5" scale="6" format="ixt:numdotdecimal">19.5</ix:nonFraction><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> million
      we received from Biogen for achieving milestones for advancing </span>IONIS-MAPT<sub>Rx</sub><sub style="color: #000000;">&#160;</sub><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">during 2020. We will
      achieve the next payment of $</span><ix:nonFraction name="ions:NextPotentialPayment" id="Fact_7bc80b0e8adf47ca8dd64914ace6d170" contextRef="c20211231_TypeOfArrangementAxis_BiogenCollaboration2012NeurologyMember" unitRef="U001" decimals="-6" scale="6" format="ixt:numdotdecimal">25</ix:nonFraction><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">&#160;</span>million
    if Biogen advances a medicine under this collaboration.</div>
</ix:continuation>
  <ix:continuation id="Text_94d04d6648bd4eb79b4d365680e182fc49" continuedAt="Text_94d04d6648bd4eb79b4d365680e182fc50">
<div><br />
  </div>
</ix:continuation>
  <ix:continuation id="Text_94d04d6648bd4eb79b4d365680e182fc50" continuedAt="Text_94d04d6648bd4eb79b4d365680e182fc51">
<div style="display:none;"><br /></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Under our collaboration, we determined we had a performance obligation to perform R&amp;D services. We allocated $<ix:nonFraction name="ions:CumulativePaymentsIncludedInTransactionPriceForPerformanceObligation" id="Fact_1381ecc294394ea081d42cec69196f2b" contextRef="c20211231_ProductOrServiceAxis_ResearchAndDevelopmentRevenueUnderCollaborativeAgreementsMember_TypeOfArrangementAxis_BiogenCollaboration2012NeurologyMember" unitRef="U001" decimals="-6" scale="6" format="ixt:numdotdecimal">40</ix:nonFraction> million in total payments to the transaction price for our R&amp;D services performance obligation. In the third quarter of 2019, we completed our
    R&amp;D services performance obligation when we designated a development candidate and Biogen accepted the development candidate. Biogen&#8217;s decision to accept the development candidate was not within our control. We were recognizing revenue as we
    performed services based on our effort to satisfy our performance obligation relative to the total effort expected to satisfy our performance obligation. Because Biogen accepted the development candidate earlier than when we were previously estimating,
    we recognized $<ix:nonFraction name="us-gaap:RevenueFromContractWithCustomerExcludingAssessedTax" id="Fact_6edc31f3d40d48f3944b9cbb4ebd25f4" contextRef="c20190701to20190930_TypeOfArrangementAxis_BiogenCollaboration2012NeurologyMember" unitRef="U001" decimals="-5" scale="6" format="ixt:numdotdecimal">6.3</ix:nonFraction> million of accelerated revenue in the third quarter of 2019.</div>
</ix:continuation>
  <ix:continuation id="Text_94d04d6648bd4eb79b4d365680e182fc51" continuedAt="Text_94d04d6648bd4eb79b4d365680e182fc52">
<div><br />
  </div>
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  <ix:continuation id="Text_94d04d6648bd4eb79b4d365680e182fc52" continuedAt="Text_94d04d6648bd4eb79b4d365680e182fc53">
<div style="display:none;"><br /></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">When we commenced development for IONIS-MAPT<sub>Rx</sub> we identified our development work as a separate performance obligation. We are
    recognizing our IONIS-MAPT<sub>Rx</sub> development performance obligation based on the percentage of completion. From inception through December 2021, we have included $<ix:nonFraction name="ions:CumulativePaymentsIncludedInTransactionPriceForPerformanceObligation" id="Fact_65c25865c5cb46d88f766f99f72dcb07" contextRef="c20211231_ProductOrServiceAxis_IonisMaptMember_TypeOfArrangementAxis_BiogenCollaboration2012NeurologyMember" unitRef="U001" decimals="-6" scale="6" format="ixt:numdotdecimal">57</ix:nonFraction> million in the transaction price for our IONIS-MAPT<sub>Rx</sub> development performance obligation, including $<ix:nonFraction name="ions:MilestonePaymentsAchievedAndIncludedInTransactionPriceForPerformanceObligation" id="Fact_df759cd0c35040108b92f1c5367ad0c1" contextRef="c20200101to20201231_ProductOrServiceAxis_IonisMaptMember_TypeOfArrangementAxis_BiogenCollaboration2012NeurologyMember" unitRef="U001" decimals="-5" scale="6" format="ixt:numdotdecimal">19.5</ix:nonFraction> million milestone payments we earned from Biogen in 2020 when we advanced IONIS-MAPT<sub>Rx</sub>. We currently estimate we will satisfy our performance obligation in 2022.</div>
</ix:continuation>
  <ix:continuation id="Text_94d04d6648bd4eb79b4d365680e182fc53" continuedAt="Text_94d04d6648bd4eb79b4d365680e182fc54">
<div><br />
  </div>
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<div style="display:none;"><br /></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">In the fourth quarter of 2019, we identified another performance obligation upon Biogen&#8217;s license of IONIS-MAPT<sub>Rx</sub> because the
    license we granted to Biogen is distinct from our other performance obligations. We recognized the $<ix:nonFraction name="us-gaap:RevenueFromContractWithCustomerExcludingAssessedTax" id="Fact_15e8499c99b84633ab63c1a97bb470f3" contextRef="c20191001to20191231_ProductOrServiceAxis_IonisMaptMember_TypeOfArrangementAxis_BiogenCollaboration2012NeurologyMember" unitRef="U001" decimals="-6" scale="6" format="ixt:numdotdecimal">45</ix:nonFraction> million license fee for IONIS-MAPT<sub>Rx</sub>
    as revenue at that time because Biogen had full use of the license without any continuing involvement from us. Additionally, we did not have any further performance obligations related to the license after we delivered it to Biogen.</div>
</ix:continuation>
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<div><br />
  </div>
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  <ix:continuation id="Text_94d04d6648bd4eb79b4d365680e182fc56" continuedAt="Text_94d04d6648bd4eb79b4d365680e182fc57">
<div style="display:none;"><br /></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">In the fourth quarter of 2021, we <span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">earned a $</span><ix:nonFraction name="us-gaap:RevenueFromContractWithCustomerExcludingAssessedTax" id="Fact_68b4f122e6a446cf9ecf4f8f9556c677" contextRef="c20211001to20211231_ProductOrServiceAxis_Ion582Member_TypeOfArrangementAxis_BiogenCollaboration2012NeurologyMember" unitRef="U001" decimals="-6" scale="6" format="ixt:numdotdecimal">10</ix:nonFraction><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> million milestone payment when Biogen advanced ION582, which
      we recognized in full because we did not have any performance obligations related to this milestone payment.</span></div>
</ix:continuation>
  <ix:continuation id="Text_94d04d6648bd4eb79b4d365680e182fc57" continuedAt="Text_94d04d6648bd4eb79b4d365680e182fc58">
<div><br />
  </div>
</ix:continuation>
  <ix:continuation id="Text_94d04d6648bd4eb79b4d365680e182fc58" continuedAt="Text_94d04d6648bd4eb79b4d365680e182fc59"><ix:nonNumeric name="us-gaap:SchedulesOfConcentrationOfRiskByRiskFactorTextBlock" id="Text_c07dfa8d25614932afb2c14ec2f25b57" contextRef="c20210101to20211231_TypeOfArrangementAxis_BiogenCollaborationsMember" escape="true" continuedAt="Text_7259a4301b42441e9b31c1496e089e7b1">
<div style="display:none;"><br /></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">During the years ended December 31, 2021, 2020 and 2019, we earned the following revenue from our relationship with Biogen (in millions, except percentage amounts):</div>
</ix:nonNumeric></ix:continuation>
  <ix:continuation id="Text_94d04d6648bd4eb79b4d365680e182fc59" continuedAt="Text_94d04d6648bd4eb79b4d365680e182fc60"><ix:continuation id="Text_7259a4301b42441e9b31c1496e089e7b1" continuedAt="Text_7259a4301b42441e9b31c1496e089e7b2">
<div><br />
  </div>
</ix:continuation></ix:continuation>
  <ix:continuation id="Text_94d04d6648bd4eb79b4d365680e182fc60" continuedAt="Text_94d04d6648bd4eb79b4d365680e182fc61"><ix:continuation id="Text_7259a4301b42441e9b31c1496e089e7b2">
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  <tr>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">

        </td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;" colspan="1">&#160;</td>

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          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Year Ended December 31,</div>
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

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  <tr>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;" colspan="1">&#160;</td>

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          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2021</div>
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" colspan="2">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2020</div>
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;" colspan="1">&#160;</td>

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          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2019</div>
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;">
          <div style="text-align: left; text-indent: -27pt; margin-left: 27pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">SPINRAZA royalties (commercial revenue)</div>
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    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
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    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
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    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

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  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 2px;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">R&amp;D revenue</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:RevenueFromContractWithCustomerExcludingAssessedTax" id="Fact_d521219505d14ed8ba28900af2b4eef0" contextRef="c20210101to20211231_ProductOrServiceAxis_ResearchAndDevelopmentRevenueUnderCollaborativeAgreementsMember_TypeOfArrangementAxis_BiogenCollaborationsMember" unitRef="U001" decimals="-5" scale="6" format="ixt:numdotdecimal">161.0</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:RevenueFromContractWithCustomerExcludingAssessedTax" id="Fact_9cfd5dd6b460430ca49c4c87b102810e" contextRef="c20200101to20201231_ProductOrServiceAxis_ResearchAndDevelopmentRevenueUnderCollaborativeAgreementsMember_TypeOfArrangementAxis_BiogenCollaborationsMember" unitRef="U001" decimals="-5" scale="6" format="ixt:numdotdecimal">122.0</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:RevenueFromContractWithCustomerExcludingAssessedTax" id="Fact_0be9c7e59ca144e3bbe8fe61671d767b" contextRef="c20190101to20191231_ProductOrServiceAxis_ResearchAndDevelopmentRevenueUnderCollaborativeAgreementsMember_TypeOfArrangementAxis_BiogenCollaborationsMember" unitRef="U001" decimals="-5" scale="6" format="ixt:numdotdecimal">180.6</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;">
          <div style="text-align: left; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Total revenue from our relationship with Biogen</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:RevenueFromContractWithCustomerExcludingAssessedTax" id="Fact_1fd9f9b2ff4242a8ba5d5dc97a5064da" contextRef="c20210101to20211231_TypeOfArrangementAxis_BiogenCollaborationsMember" unitRef="U001" decimals="-5" scale="6" format="ixt:numdotdecimal">428.8</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:RevenueFromContractWithCustomerExcludingAssessedTax" id="Fact_73c0a219d58348498ce8dc987fd9d27e" contextRef="c20200101to20201231_TypeOfArrangementAxis_BiogenCollaborationsMember" unitRef="U001" decimals="-5" scale="6" format="ixt:numdotdecimal">408.6</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:RevenueFromContractWithCustomerExcludingAssessedTax" id="Fact_542df45308ad4ee9a37c56efe7fa18d1" contextRef="c20190101to20191231_TypeOfArrangementAxis_BiogenCollaborationsMember" unitRef="U001" decimals="-5" scale="6" format="ixt:numdotdecimal">473.6</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 64%;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Percentage of total revenue</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:ConcentrationRiskPercentage1" id="Fact_b18b889b350941048d2231c689a9f351" contextRef="c20210101to20211231_ConcentrationRiskByBenchmarkAxis_RevenueFromContractWithCustomerMember_ConcentrationRiskByTypeAxis_CustomerConcentrationRiskMember_TypeOfArrangementAxis_BiogenCollaborationsMember" unitRef="U003" decimals="2" scale="-2" format="ixt:numdotdecimal">53</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">%</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:ConcentrationRiskPercentage1" id="Fact_33938ec04f5e40b889d8fcae645d637a" contextRef="c20200101to20201231_ConcentrationRiskByBenchmarkAxis_RevenueFromContractWithCustomerMember_ConcentrationRiskByTypeAxis_CustomerConcentrationRiskMember_TypeOfArrangementAxis_BiogenCollaborationsMember" unitRef="U003" decimals="2" scale="-2" format="ixt:numdotdecimal">56</ix:nonFraction></div>
        </td>

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          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">%</div>
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    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:ConcentrationRiskPercentage1" id="Fact_6c809afdaa814005b1f6b0887bff71f2" contextRef="c20190101to20191231_ConcentrationRiskByBenchmarkAxis_RevenueFromContractWithCustomerMember_ConcentrationRiskByTypeAxis_CustomerConcentrationRiskMember_TypeOfArrangementAxis_BiogenCollaborationsMember" unitRef="U003" decimals="2" scale="-2" format="ixt:numdotdecimal">42</ix:nonFraction></div>
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          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">%</div>
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<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">Our </span>consolidated balance sheet at
    December 31<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">, </span>2021<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> and </span>2020<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> included deferred revenue of $</span><ix:nonFraction name="us-gaap:ContractWithCustomerLiability" id="Fact_f8f7b974cb2a433882a0fd53fe341a83" contextRef="c20211231_TypeOfArrangementAxis_BiogenCollaborationsMember" unitRef="U001" decimals="-5" scale="6" format="ixt:numdotdecimal">407.5</ix:nonFraction><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> million and $</span><ix:nonFraction name="us-gaap:ContractWithCustomerLiability" id="Fact_35c30aecc55949b1afd1112082165450" contextRef="c20201231_TypeOfArrangementAxis_BiogenCollaborationsMember" unitRef="U001" decimals="-5" scale="6" format="ixt:numdotdecimal">465.8</ix:nonFraction><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> million, respectively, related to our relationship with Biogen.</span></div>
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<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;">AstraZeneca</div>
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<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;">Eplontersen Collaboration</div>
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<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">In December 2021, we entered into a joint development and commercialization agreement with AstraZeneca to develop and
    commercialize eplontersen for the treatment of ATTR. We are jointly developing and preparing to commercialize eplontersen with AstraZeneca in the U.S. We granted AstraZeneca exclusive rights to commercialize eplontersen outside the U.S., except certain
    countries in Latin America. Under the terms of the agreement, we received a $<ix:nonFraction name="ions:UpfrontPaymentReceived" id="Fact_9dd7d53c8eee485eacad6e97dffdd4c2" contextRef="c20211201to20211231_TypeOfArrangementAxis_AstrazenecaCollaborationEplontersenMember" unitRef="U001" decimals="-6" scale="6" format="ixt:numdotdecimal">200</ix:nonFraction> million upfront payment. We are eligible to receive up to $<ix:nonFraction name="ions:MaximumAmountOfPaymentsReceivableForDevelopmentAndRegulatoryMilestones" id="Fact_7c6f989ad85b49c8b6bfede72712bef2" contextRef="c20211231_TypeOfArrangementAxis_AstrazenecaCollaborationEplontersenMember" unitRef="U001" decimals="-6" scale="6" format="ixt:numdotdecimal">485</ix:nonFraction> million in development and approval milestones, and up to $<ix:nonFraction name="ions:MaximumAmountOfPaymentsReceivableForSalesRelatedMilestones" id="Fact_062b2352c9f546cca5d16c63150ff4fa" contextRef="c20211231_TypeOfArrangementAxis_AstrazenecaCollaborationEplontersenMember" unitRef="U001" decimals="-8" scale="9" format="ixt:numdotdecimal">2.9</ix:nonFraction>
    billion in sales-related milestone payments. The agreement also includes territory-specific development, commercial and medical affairs cost-sharing provisions. In addition, we are eligible to receive up to mid-<ix:nonFraction name="ions:RoyaltyPercentageReceivedOnSalesOfMedicineInUnitedStates" id="Fact_0b4829fbe9d847069807a9be4cf64ebe" contextRef="c20210101to20211231_TypeOfArrangementAxis_AstrazenecaCollaborationEplontersenMember" unitRef="U003" decimals="2" scale="-2" format="ixt:numdotdecimal">20</ix:nonFraction> percent royalties for sales in the U.S. and tiered royalties up to the high teens for sales outside the U.S.</div>
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<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We evaluated our eplontersen collaboration under ASC 808 and identified <ix:nonFraction name="ions:NumberOfMaterialComponents" id="Fact_d4f80df42eb24e19af6957ccd65c9827" contextRef="c20211231_TypeOfArrangementAxis_AstrazenecaCollaborationEplontersenMember" unitRef="U019" decimals="INF" scale="0" format="ixt-sec:numwordsen">four</ix:nonFraction> material components: (i) the license we granted to AstraZeneca in 2021, (ii) the co-development activities that we and AstraZeneca will perform, (iii) the co-commercialization
    activities that we and AstraZeneca will perform and (iv) the co-medical affairs activities that we and AstraZeneca will perform.</div>
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<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We determined that we had a vendor-customer relationship within the scope of ASC 606 for the license we granted to
    AstraZeneca and as a result we had <ix:nonFraction name="ions:RevenueFromContractWithCustomerNumberOfSeparatePerformanceObligations" id="Fact_4fa62bc3f1be4c069e70a0000c4e2a73" contextRef="c20211231_TypeOfArrangementAxis_AstrazenecaCollaborationEplontersenMember" unitRef="U006" decimals="INF" scale="0" format="ixt-sec:numwordsen">one</ix:nonFraction> performance obligation.&#160; For our sole performance obligation, we determined the transaction price was the
    $<ix:nonFraction name="ions:RevenueFromContractWithCustomerTransactionPrice" id="Fact_44e63366a6fb46c893bca11b7dcc2c44" contextRef="c20211231_TypeOfArrangementAxis_AstrazenecaCollaborationEplontersenMember" unitRef="U001" decimals="-6" scale="6" format="ixt:numdotdecimal">200</ix:nonFraction> million upfront payment we received. We recognized the upfront payment in full in 2021 because we did not have any remaining performance
    obligations after we delivered the license to AstraZeneca.</div>
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<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We also concluded that the co-development activities, the co-commercialization activities and the co-medical affairs
    activities are within the scope of ASC 808 because we and AstraZeneca are active participants exposed to the risks and benefits of the activities under the collaboration.&#160; AstraZeneca will pay <ix:nonFraction name="ions:PercentageOfCostsAssociatedWithOngoingGlobalPhase3DevelopmentProgramPaidByCollaborationPartner" id="Fact_d54fda2f005e411087fa50cc25d7061d" contextRef="c20210101to20211231_TypeOfArrangementAxis_AstrazenecaCollaborationEplontersenMember" unitRef="U003" decimals="2" scale="-2" format="ixt:numdotdecimal">55</ix:nonFraction> percent of the costs associated with the ongoing global Phase 3 development program. As we will continue to lead the Phase 3 development program, we will recognize as revenue the <ix:nonFraction name="ions:PercentageOfCostsAssociatedWithOngoingGlobalPhase3DevelopmentProgramPaidByCollaborationPartner" id="Fact_cdef7d861b704faaa5f351d6c9d584db" contextRef="c20210101to20211231_TypeOfArrangementAxis_AstrazenecaCollaborationEplontersenMember" unitRef="U003" decimals="2" scale="-2" format="ixt:numdotdecimal">55</ix:nonFraction> percent of cost-share funding AstraZeneca is responsible for in the same period we incur the related development expenses. As AstraZeneca is responsible
    for the majority of the commercial and medical affairs costs in the U.S. and all costs associated with bringing eplontersen to market outside the U.S., we will recognize cost-share funding we receive from AstraZeneca related to these activities as a
    reduction of our commercial and medical affairs expenses.</div>
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<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We will achieve the next payment of up to $<ix:nonFraction name="ions:NextPotentialPayment" id="Fact_b4e8aeaa28b84369b2caf9992e5b9833" contextRef="c20211231_TypeOfArrangementAxis_AstrazenecaCollaborationEplontersenMember" unitRef="U001" decimals="-6" scale="6" format="ixt:numdotdecimal">50</ix:nonFraction> million upon the first regulatory approval under this collaboration. Through December 2021, we have generated $<ix:nonFraction name="us-gaap:RevenueFromContractWithCustomerExcludingAssessedTax" id="Fact_a16d8c175b84442a88000f2e06fd82db" contextRef="c20211201to20211231_TypeOfArrangementAxis_AstrazenecaCollaborationEplontersenMember" unitRef="U001" decimals="-6" scale="6" format="ixt:numdotdecimal">200</ix:nonFraction> million in payments under this collaboration.</div>
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<div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Research and Development Partners</div>
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<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;">AstraZeneca</div>
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<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">In addition to our collaboration for eplontersen, we have <ix:nonFraction name="ions:NumberOfCollaborationAgreements" id="Fact_ffec5f3a028c48869affd14e2df2fca8" contextRef="c20211231_TypeOfArrangementAxis_AstraZenecaCollaborationsResearchAndDevelopmentMember" unitRef="U007" decimals="INF" scale="0" format="ixt-sec:numwordsen">two</ix:nonFraction> other collaborations with AstraZeneca. <ix:nonFraction name="ions:NumberOfCollaborationAgreements" id="Fact_d13954a1b4bd46819f6a35c899514e19" contextRef="c20211231_TypeOfArrangementAxis_AstrazenecaCollaborationCardiovascularRenalAndMetabolicDiseasesMember" unitRef="U007" decimals="INF" scale="0" format="ixt-sec:numwordsen">One</ix:nonFraction> is focused on the treatment of
    cardiovascular, renal and metabolic diseases and the <span style="-sec-ix-hidden:Fact_e7c38e1898fc4f72b5cb9e5bb0749c53">other</span> is focused on the treatment of oncology diseases. We and AstraZeneca are currently
    developing <ix:nonFraction name="ions:NumberOfMedicinesBeingDeveloped" id="Fact_a6439f3e58af44fb86cb0244dee8cd06" contextRef="c20211231_TypeOfArrangementAxis_AstraZenecaCollaborationsResearchAndDevelopmentMember" unitRef="U017" decimals="INF" scale="0" format="ixt-sec:numwordsen">six</ix:nonFraction> medicines under these collaborations, including medicines in development to treat people with ATTR amyloidosis, cardiovascular
    disease, a genetically associated form of kidney disease, <span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">NASH and cancer</span>. From inception through December 2021, we have received more than $<ix:nonFraction name="ions:CumulativePaymentsReceived" id="Fact_e83456d0c72b4d9192e49f416b55c59b" contextRef="c20211231_TypeOfArrangementAxis_AstraZenecaCollaborationsResearchAndDevelopmentMember" unitRef="U001" decimals="-6" scale="6" format="ixt:numdotdecimal">386</ix:nonFraction> million from our AstraZeneca research and
    development collaborations.</div>
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<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;">Cardiovascular, Renal and Metabolic Diseases Collaboration</div>
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<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">In July 2015, we and AstraZeneca formed a collaboration to discover and develop antisense therapies for treating
    cardiovascular, renal and metabolic diseases. Under our collaboration, AstraZeneca has licensed <ix:nonFraction name="ions:NumberOfLicensedMedicines" id="Fact_b682e7d57d3a45c18d753ca8d347beeb" contextRef="c20211231_TypeOfArrangementAxis_AstrazenecaCollaborationCardiovascularRenalAndMetabolicDiseasesMember" unitRef="U017" decimals="INF" scale="0" format="ixt-sec:numwordsen">five</ix:nonFraction> medicines from us. AstraZeneca is
    responsible for global development, regulatory and commercialization activities and costs for each of the medicines it has licensed from us.</div>
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<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Under the terms of the agreement, we received a $<ix:nonFraction name="ions:UpfrontPaymentReceived" id="Fact_afe0e303f52c47de8fef2665adbb52f3" contextRef="c20150701to20150731_TypeOfArrangementAxis_AstrazenecaCollaborationCardiovascularRenalAndMetabolicDiseasesMember" unitRef="U001" decimals="-6" scale="6" format="ixt:numdotdecimal">65</ix:nonFraction> million upfront payment. We are eligible to receive license fees and milestone payments of up to more than $<ix:nonFraction name="ions:MinimumAmountOfPaymentsReceivableForLicenseFeesAndMilestonePayments" id="Fact_681cbdadca67472d9b022f4711037c7f" contextRef="c20211231_TypeOfArrangementAxis_AstrazenecaCollaborationCardiovascularRenalAndMetabolicDiseasesMember" unitRef="U001" decimals="-8" scale="9" format="ixt:numdotdecimal">5.5</ix:nonFraction> billion as medicines under this collaboration advance, including up to $<ix:nonFraction name="ions:MaximumAmountOfPaymentsReceivableForDevelopmentMilestones" id="Fact_8bf17f1115c642a893b55340a0970cea" contextRef="c20211231_TypeOfArrangementAxis_AstrazenecaCollaborationCardiovascularRenalAndMetabolicDiseasesMember" unitRef="U001" decimals="-8" scale="9" format="ixt:numdotdecimal">1.1</ix:nonFraction> billion
    for the achievement of development milestones, up to $<ix:nonFraction name="ions:MaximumAmountOfPaymentsReceivableForRegulatoryMilestones" id="Fact_efb4704088a04a6e826d67ea5c2f326d" contextRef="c20211231_TypeOfArrangementAxis_AstrazenecaCollaborationCardiovascularRenalAndMetabolicDiseasesMember" unitRef="U001" decimals="-8" scale="9" format="ixt:numdotdecimal">2.9</ix:nonFraction> billion for regulatory milestones and up to $<ix:nonFraction name="ions:MaximumAmountOfPaymentsReceivableForCommercializationMilestones" id="Fact_dec66cb0ecac4e4691af3624c8c46a68" contextRef="c20211231_TypeOfArrangementAxis_AstrazenecaCollaborationCardiovascularRenalAndMetabolicDiseasesMember" unitRef="U001" decimals="-8" scale="9" format="ixt:numdotdecimal">1.5</ix:nonFraction> billion for commercial milestones. In addition, we are eligible to receive tiered royalties up to the low teens on net sales from any product that AstraZeneca successfully
    commercializes under this collaboration agreement. We will achieve the next payment of $<ix:nonFraction name="ions:NextPotentialPayment" id="Fact_2b949e7c63b941a3955f5c01227834d5" contextRef="c20211231_TypeOfArrangementAxis_AstrazenecaCollaborationCardiovascularRenalAndMetabolicDiseasesMember" unitRef="U001" decimals="-6" scale="6" format="ixt:numdotdecimal">10</ix:nonFraction> million under this collaboration if AstraZeneca
    advances a medicine under this collaboration<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">.</span> From inception through December 2021, we have received over $<ix:nonFraction name="ions:CumulativePaymentsReceived" id="Fact_b46d3be360f94ea788b2b83ce6c73f6f" contextRef="c20211231_RangeAxis_MinimumMember_TypeOfArrangementAxis_AstrazenecaCollaborationCardiovascularRenalAndMetabolicDiseasesMember" unitRef="U001" decimals="-6" scale="6" format="ixt:numdotdecimal">282</ix:nonFraction> million in an upfront fee, license fees, milestone payments, and other payments under this collaboration, including $<ix:nonFraction name="us-gaap:RevenueFromContractWithCustomerExcludingAssessedTax" id="Fact_75848da8d5a6444d9e307b3b2ba16927" contextRef="c20210101to20211231_ProductOrServiceAxis_TargetForMetabolicDiseaseMember_TypeOfArrangementAxis_AstrazenecaCollaborationCardiovascularRenalAndMetabolicDiseasesMember" unitRef="U001" decimals="-6" scale="6" format="ixt:numdotdecimal">30</ix:nonFraction> million we earned in 2021 when AstraZeneca licensed a target for a metabolic disease and $<ix:nonFraction name="us-gaap:RevenueFromContractWithCustomerExcludingAssessedTax" id="Fact_b1f51943b85a4df1b0dd94b8955dbf27" contextRef="c20210101to20211231_TypeOfArrangementAxis_AstrazenecaCollaborationCardiovascularRenalAndMetabolicDiseasesMember" unitRef="U001" decimals="-6" scale="6" format="ixt:numdotdecimal">10</ix:nonFraction>
    million we earned in 2021 when AstraZeneca advanced a target for a metabolic disease.</div>
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<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">At the commencement of this collaboration, we identified <ix:nonFraction name="ions:RevenueFromContractWithCustomerNumberOfSeparatePerformanceObligations" id="Fact_12852f4c3cee4a69b4f4fee5d29498e6" contextRef="c20150731_TypeOfArrangementAxis_AstrazenecaCollaborationCardiovascularRenalAndMetabolicDiseasesMember" unitRef="U006" decimals="INF" scale="0" format="ixt-sec:numwordsen">one</ix:nonFraction> performance obligation, which was to perform R&amp;D services for AstraZeneca. We determined the transaction price to be the $<ix:nonFraction name="ions:RevenueFromContractWithCustomerTransactionPrice" id="Fact_321f6d91fea64a57a4103c135ba57bd1" contextRef="c20150731_TypeOfArrangementAxis_AstrazenecaCollaborationCardiovascularRenalAndMetabolicDiseasesMember" unitRef="U001" decimals="-6" scale="6" format="ixt:numdotdecimal">65</ix:nonFraction> million upfront payment we received and we allocated it to our single performance obligation. We recognized revenue for our R&amp;D services performance obligation as we performed services
    based on our effort to satisfy this performance obligation relative to our total effort expected to satisfy our performance obligation. We<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> completed our
      performance obligation in</span> the fourth quarter of 2021. As we achieve milestone payments for our R&amp;D services, we include these amounts in our transaction price for our R&amp;D services performance obligation. From inception through December<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> 2021</span>, we have included $<ix:nonFraction name="ions:CumulativePaymentsIncludedInTransactionPriceForPerformanceObligation" id="Fact_ec77e25e50654249ba1ef8f5f9e4a1d1" contextRef="c20211231_ProductOrServiceAxis_ResearchAndDevelopmentRevenueUnderCollaborativeAgreementsMember_TypeOfArrangementAxis_AstrazenecaCollaborationCardiovascularRenalAndMetabolicDiseasesMember" unitRef="U001" decimals="-6" scale="6" format="ixt:numdotdecimal">90</ix:nonFraction> million in payments
    in the transaction price for our R&amp;D services performance obligation.</div>
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<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Under this collaboration, we have also generated additional payments that we concluded were not part of our R&amp;D
    services performance obligation. We recognized each of these payments in full in the respective quarter we generated the payment because the payments were distinct and we did not have any performance obligations for the respective payment. For example,
    in the fourth quarter of 2021, we earned a $<ix:nonFraction name="us-gaap:RevenueFromContractWithCustomerExcludingAssessedTax" id="Fact_9a05f8f53c5a4e19b3ae826d03c122b1" contextRef="c20210101to20211231_ProductOrServiceAxis_TargetForMetabolicDiseaseMember_TypeOfArrangementAxis_AstrazenecaCollaborationCardiovascularRenalAndMetabolicDiseasesMember" unitRef="U001" decimals="-6" scale="6" format="ixt:numdotdecimal">30</ix:nonFraction> million license fee when AstraZeneca licensed a target for a metabolic disease. We recognized the
    license fee as revenue at that time because AstraZeneca had full use of the license without any continuing involvement from us. Additionally, we did not have any further performance obligations related to the license after we delivered it to
    AstraZeneca.</div>
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<div style="text-align: left; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;">Oncology Collaboration</div>
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<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">In December 2012, we entered into a collaboration agreement with AstraZeneca to discover and develop antisense medicines
    to treat cancer. We and AstraZeneca also established an oncology research program. In 2020, AstraZeneca licensed ION736, an investigational medicine in development targeting FOXP3 for the treatment of cancer. AstraZeneca is responsible for global
    development, regulatory and commercialization activities and costs for ION736.</div>
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<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">Under the terms of this agreement, we
      received $</span><ix:nonFraction name="ions:UpfrontPaymentReceived" id="Fact_2cd1bc1d00e14c1d84b80c4ee6e222db" contextRef="c20121201to20121231_TypeOfArrangementAxis_AstrazenecaCollaborationOncologyMember" unitRef="U001" decimals="-6" scale="6" format="ixt:numdotdecimal">31</ix:nonFraction><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> million in upfront payments.
      We are eligible to receive milestone payments and license fees up to $</span><ix:nonFraction name="ions:MaximumAmountOfPaymentsReceivableForLicenseFeesAndMilestones" id="Fact_4f1f67e17be24802be2180cf687dd301" contextRef="c20211231_TypeOfArrangementAxis_AstrazenecaCollaborationOncologyMember" unitRef="U001" decimals="-6" scale="6" format="ixt:numdotdecimal">160</ix:nonFraction><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> million under this collaboration, including up to $</span><ix:nonFraction name="ions:MaximumAmountOfPaymentsReceivableForDevelopmentMilestones" id="Fact_484e8f6f1dd242f5996c00b362124558" contextRef="c20211231_TypeOfArrangementAxis_AstrazenecaCollaborationOncologyMember" unitRef="U001" decimals="-6" scale="6" format="ixt:numdotdecimal">42</ix:nonFraction><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> million for the achievement of development milestones and up to $</span><ix:nonFraction name="ions:MaximumAmountOfPaymentsReceivableForRegulatoryMilestones" id="Fact_20c0e0a8259e44148a7d32d9c9881c8c" contextRef="c20211231_TypeOfArrangementAxis_AstrazenecaCollaborationOncologyMember" unitRef="U001" decimals="-6" scale="6" format="ixt:numdotdecimal">105</ix:nonFraction><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> million for the achievement of regulatory milestones. In addition, we are eligible to receive tiered royalties up to the low teens on net sales from any product that AstraZeneca
      successfully commercializes under this collaboration agreement. From inception through December 2021, we have received over $</span><ix:nonFraction name="ions:CumulativePaymentsReceived" id="Fact_ec695803788a443b8addc8655e99aaa7" contextRef="c20211231_RangeAxis_MinimumMember_TypeOfArrangementAxis_AstrazenecaCollaborationOncologyMember" unitRef="U001" decimals="-6" scale="6" format="ixt:numdotdecimal">141</ix:nonFraction><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> million in upfront fees, milestone payments, and other payments under this oncology collaboration, including $</span><ix:nonFraction name="us-gaap:RevenueFromContractWithCustomerExcludingAssessedTax" id="Fact_af2cf5e17c1149358b7f65f52652d579" contextRef="c20200101to20201231_ProductOrServiceAxis_Ion736Member_TypeOfArrangementAxis_AstrazenecaCollaborationOncologyMember" unitRef="U001" decimals="-6" scale="6" format="ixt:numdotdecimal">13</ix:nonFraction><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> million we earned when AstraZeneca licensed</span> ION736 in 2020. We <span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">will achieve the next payment of $</span><ix:nonFraction name="ions:NextPotentialPayment" id="Fact_9d85706b0d4c4c5dbc82e0700a25253c" contextRef="c20211231_TypeOfArrangementAxis_AstrazenecaCollaborationOncologyMember" unitRef="U001" decimals="-6" scale="6" format="ixt:numdotdecimal">12</ix:nonFraction><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> million if AstraZeneca advances ION736 in development.</span></div>
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<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We completed all of the performance obligations we identified under this collaboration in the first quarter of 2018.</div>
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<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">Under this collaboration, we have also
      generated additional payments that we concluded were not part of other performance obligations discussed above. We recognized each of these payments in full in the respective quarter we generated the payment because the payments were distinct and we
      did not have any performance obligations for the respective payment. In 2020, we earned a $</span><ix:nonFraction name="us-gaap:RevenueFromContractWithCustomerExcludingAssessedTax" id="Fact_1540196400da494babcf5e38f511ee10" contextRef="c20200401to20200630_ProductOrServiceAxis_Ion736Member_TypeOfArrangementAxis_AstrazenecaCollaborationOncologyMember" unitRef="U001" decimals="-6" scale="6" format="ixt:numdotdecimal">13</ix:nonFraction><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> million license fee when AstraZeneca licensed ION736</span> because AstraZeneca had full use of the license without any continuing involvement from us.</div>
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<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">During the years ended December 31, 2021, 2020 and 2019, we earned the following revenue from our relationship with AstraZeneca (in millions, except percentage amounts):</div>
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        </td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" colspan="10">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Year Ended December 31,</div>
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

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    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" colspan="2">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2021</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" colspan="2">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2020</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" colspan="2">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2019</div>
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    <td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;">
          <div style="text-align: left; text-indent: -27pt; margin-left: 27pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">R&amp;D revenue</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:RevenueFromContractWithCustomerExcludingAssessedTax" id="Fact_77009387bc654006989ae141c96c8496" contextRef="c20210101to20211231_ProductOrServiceAxis_ResearchAndDevelopmentRevenueUnderCollaborativeAgreementsMember_TypeOfArrangementAxis_AstrazenecaCollaborationsMember" unitRef="U001" decimals="-5" scale="6" format="ixt:numdotdecimal">254.6</ix:nonFraction></div>
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:RevenueFromContractWithCustomerExcludingAssessedTax" id="Fact_b4bc1487977543468f0c2592f732bfb0" contextRef="c20200101to20201231_ProductOrServiceAxis_ResearchAndDevelopmentRevenueUnderCollaborativeAgreementsMember_TypeOfArrangementAxis_AstrazenecaCollaborationsMember" unitRef="U001" decimals="-5" scale="6" format="ixt:numdotdecimal">88.0</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:RevenueFromContractWithCustomerExcludingAssessedTax" id="Fact_6f993bce8b8f4c7aa2348aedba4438cf" contextRef="c20190101to20191231_ProductOrServiceAxis_ResearchAndDevelopmentRevenueUnderCollaborativeAgreementsMember_TypeOfArrangementAxis_AstrazenecaCollaborationsMember" unitRef="U001" decimals="-5" scale="6" format="ixt:numdotdecimal">28.1</ix:nonFraction></div>
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    <td valign="bottom" style="vertical-align: bottom; width: 64%;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Percentage of total revenue</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:ConcentrationRiskPercentage1" id="Fact_146be9f3b2bd4a1390bcfa5173d38d88" contextRef="c20210101to20211231_ConcentrationRiskByBenchmarkAxis_RevenueFromContractWithCustomerMember_ConcentrationRiskByTypeAxis_CustomerConcentrationRiskMember_TypeOfArrangementAxis_AstrazenecaCollaborationsMember" unitRef="U003" decimals="2" scale="-2" format="ixt:numdotdecimal">31</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">%</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">%</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:ConcentrationRiskPercentage1" id="Fact_aa247af696394bd6806e0b89dffcff91" contextRef="c20190101to20191231_ConcentrationRiskByBenchmarkAxis_RevenueFromContractWithCustomerMember_ConcentrationRiskByTypeAxis_CustomerConcentrationRiskMember_TypeOfArrangementAxis_AstrazenecaCollaborationsMember" unitRef="U003" decimals="2" scale="-2" format="ixt:numdotdecimal">3</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">%</div>
        </td>

  </tr>


</table>
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<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">We did </span><ix:nonFraction name="us-gaap:ContractWithCustomerLiability" id="Fact_b22d4dca96604e1cb60121e3c991236b" contextRef="c20211231_TypeOfArrangementAxis_AstrazenecaCollaborationsMember" unitRef="U001" decimals="-6" scale="6" format="ixt-sec:numwordsen">no</ix:nonFraction><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">t have any deferred revenue from our relationship with
      AstraZeneca at December 31, 2021. Our </span>consolidated balance sheet at <span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">December 31, </span>2020<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> included deferred revenue of $</span><ix:nonFraction name="us-gaap:ContractWithCustomerLiability" id="Fact_29e93280d0e245d79babbeeaf1bba43f" contextRef="c20201231_TypeOfArrangementAxis_AstrazenecaCollaborationsMember" unitRef="U001" decimals="-5" scale="6" format="ixt:numdotdecimal">10.0</ix:nonFraction><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> million from our relationship with AstraZeneca.</span></div>
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      <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">F-<span class="DSPFPageNumber">45</span></div>

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<div style="text-align: left; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;">Bayer</div>
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<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">In May 2015, we entered into an exclusive license agreement with Bayer to develop and commercialize IONIS-FXI<sub>Rx</sub>
      for the prevention of thrombosis. We were responsible for completing a Phase 2 study of IONIS-FXI<sub>Rx</sub> in people with end-stage renal disease on hemodialysis. Under the terms of the agreement, we received a $<ix:nonFraction name="ions:UpfrontPaymentReceived" id="Fact_1ecc831150824141bd76a92d58b3f591" contextRef="c20150401to20150630_TypeOfArrangementAxis_BayerCollaborationIonisFxiMember" unitRef="U001" decimals="-6" scale="6" format="ixt:numdotdecimal">100</ix:nonFraction> million upfront payment in the second quarter of 2015. In February 2017, we amended our agreement with Bayer to advance IONIS-FXI<sub>Rx</sub> and to
      initiate development of fesomersen, which Bayer licensed. In conjunction with the decision to advance these programs, we received a $<ix:nonFraction name="ions:PaymentReceivedForAdvancingPrograms" id="Fact_27a5975c2c5d4ed98e446e999c953f35" contextRef="c20170201to20170228_TypeOfArrangementAxis_BayerCollaborationIonisFxiAmendmentMember" unitRef="U001" decimals="-6" scale="6" format="ixt:numdotdecimal">75</ix:nonFraction> million
      payment from Bayer. In October 2019, Bayer decided it would advance fesomersen following positive clinical results. Bayer is now responsible for all global development, regulatory and commercialization activities and costs for the FXI program.</div>
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<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We are eligible to receive up to $<ix:nonFraction name="ions:MaximumAmountOfPaymentsReceivableForLicenseFeesAndMilestones" id="Fact_1ea7b17e0fd54a53ba9ea212e481602c" contextRef="c20211231_TypeOfArrangementAxis_BayerCollaborationIonisFxiMember" unitRef="U001" decimals="-6" scale="6" format="ixt:numdotdecimal">385</ix:nonFraction> million in license fees, milestone payments and other payments, including up to $<ix:nonFraction name="ions:MaximumAmountOfPaymentsReceivableForDevelopmentMilestones" id="Fact_e03c5e12d8dc4479948a18adba98b88c" contextRef="c20211231_TypeOfArrangementAxis_BayerCollaborationIonisFxiMember" unitRef="U001" decimals="-6" scale="6" format="ixt:numdotdecimal">125</ix:nonFraction>
    million for the achievement of development milestones and up to $<ix:nonFraction name="ions:MaximumAmountOfPaymentsReceivableForSalesMilestones" id="Fact_ab70c484782f41e4acf44792bd373694" contextRef="c20211231_TypeOfArrangementAxis_BayerCollaborationIonisFxiMember" unitRef="U001" decimals="-6" scale="6" format="ixt:numdotdecimal">110</ix:nonFraction> million for the achievement of sales milestones. In addition, we are
    eligible to receive tiered royalties in the low to high <ix:nonFraction name="ions:RoyaltyPercentageReceivedOnGrossMarginsOfMedicinesUnderCollaborationAgreement" id="Fact_fb2e5156c6b544b98419218e7a28691b" contextRef="c20210101to20211231_TypeOfArrangementAxis_BayerCollaborationIonisFxiMember" unitRef="U003" decimals="2" scale="-2" format="ixt:numdotdecimal">20</ix:nonFraction> percent range on gross margins of both medicines combined. From inception through
    December 2021, we have received over $<ix:nonFraction name="ions:CumulativePaymentsReceived" id="Fact_55c7b99eec38441eb299ea5fe41b3ea2" contextRef="c20211231_RangeAxis_MinimumMember_TypeOfArrangementAxis_BayerCollaborationIonisFxiMember" unitRef="U001" decimals="-6" scale="6" format="ixt:numdotdecimal">191</ix:nonFraction> million from this collaboration. We will achieve the next payment of $<ix:nonFraction name="ions:NextPotentialPayment" id="Fact_abb5e5bfab0742a594537d03e99e580c" contextRef="c20211231_TypeOfArrangementAxis_BayerCollaborationIonisFxiMember" unitRef="U001" decimals="-6" scale="6" format="ixt:numdotdecimal">20</ix:nonFraction> million if Bayer initiates a Phase 3 study for the FXI program.</div>
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<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">At the commencement of this collaboration, we identified <ix:nonFraction name="ions:RevenueFromContractWithCustomerNumberOfSeparatePerformanceObligations" id="Fact_1279bd3e4793428181ec1aad1e8b44ba" contextRef="c20150531_TypeOfArrangementAxis_BayerCollaborationIonisFxiMember" unitRef="U006" decimals="INF" scale="0" format="ixt-sec:numwordsen">three</ix:nonFraction> performance obligations, the license of IONIS-FXI<sub>Rx</sub>, R&amp;D services and delivery of API, all of which we completed in 2016.</div>
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<div style="display:none;"><br /></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">In February 2017, when we amended our collaboration with Bayer, we identified <ix:nonFraction name="ions:RevenueFromContractWithCustomerNumberOfNewPerformanceObligations" id="Fact_88bf8c1f8dfc4704bd5e5ef69d1688f0" contextRef="c20170201to20170228_TypeOfArrangementAxis_BayerCollaborationIonisFxiAmendmentMember" unitRef="U006" decimals="INF" scale="0" format="ixt-sec:numwordsen">two</ix:nonFraction> new performance obligations<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">, </span><ix:nonFraction name="ions:RevenueFromContractWithCustomerNumberOfNewPerformanceObligations" id="Fact_036ca3d6a65a45808b611cf2f29cf18c" contextRef="c20170201to20170228_ProductOrServiceAxis_FesomersenMember_TypeOfArrangementAxis_BayerCollaborationIonisFxiAmendmentMember" unitRef="U006" decimals="INF" scale="0" format="ixt-sec:numwordsen">one</ix:nonFraction><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> for the license of fesomersen and </span><ix:nonFraction name="ions:RevenueFromContractWithCustomerNumberOfNewPerformanceObligations" id="Fact_84ed394b95dc4b689089483bec9ee81d" contextRef="c20170201to20170228_ProductOrServiceAxis_ResearchAndDevelopmentServicesForFesomersenMember_TypeOfArrangementAxis_BayerCollaborationIonisFxiAmendmentMember" unitRef="U006" decimals="INF" scale="0" format="ixt-sec:numwordsen">one</ix:nonFraction><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> for R&amp;D services</span>. We determined the transaction price to be the $<ix:nonFraction name="ions:RevenueFromContractWithCustomerTransactionPrice" id="Fact_c9e8f99e0b5547cfa910d6da0c7fa156" contextRef="c20170228_TypeOfArrangementAxis_BayerCollaborationIonisFxiAmendmentMember" unitRef="U001" decimals="-6" scale="6" format="ixt:numdotdecimal">75</ix:nonFraction> million payment. We allocated $<ix:nonFraction name="ions:RevenueFromContractWithCustomerTransactionPrice" id="Fact_671c15f958d449e1b0996ae26fb02f7f" contextRef="c20170228_ProductOrServiceAxis_FesomersenMember_TypeOfArrangementAxis_BayerCollaborationIonisFxiAmendmentMember" unitRef="U001" decimals="-5" scale="6" format="ixt:numdotdecimal">64.9</ix:nonFraction> million to
    <span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">the license of fesomersen based on its estimated relative stand-alone selling price and recognized the associated revenue upon our delivery of the license in
      the first quarter of 2017. We allocated $</span><ix:nonFraction name="ions:RevenueFromContractWithCustomerTransactionPrice" id="Fact_66e51b39565d4d5491b40a7ff56ff227" contextRef="c20170228_ProductOrServiceAxis_ResearchAndDevelopmentServicesForFesomersenMember_TypeOfArrangementAxis_BayerCollaborationIonisFxiMember" unitRef="U001" decimals="-5" scale="6" format="ixt:numdotdecimal">10.1</ix:nonFraction><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> million to our R&amp;D services performance obligation based on an estimated relative stand-alone selling price. </span>We recognized revenue for our R&amp;D services performance obligation as we performed services based on our effort to
    satisfy our performance obligation relative to our total effort expected to satisfy our performance obligation. We completed our obligation in the third quarter of 2019.</div>
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<div style="display:none;"><br /></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">In the fourth quarter of 2019, we earned a $<ix:nonFraction name="us-gaap:RevenueFromContractWithCustomerExcludingAssessedTax" id="Fact_9fa6b92a37764bc4ad97b1ac44dab174" contextRef="c20191001to20191231_TypeOfArrangementAxis_BayerCollaborationsMember" unitRef="U001" decimals="-6" scale="6" format="ixt:numdotdecimal">10</ix:nonFraction> million milestone payment when Bayer decided it would advance fesomersen. We recognized this milestone payment in full in the fourth quarter of 2019 because we did not have any performance
    obligations related to this milestone payment.</div>
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<div style="display:none;"><br /></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">During the years ended December 31, 2021, 2020 and 2019, we earned the following revenue from our relationship with Bayer (in millions, except percentage amounts):</div>
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        </td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;" colspan="1">&#160;</td>

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          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Year Ended December 31,</div>
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

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    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;" colspan="1">&#160;</td>

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          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2021</div>
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" colspan="2">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2020</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" colspan="2">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2019</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

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          <div style="text-align: left; text-indent: -27pt; margin-left: 27pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">R&amp;D revenue</div>
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    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
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    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
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    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:RevenueFromContractWithCustomerExcludingAssessedTax" id="Fact_59362cd04b3741fd938d03dcb0e698f6" contextRef="c20190101to20191231_ProductOrServiceAxis_ResearchAndDevelopmentRevenueUnderCollaborativeAgreementsMember_TypeOfArrangementAxis_BayerCollaborationsMember" unitRef="U001" decimals="-5" scale="6" format="ixt:numdotdecimal">14.3</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

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    <td valign="bottom" style="vertical-align: bottom; width: 64%;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Percentage of total revenue</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

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    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
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    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

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<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Our consolidated balance sheet at December 31, 2021 included an <span style="-sec-ix-hidden:Fact_613e73fd93424660870569ffe2993ea8">insignificant</span> amount of deferred revenue related to our relationship with Bayer. We did <ix:nonFraction name="us-gaap:ContractWithCustomerLiability" id="Fact_5bd706afd5d646f0bc9300a69a0ceee9" contextRef="c20201231_TypeOfArrangementAxis_BayerCollaborationsMember" unitRef="U001" decimals="-6" scale="6" format="ixt-sec:numwordsen">no</ix:nonFraction>t
    have any deferred revenue from our relationship with Bayer at December 31, 2020.</div>
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<div style="display:none;"><br /></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;">GSK</div>
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<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">In March 2010, we entered into an alliance with GSK using our antisense drug discovery platform to discover and develop
    new medicines against targets for serious and rare diseases, including infectious diseases and some conditions causing blindness. Under the terms of the agreement, we received upfront payments of $<ix:nonFraction name="ions:UpfrontPaymentReceived" id="Fact_7283fa5013cc4c8f8847969829246bd2" contextRef="c20100301to20100331_TypeOfArrangementAxis_GlaxoSmithKlineCollaborationMember" unitRef="U001" decimals="-6" scale="6" format="ixt:numdotdecimal">35</ix:nonFraction> million. Our collaboration with GSK currently includes <ix:nonFraction name="ions:NumberOfMedicinesBeingDeveloped" id="Fact_34359473758b4342a786a2bfd26d9b28" contextRef="c20211231_TypeOfArrangementAxis_GlaxoSmithKlineCollaborationMember" unitRef="U017" decimals="INF" scale="0" format="ixt-sec:numwordsen">two</ix:nonFraction> medicines targeting
    hepatitis B virus, or HBV: bepirovirsen and IONIS-HBV-L<sub>Rx</sub>. We designed these medicines to reduce the production of viral proteins associated with HBV infection. In the third quarter of 2019, following positive Phase 2 results, GSK licensed
    our HBV program. GSK is responsible for all global development, regulatory and commercialization activities and costs for the HBV program.</div>
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<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Under our agreement, if GSK successfully develops these medicines and achieves pre-agreed sales targets, we could receive
    license fees and milestone payments of more than $<ix:nonFraction name="ions:MinimumAmountOfPaymentsReceivableForLicenseFeesAndMilestonePayments" id="Fact_4efd385d112840afad0e4faa46214870" contextRef="c20211231_TypeOfArrangementAxis_GlaxoSmithKlineCollaborationMember" unitRef="U001" decimals="-6" scale="6" format="ixt:numdotdecimal">260</ix:nonFraction> million, including up to $<ix:nonFraction name="ions:MaximumAmountOfPaymentsReceivableForDevelopmentMilestones" id="Fact_229776738d884ce8aee54ac341784a2d" contextRef="c20211231_TypeOfArrangementAxis_GlaxoSmithKlineCollaborationMember" unitRef="U001" decimals="-5" scale="6" format="ixt:numdotdecimal">47.5</ix:nonFraction> million for the achievement of development milestones, up to $<ix:nonFraction name="ions:MaximumAmountOfPaymentsReceivableForRegulatoryMilestones" id="Fact_131e23080dcc40398152b2bd4d048056" contextRef="c20211231_TypeOfArrangementAxis_GlaxoSmithKlineCollaborationMember" unitRef="U001" decimals="-6" scale="6" format="ixt:numdotdecimal">120</ix:nonFraction> million for the
    achievement of regulatory milestones and up to $<ix:nonFraction name="ions:MaximumAmountOfPaymentsReceivableForSalesMilestones" id="Fact_a5c67dd2e09b4b708ea1ffa029688a59" contextRef="c20211231_TypeOfArrangementAxis_GlaxoSmithKlineCollaborationMember" unitRef="U001" decimals="-6" scale="6" format="ixt:numdotdecimal">70</ix:nonFraction> million for the achievement of sales milestones. In addition, we are eligible to receive
    tiered royalties up to the mid-teens on net sales from any product that GSK successfully commercializes under this alliance. From inception through December 2021, we have received more than $<ix:nonFraction name="ions:CumulativePaymentsReceived" id="Fact_80b40aad4e4f428d854cce06e968dea2" contextRef="c20211231_RangeAxis_MinimumMember_TypeOfArrangementAxis_GlaxoSmithKlineCollaborationMember" unitRef="U001" decimals="-6" scale="6" format="ixt:numdotdecimal">190</ix:nonFraction> million in payments under this alliance with GSK. We will achieve the next payment of $<ix:nonFraction name="ions:NextPotentialPayment" id="Fact_5f7e1c8f371048a4aa050ce4806c0edf" contextRef="c20211231_TypeOfArrangementAxis_GlaxoSmithKlineCollaborationMember" unitRef="U001" decimals="-6" scale="6" format="ixt:numdotdecimal">15</ix:nonFraction>
    million if GSK initiates a Phase 3 study of a medicine under this program.</div>
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<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">We completed our R&amp;D services performance
      obligations under our collaboration in the first quarter of 2015. </span>We identified a new performance obligation when we granted GSK the license of the HBV program and assigned related intellectual property rights in the third quarter of 2019
    because the license was distinct from our other performance obligations. We recognized the $<ix:nonFraction name="us-gaap:RevenueFromContractWithCustomerExcludingAssessedTax" id="Fact_eaf6203cfa224f3791cb9bffe7977090" contextRef="c20190701to20190930_TypeOfArrangementAxis_GlaxoSmithKlineCollaborationMember" unitRef="U001" decimals="-6" scale="6" format="ixt:numdotdecimal">25</ix:nonFraction> million license fee for the HBV program as revenue
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<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We do not have any remaining performance obligations under our collaboration with GSK; however, we can still earn additional payments and
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<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">During the years ended December 31, 2021, 2020 and 2019, we earned the following revenue from our relationship with GSK (in millions, except percentage amounts):</div>
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    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;" colspan="1">&#160;</td>

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    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;" colspan="1">&#160;</td>

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    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;" colspan="1">&#160;</td>

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    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

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          <div style="text-align: left; text-indent: -27pt; margin-left: 27pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">R&amp;D revenue</div>
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    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

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          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

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    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
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    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">%</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:ConcentrationRiskPercentage1" id="Fact_64cbaaeaf4c249c28f7644f151cd8a75" contextRef="c20190101to20191231_ConcentrationRiskByBenchmarkAxis_RevenueFromContractWithCustomerMember_ConcentrationRiskByTypeAxis_CustomerConcentrationRiskMember_TypeOfArrangementAxis_GlaxoSmithKlineCollaborationMember" unitRef="U003" decimals="2" scale="-2" format="ixt:numdotdecimal">2</ix:nonFraction></div>
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">%</div>
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</table>
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<div style="display:none;"><br /></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We did <ix:nonFraction name="us-gaap:ContractWithCustomerLiability" id="Fact_b211069271df4c4a802417ef5e7b0d32" contextRef="c20201231_TypeOfArrangementAxis_GlaxoSmithKlineCollaborationMember" unitRef="U001" decimals="-6" scale="6" format="ixt-sec:numwordsen"><ix:nonFraction name="us-gaap:ContractWithCustomerLiability" id="Fact_59e8ee0b0973416987e4c07862acaea5" contextRef="c20211231_TypeOfArrangementAxis_GlaxoSmithKlineCollaborationMember" unitRef="U001" decimals="-6" scale="6" format="ixt-sec:numwordsen">no</ix:nonFraction></ix:nonFraction>t
    have any deferred revenue from our relationship with GSK at December 31, 2021 and 2020.</div>
</ix:continuation>
  <ix:continuation id="Text_94d04d6648bd4eb79b4d365680e182fc145" continuedAt="Text_94d04d6648bd4eb79b4d365680e182fc146">
<div><br />
  </div>
</ix:continuation>
  <ix:continuation id="Text_94d04d6648bd4eb79b4d365680e182fc146" continuedAt="Text_94d04d6648bd4eb79b4d365680e182fc147">
<div style="display:none;"><br /></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;">Novartis</div>
</ix:continuation>
  <ix:continuation id="Text_94d04d6648bd4eb79b4d365680e182fc147" continuedAt="Text_94d04d6648bd4eb79b4d365680e182fc148">
<div><br />
  </div>
</ix:continuation>
  <ix:continuation id="Text_94d04d6648bd4eb79b4d365680e182fc148" continuedAt="Text_94d04d6648bd4eb79b4d365680e182fc149">
<div style="display:none;"><br /></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">In January 2017, we initiated a collaboration
      with Novartis to develop and commercialize pelacarsen and olezarsen.</span><sub style="color: #000000;">&#160;</sub>We received a $<ix:nonFraction name="ions:UpfrontPaymentReceived" id="Fact_f101e92127dd43ef9f460e172673d2f2" contextRef="c20170101to20170331_TypeOfArrangementAxis_NovartisCollaborationMember" unitRef="U001" decimals="-6" scale="6" format="ixt:numdotdecimal">75</ix:nonFraction> million
    upfront payment in the first quarter of 2017. <span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">In the first quarter of 2019, Novartis licensed pelacarsen</span> and we earned a $<ix:nonFraction name="us-gaap:RevenueFromContractWithCustomerExcludingAssessedTax" id="Fact_0515b2fff4b64bc6b94f554c3b656d06" contextRef="c20190101to20190331_ProductOrServiceAxis_LicensingAndOtherRoyaltiesMember_TypeOfArrangementAxis_NovartisCollaborationMember" unitRef="U001" decimals="-6" scale="6" format="ixt:numdotdecimal">150</ix:nonFraction> million license fee. Novartis is responsible for conducting and funding future development and regulatory activities for pelacarsen, including a global
    Phase 3 cardiovascular outcomes study that Novartis initiated in the fourth quarter 2019.<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">&#160;</span>In connection with Novartis&#8217; license of pelacarsen, we and
    Novartis established a more definitive framework under which the companies would negotiate the co-commercialization of pelacarsen in selected markets. Included in this framework is an option by which Novartis could solely commercialize pelacarsen in
    exchange for Novartis paying us increased sales milestone payments based on sales of pelacarsen.<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">&#160;When Novartis decided to not exercise its option for </span>olezarsen,
    we retained rights to develop and commercialize olezarsen.</div>
</ix:continuation>
  <ix:continuation id="Text_94d04d6648bd4eb79b4d365680e182fc149" continuedAt="Text_94d04d6648bd4eb79b4d365680e182fc150">
<div><br />
  </div>
</ix:continuation>
  <ix:continuation id="Text_94d04d6648bd4eb79b4d365680e182fc150" continuedAt="Text_94d04d6648bd4eb79b4d365680e182fc151">
<div style="display:none;"><br /></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Under the collaboration, we are eligible to receive up to $<ix:nonFraction name="ions:MaximumAmountOfPaymentsReceivableForMilestones" id="Fact_d2d27d33e1b24ff79741dbb8504b3a12" contextRef="c20211231_TypeOfArrangementAxis_NovartisCollaborationMember" unitRef="U001" decimals="-6" scale="6" format="ixt:numdotdecimal">675</ix:nonFraction> million in milestone payments, including $<ix:nonFraction name="ions:MaximumAmountOfPaymentsReceivableForDevelopmentMilestones" id="Fact_b0160b60708f4f9cac5ee7648f0ee321" contextRef="c20211231_TypeOfArrangementAxis_NovartisCollaborationMember" unitRef="U001" decimals="-6" scale="6" format="ixt:numdotdecimal">25</ix:nonFraction> million for the achievement of a
    development milestone, up to $<ix:nonFraction name="ions:MaximumAmountOfPaymentsReceivableForRegulatoryMilestones" id="Fact_788a557118454c209aecf3914c029c91" contextRef="c20211231_TypeOfArrangementAxis_NovartisCollaborationMember" unitRef="U001" decimals="-6" scale="6" format="ixt:numdotdecimal">290</ix:nonFraction> million for the achievement of regulatory milestones and up to $<ix:nonFraction name="ions:MaximumAmountOfPaymentsReceivableForSalesMilestones" id="Fact_b32f437673cc4aac8bfcce020d51b7b0" contextRef="c20211231_TypeOfArrangementAxis_NovartisCollaborationMember" unitRef="U001" decimals="-6" scale="6" format="ixt:numdotdecimal">360</ix:nonFraction> million for the achievement of sales milestones. <span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">From inception through December
      2021, we have received nearly $</span><ix:nonFraction name="ions:CumulativePaymentsReceived" id="Fact_f70b581c4c184bd7afb533f20dd7fa6d" contextRef="c20211231_TypeOfArrangementAxis_NovartisCollaborationMember" unitRef="U001" decimals="-6" scale="6" format="ixt:numdotdecimal">425</ix:nonFraction><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> million
      in upfront payments, milestone payments, license fees and other payments from this collaboration. </span>We are also eligible to receive tiered royalties in the mid-teens to low <ix:nonFraction name="ions:RoyaltyPercentageReceivedOnSalesOfMedicine" id="Fact_016f76af44eb49289c02150198f2a523" contextRef="c20210101to20211231_ProductOrServiceAxis_PelacarsenActivePharmaceuticalIngredientMember_TypeOfArrangementAxis_NovartisCollaborationMember" unitRef="U003" decimals="2" scale="-2" format="ixt:numdotdecimal">20</ix:nonFraction> percent range on net sales of pelacarsen. In August 2021, we earned a $<ix:nonFraction name="us-gaap:RevenueFromContractWithCustomerExcludingAssessedTax" id="Fact_a546477fafc7419eb5a05bc5771e3598" contextRef="c20210701to20210930_ProductOrServiceAxis_PelacarsenActivePharmaceuticalIngredientMember_TypeOfArrangementAxis_NovartisCollaborationMember" unitRef="U001" decimals="-6" scale="6" format="ixt:numdotdecimal">25</ix:nonFraction> million
    milestone payment from Novartis when Novartis achieved <ix:nonFraction name="ions:PercentageEnrollmentInPhase3Study" id="Fact_5dc0a4808eb44213834bff6589f33d9b" contextRef="c20210831_ProductOrServiceAxis_PelacarsenActivePharmaceuticalIngredientMember_TypeOfArrangementAxis_NovartisCollaborationMember" unitRef="U003" decimals="2" scale="-2" format="ixt:numdotdecimal">50</ix:nonFraction> percent enrollment in the Lp(a) HORIZON Phase 3 cardiovascular outcome study of
    pelacarsen. We recognized the milestone payment in full in the third quarter of 2021 because we did not have any remaining performance obligations related to the milestone payment. <span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">We</span><span style="background-color: #FBFBFB; font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> will achieve the next payment of up to $</span><ix:nonFraction name="ions:NextPotentialPayment" id="Fact_3b19b0a102744ca58f85eea2983e6a84" contextRef="c20211231_TypeOfArrangementAxis_NovartisCollaborationMember" unitRef="U001" decimals="-6" scale="6" format="ixt:numdotdecimal">75</ix:nonFraction><span style="background-color: #FBFBFB; font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> million if Novartis advances regulatory activities for
      pelacarsen.</span></div>
</ix:continuation>
  <ix:continuation id="Text_94d04d6648bd4eb79b4d365680e182fc151" continuedAt="Text_94d04d6648bd4eb79b4d365680e182fc152">
<div><br />
  </div>
</ix:continuation>
  <ix:continuation id="Text_94d04d6648bd4eb79b4d365680e182fc152" continuedAt="Text_94d04d6648bd4eb79b4d365680e182fc153">
<div style="display:none;"><br /></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">In conjunction with this collaboration, we entered into a SPA with Novartis. As part of the SPA, Novartis purchased <ix:nonFraction name="us-gaap:StockIssuedDuringPeriodSharesNewIssues" id="Fact_21e55b070897453d838adbfcb2e0f867" contextRef="c20170101to20170331_TypeOfArrangementAxis_NovartisCollaborationMember" unitRef="U002" decimals="-5" scale="6" format="ixt:numdotdecimal">1.6</ix:nonFraction> million shares of our common stock for $<ix:nonFraction name="ions:ProceedsFromSaleOfCommonStockIncludingPremiumPaid" id="Fact_3a1b3a249b30451fa1ce1c491bcb7999" contextRef="c20170101to20170331_TypeOfArrangementAxis_NovartisCollaborationMember" unitRef="U001" decimals="-6" scale="6" format="ixt:numdotdecimal">100</ix:nonFraction>
    million in the first quarter of 2017.</div>
</ix:continuation>
  <ix:continuation id="Text_94d04d6648bd4eb79b4d365680e182fc153" continuedAt="Text_94d04d6648bd4eb79b4d365680e182fc154">
<div><br />
  </div>
</ix:continuation>
  <ix:continuation id="Text_94d04d6648bd4eb79b4d365680e182fc154" continuedAt="Text_94d04d6648bd4eb79b4d365680e182fc155">
<div style="display:none;"><br /></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">At the commencement of this collaboration, we identified <ix:nonFraction name="ions:RevenueFromContractWithCustomerNumberOfSeparatePerformanceObligations" id="Fact_45dfae68b384426d9e7f35800c5ee5da" contextRef="c20170331_TypeOfArrangementAxis_NovartisCollaborationMember" unitRef="U006" decimals="INF" scale="0" format="ixt-sec:numwordsen">four</ix:nonFraction> separate performance obligations:</div>
</ix:continuation>
  <ix:continuation id="Text_94d04d6648bd4eb79b4d365680e182fc155" continuedAt="Text_94d04d6648bd4eb79b4d365680e182fc156">
<div><br />
  </div>
</ix:continuation>
  <ix:continuation id="Text_94d04d6648bd4eb79b4d365680e182fc156" continuedAt="Text_94d04d6648bd4eb79b4d365680e182fc157">
<table cellspacing="0" cellpadding="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">


  <tr>

    <td style="width: 36pt;"></td>

    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;">R&amp;D services for pelacarsen;</div>
        </td>

  </tr>


</table>
</ix:continuation>
  <ix:continuation id="Text_94d04d6648bd4eb79b4d365680e182fc157" continuedAt="Text_94d04d6648bd4eb79b4d365680e182fc158">
<table cellspacing="0" cellpadding="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">


  <tr>

    <td style="width: 36pt;"></td>

    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;">R&amp;D services for olezarsen;</div>
        </td>

  </tr>


</table>
</ix:continuation>
  <ix:continuation id="Text_94d04d6648bd4eb79b4d365680e182fc158" continuedAt="Text_94d04d6648bd4eb79b4d365680e182fc159">
<table cellspacing="0" cellpadding="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">


  <tr>

    <td style="width: 36pt;"></td>

    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;">API for pelacarsen; and</div>
        </td>

  </tr>


</table>
</ix:continuation>
  <ix:continuation id="Text_94d04d6648bd4eb79b4d365680e182fc159" continuedAt="Text_94d04d6648bd4eb79b4d365680e182fc160">
<table cellspacing="0" cellpadding="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">


  <tr>

    <td style="width: 36pt;"></td>

    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;">API for olezarsen.</div>
        </td>

  </tr>


</table>
</ix:continuation>
  <ix:continuation id="Text_94d04d6648bd4eb79b4d365680e182fc160" continuedAt="Text_94d04d6648bd4eb79b4d365680e182fc161">
<div><br />
  </div>
</ix:continuation>
  <ix:continuation id="Text_94d04d6648bd4eb79b4d365680e182fc161" continuedAt="Text_94d04d6648bd4eb79b4d365680e182fc162">
<div style="display:none;"><br /></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We determined that the R&amp;D services for each medicine and the API for each medicine were distinct performance obligations.</div>
</ix:continuation></div>

  <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" class="DSPFPageBreakArea">
    <div class="DSPFPageFooter">
      <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">F-<span class="DSPFPageNumber">47</span></div>

    </div>

    <div style="page-break-after:always;" class="DSPFPageBreak">
      <hr style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;" /></div>


  </div>
<div><ix:continuation id="Text_94d04d6648bd4eb79b4d365680e182fc162" continuedAt="Text_94d04d6648bd4eb79b4d365680e182fc163">
<div><br />
  </div>
</ix:continuation>

  <ix:continuation id="Text_94d04d6648bd4eb79b4d365680e182fc163" continuedAt="Text_94d04d6648bd4eb79b4d365680e182fc164">
<div style="display:none;"><br /></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We determined our transaction price to be $<ix:nonFraction name="ions:RevenueFromContractWithCustomerTransactionPrice" id="Fact_6dbe3e18253b42678289e91bfc07aa2b" contextRef="c20170331_TypeOfArrangementAxis_NovartisCollaborationMember" unitRef="U001" decimals="-5" scale="6" format="ixt:numdotdecimal">108.4</ix:nonFraction>
    million, comprised of the following:</div>
</ix:continuation>
  <ix:continuation id="Text_94d04d6648bd4eb79b4d365680e182fc164" continuedAt="Text_94d04d6648bd4eb79b4d365680e182fc165">
<div><br />
  </div>
</ix:continuation>
  <ix:continuation id="Text_94d04d6648bd4eb79b4d365680e182fc165" continuedAt="Text_94d04d6648bd4eb79b4d365680e182fc166">
<table cellspacing="0" cellpadding="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">


  <tr>

    <td style="width: 36pt;"></td>

    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$<ix:nonFraction name="ions:UpfrontPaymentReceived" id="Fact_5578c7a91e964f86994ba7891b038b6c" contextRef="c20170101to20170331_TypeOfArrangementAxis_NovartisCollaborationMember" unitRef="U001" decimals="-6" scale="6" format="ixt:numdotdecimal">75</ix:nonFraction> million from the upfront payment;</div>
        </td>

  </tr>


</table>
</ix:continuation>
  <ix:continuation id="Text_94d04d6648bd4eb79b4d365680e182fc166" continuedAt="Text_94d04d6648bd4eb79b4d365680e182fc167">
<table cellspacing="0" cellpadding="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">


  <tr>

    <td style="width: 36pt;"></td>

    <td style="width: 18pt; vertical-align: top; align: right; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$<ix:nonFraction name="ions:PremiumReceivedOnSharesIssued" id="Fact_a374896a5baf4a14a92524dbf907cb65" contextRef="c20170101to20170331_TypeOfArrangementAxis_NovartisCollaborationMember" unitRef="U001" decimals="-5" scale="6" format="ixt:numdotdecimal">28.4</ix:nonFraction> million for the premium paid by Novartis for its purchase
            of our common stock at a premium in the first quarter of 2017; and</div>
        </td>

  </tr>


</table>
</ix:continuation>
  <ix:continuation id="Text_94d04d6648bd4eb79b4d365680e182fc167" continuedAt="Text_94d04d6648bd4eb79b4d365680e182fc168">
<table cellspacing="0" cellpadding="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">


  <tr>

    <td style="width: 36pt;"></td>

    <td style="width: 18pt; vertical-align: top; align: right; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$<ix:nonFraction name="ions:PotentialPremiumReceivedIfCommonStockIsPurchasedInFuture" id="Fact_844ad8b58c81489eb92908f6d9b9a1e0" contextRef="c20170331_TypeOfArrangementAxis_NovartisCollaborationMember" unitRef="U001" decimals="-5" scale="6" format="ixt:numdotdecimal">5.0</ix:nonFraction> million for the potential premium Novartis would have paid
            if they purchased our common stock in the future.</div>
        </td>

  </tr>


</table>
</ix:continuation>
  <ix:continuation id="Text_94d04d6648bd4eb79b4d365680e182fc168" continuedAt="Text_94d04d6648bd4eb79b4d365680e182fc169">
<div><br />
  </div>
</ix:continuation>
  <ix:continuation id="Text_94d04d6648bd4eb79b4d365680e182fc169" continuedAt="Text_94d04d6648bd4eb79b4d365680e182fc170">
<div style="display:none;"><br /></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We allocated the transaction price based on the estimated stand-alone selling price of each performance obligation as follows:</div>
</ix:continuation>
  <ix:continuation id="Text_94d04d6648bd4eb79b4d365680e182fc170" continuedAt="Text_94d04d6648bd4eb79b4d365680e182fc171">
<div><br />
  </div>
</ix:continuation>
  <ix:continuation id="Text_94d04d6648bd4eb79b4d365680e182fc171" continuedAt="Text_94d04d6648bd4eb79b4d365680e182fc172">
<table cellspacing="0" cellpadding="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">


  <tr>

    <td style="width: 36pt;"></td>

    <td style="width: 18pt; vertical-align: top; align: right; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">$</span><ix:nonFraction name="ions:RevenueFromContractWithCustomerTransactionPrice" id="Fact_40c2b997e5d94404a5664d9c274e413e" contextRef="c20170331_ProductOrServiceAxis_ResearchAndDevelopmentServicesForPelacarsenMember_TypeOfArrangementAxis_NovartisCollaborationMember" unitRef="U001" decimals="-5" scale="6" format="ixt:numdotdecimal">64.0</ix:nonFraction><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> million for the R&amp;D services for pelacarsen;</span></div>
        </td>

  </tr>


</table>
</ix:continuation>
  <ix:continuation id="Text_94d04d6648bd4eb79b4d365680e182fc172" continuedAt="Text_94d04d6648bd4eb79b4d365680e182fc173">
<table cellspacing="0" cellpadding="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">


  <tr>

    <td style="width: 36pt;"></td>

    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$<ix:nonFraction name="ions:RevenueFromContractWithCustomerTransactionPrice" id="Fact_051befe7d00048df8a2b3cb0405d5ae3" contextRef="c20170331_ProductOrServiceAxis_ResearchAndDevelopmentServicesForOlezarsenMember_TypeOfArrangementAxis_NovartisCollaborationMember" unitRef="U001" decimals="-5" scale="6" format="ixt:numdotdecimal">40.1</ix:nonFraction> million for the R&amp;D services for <span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">olezarsen</span>; </div>
        </td>

  </tr>


</table>
</ix:continuation>
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<table cellspacing="0" cellpadding="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">


  <tr>

    <td style="width: 36pt;"></td>

    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$<ix:nonFraction name="ions:RevenueFromContractWithCustomerTransactionPrice" id="Fact_b3744373869c4288908b09e14ce88277" contextRef="c20170331_ProductOrServiceAxis_PelacarsenActivePharmaceuticalIngredientMember_TypeOfArrangementAxis_NovartisCollaborationMember" unitRef="U001" decimals="-5" scale="6" format="ixt:numdotdecimal">1.5</ix:nonFraction></span> million for the delivery of pelacarsen API; and</div>
        </td>

  </tr>


</table>
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    <td style="width: 36pt;"></td>

    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$<ix:nonFraction name="ions:RevenueFromContractWithCustomerTransactionPrice" id="Fact_060f939deb0d4433a9dd740934afd81c" contextRef="c20170331_ProductOrServiceAxis_OlezarsenActivePharmaceuticalIngredientMember_TypeOfArrangementAxis_NovartisCollaborationMember" unitRef="U001" decimals="-5" scale="6" format="ixt:numdotdecimal">2.8</ix:nonFraction></span> million for the delivery of olezarsen API.</div>
        </td>

  </tr>


</table>
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<div style="display:none;"><br /></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We completed our R&amp;D services performance obligations for olezarsen and pelacarsen<sub>&#160;</sub>in 2019. As such, we recognized all
    revenue we allocated to the olezarsen and pelacarsen<sub>&#160;</sub>R&amp;D services as of the end of 2019.</div>
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  </div>
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<div style="display:none;"><br /></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">We recognized revenue related to the R&amp;D
      services for pelacarsen and olezarsen performance obligations as we performed services </span>based on our effort to satisfy our performance obligations relative to our total effort expected to satisfy our performance obligations<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">.</span></div>
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  <ix:continuation id="Text_94d04d6648bd4eb79b4d365680e182fc180" continuedAt="Text_94d04d6648bd4eb79b4d365680e182fc181"><ix:nonNumeric name="us-gaap:SchedulesOfConcentrationOfRiskByRiskFactorTextBlock" id="Text_f417927e6ea44049a9024dea0c69d56b" contextRef="c20210101to20211231_TypeOfArrangementAxis_NovartisCollaborationMember" escape="true" continuedAt="Text_72f519094bb24efca04fd24fade09fa21">
<div style="display:none;"><br /></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">During the years ended December 31, 2021, 2020 and 2019, we earned the following revenue from our
    relationship with Novartis (in millions, except percentage amounts):</div>
</ix:nonNumeric></ix:continuation>
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<div><br />
  </div>
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<table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;" class="cfttable">


  <tr>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">

        </td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" colspan="10">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Year Ended December 31,</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" colspan="2">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2021</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" colspan="2">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2020</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" colspan="2">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2019</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;">
          <div style="text-align: left; text-indent: -27pt; margin-left: 27pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">R&amp;D revenue</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:RevenueFromContractWithCustomerExcludingAssessedTax" id="Fact_34a7cbc53ddb475aaaa8bcec238b44ce" contextRef="c20210101to20211231_ProductOrServiceAxis_ResearchAndDevelopmentRevenueUnderCollaborativeAgreementsMember_TypeOfArrangementAxis_NovartisCollaborationMember" unitRef="U001" decimals="-5" scale="6" format="ixt:numdotdecimal">25.5</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:RevenueFromContractWithCustomerExcludingAssessedTax" id="Fact_cd2c4f63152b45998731917ab0309ed1" contextRef="c20200101to20201231_ProductOrServiceAxis_ResearchAndDevelopmentRevenueUnderCollaborativeAgreementsMember_TypeOfArrangementAxis_NovartisCollaborationMember" unitRef="U001" decimals="-5" scale="6" format="ixt:numdotdecimal">1.0</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:RevenueFromContractWithCustomerExcludingAssessedTax" id="Fact_4ff5f9c394c349349b7bc24fd95d7574" contextRef="c20190101to20191231_ProductOrServiceAxis_ResearchAndDevelopmentRevenueUnderCollaborativeAgreementsMember_TypeOfArrangementAxis_NovartisCollaborationMember" unitRef="U001" decimals="-5" scale="6" format="ixt:numdotdecimal">187.4</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 64%;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Percentage of total revenue</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:ConcentrationRiskPercentage1" id="Fact_1f40d9d87ee4435c83ab9656d281b655" contextRef="c20210101to20211231_ConcentrationRiskByBenchmarkAxis_RevenueFromContractWithCustomerMember_ConcentrationRiskByTypeAxis_CustomerConcentrationRiskMember_TypeOfArrangementAxis_NovartisCollaborationMember" unitRef="U003" decimals="2" scale="-2" format="ixt:numdotdecimal">3</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">%</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:ConcentrationRiskPercentage1" id="Fact_130e18fe0f0c441186a0e17a58f664d9" contextRef="c20200101to20201231_ConcentrationRiskByBenchmarkAxis_RevenueFromContractWithCustomerMember_ConcentrationRiskByTypeAxis_CustomerConcentrationRiskMember_TypeOfArrangementAxis_NovartisCollaborationMember" unitRef="U003" decimals="2" scale="-2" format="ixt:numdotdecimal">0</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">%</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:ConcentrationRiskPercentage1" id="Fact_3cbf0264fff04ba19d7c857cee72d9f4" contextRef="c20190101to20191231_ConcentrationRiskByBenchmarkAxis_RevenueFromContractWithCustomerMember_ConcentrationRiskByTypeAxis_CustomerConcentrationRiskMember_TypeOfArrangementAxis_NovartisCollaborationMember" unitRef="U003" decimals="2" scale="-2" format="ixt:numdotdecimal">17</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">%</div>
        </td>

  </tr>


</table>
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  </div>
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<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We did <ix:nonFraction name="us-gaap:ContractWithCustomerLiability" id="Fact_202ff57e88d8402cb5c44dcb77bc2901" contextRef="c20201231_TypeOfArrangementAxis_NovartisCollaborationMember" unitRef="U001" decimals="-6" scale="6" format="ixt-sec:numwordsen"><ix:nonFraction name="us-gaap:ContractWithCustomerLiability" id="Fact_10f623e4621745d8a337c5cf9f0bb013" contextRef="c20211231_TypeOfArrangementAxis_NovartisCollaborationMember" unitRef="U001" decimals="-6" scale="6" format="ixt-sec:numwordsen">no</ix:nonFraction></ix:nonFraction>t
    have any deferred revenue from our relationship with Novartis at December 31, 2021 and 2020.</div>
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  </div>
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<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;">Roche</div>
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  </div>
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<div style="text-align: left; margin-left: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;">Huntington&#8217;s Disease</div>
</ix:continuation></div>

  <div>
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    </div>
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  </div>

  <div>
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<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">In April 2013, we formed an alliance with Hoffman-La Roche Inc. and F. Hoffmann-La Roche Ltd., collectively Roche, to
      develop treatments for HD based on our antisense technology. Under the agreement, we discovered and developed tominersen, an investigational medicine targeting HTT protein. We developed tominersen through completion of our Phase 1/2 clinical study in
      people with early stage HD. In the fourth quarter of 2017, upon completion of the Phase 1/2 study, Roche exercised its option to license tominersen. Roche is responsible for all global development, regulatory and commercialization activities and
      costs for tominersen.</div>
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  </div>
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<div style="display:none;"><br /></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Under the terms of the agreement, we received an upfront payment of $<ix:nonFraction name="ions:UpfrontPaymentReceived" id="Fact_9f09a173393d49bc818e79aacee84764" contextRef="c20130401to20130430_TypeOfArrangementAxis_RocheCollaborationHuntingtonsDiseaseMember" unitRef="U001" decimals="-6" scale="6" format="ixt:numdotdecimal">30</ix:nonFraction> million in April 2013 and an additional $<ix:nonFraction name="ions:MilestonePaymentsReceived" id="Fact_8432cd12b85e48c6b111a7bdcb5f2ac8" contextRef="c20170101to20171231_TypeOfArrangementAxis_RocheCollaborationHuntingtonsDiseaseMember" unitRef="U001" decimals="-6" scale="6" format="ixt:numdotdecimal">3</ix:nonFraction> million payment in 2017. We are eligible
    to receive up to $<ix:nonFraction name="ions:MaximumAmountOfPaymentsReceivableForLicenseFeesAndMilestones" id="Fact_d8d42ebb32dc46b7895c83156cf73607" contextRef="c20211231_TypeOfArrangementAxis_RocheCollaborationHuntingtonsDiseaseMember" unitRef="U001" decimals="-6" scale="6" format="ixt:numdotdecimal">365</ix:nonFraction> million in a license fee and milestone payments including up to $<ix:nonFraction name="ions:MaximumAmountOfPaymentsReceivableForDevelopmentMilestones" id="Fact_70a5f7bc239446719e9285ed2ff78c07" contextRef="c20211231_TypeOfArrangementAxis_RocheCollaborationHuntingtonsDiseaseMember" unitRef="U001" decimals="-6" scale="6" format="ixt:numdotdecimal">70</ix:nonFraction> million for the achievement of development milestones, up to $<ix:nonFraction name="ions:MaximumAmountOfPaymentsReceivableForRegulatoryMilestones" id="Fact_884490256579410c93629768255d304a" contextRef="c20211231_TypeOfArrangementAxis_RocheCollaborationHuntingtonsDiseaseMember" unitRef="U001" decimals="-6" scale="6" format="ixt:numdotdecimal">170</ix:nonFraction> million for the
    achievement of regulatory milestones and up to $<ix:nonFraction name="ions:MaximumAmountOfPaymentsReceivableForSalesMilestones" id="Fact_a9fce437f8684220b259d8408d43875f" contextRef="c20211231_TypeOfArrangementAxis_RocheCollaborationHuntingtonsDiseaseMember" unitRef="U001" decimals="-6" scale="6" format="ixt:numdotdecimal">80</ix:nonFraction> million for the achievement of sales milestones. In addition, we are eligible to receive up to
    $<ix:nonFraction name="ions:MaximumAmountOfPaymentReceivableForEachAdditionalMedicineDeveloped" id="Fact_67793d8d7c8843aba2b236e8d909758e" contextRef="c20211231_TypeOfArrangementAxis_RocheCollaborationHuntingtonsDiseaseMember" unitRef="U001" decimals="-5" scale="6" format="ixt:numdotdecimal">136.5</ix:nonFraction> million in milestone payments for each additional medicine successfully developed. We are also eligible to receive tiered royalties up to
    the mid-teens on net sales of any product resulting from this alliance. From inception through December 2021, we have received $<ix:nonFraction name="ions:CumulativePaymentsReceived" id="Fact_3aa74885781e415aa4fe5dd8e04e1eda" contextRef="c20211231_TypeOfArrangementAxis_RocheCollaborationHuntingtonsDiseaseMember" unitRef="U001" decimals="-6" scale="6" format="ixt:numdotdecimal">150</ix:nonFraction> million in upfront fees, milestone payments and license fees under this collaboration. We will achieve the next payment of $<ix:nonFraction name="ions:NextPotentialPayment" id="Fact_cb403b59db80408fb4a9b96e8393b762" contextRef="c20211231_TypeOfArrangementAxis_RocheCollaborationHuntingtonsDiseaseMember" unitRef="U001" decimals="-6" scale="6" format="ixt:numdotdecimal">15</ix:nonFraction> million if Roche advances tominersen into registration.</div>
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  </div>
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<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">At the commencement of this collaboration, we identified <ix:nonFraction name="ions:RevenueFromContractWithCustomerNumberOfSeparatePerformanceObligations" id="Fact_efae3e04708b4937bacd7fa2bb5963f7" contextRef="c20130430_TypeOfArrangementAxis_RocheCollaborationHuntingtonsDiseaseMember" unitRef="U006" decimals="INF" scale="0" format="ixt-sec:numwordsen">one</ix:nonFraction> performance obligation, which was to perform R&amp;D services for Roche. We determined the transaction price to be the $<ix:nonFraction name="ions:RevenueFromContractWithCustomerTransactionPrice" id="Fact_872b6a5c29be484ca3beb5fa683f1784" contextRef="c20130430_TypeOfArrangementAxis_RocheCollaborationHuntingtonsDiseaseMember" unitRef="U001" decimals="-6" scale="6" format="ixt:numdotdecimal">30</ix:nonFraction> million upfront payment we received and allocated it to our single performance obligation. As we achieved milestone payments for our R&amp;D services, we included these amounts in our
    transaction price for our R&amp;D services performance obligation. We recognized revenue for our R&amp;D services performance obligation over our period of performance, which ended in the third quarter of 2017.</div>
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<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Under this collaboration, we have also generated additional payments that we concluded were not part of our R&amp;D
    services performance obligation. We recognized each of these payments in full in the respective quarter in which we generated the payment because the payments were distinct and we did not have any performance obligations for the respective payment. In
    2019, we earned $<ix:nonFraction name="us-gaap:RevenueFromContractWithCustomerExcludingAssessedTax" id="Fact_7314f04e9d0e40a49fbaacf4f47109de" contextRef="c20190101to20191231_TypeOfArrangementAxis_RocheCollaborationHuntingtonsDiseaseMember" unitRef="U001" decimals="-6" scale="6" format="ixt:numdotdecimal">35</ix:nonFraction> million in milestone payments when Roche dosed the first patient in the Phase 3 study of tominersen.</div>
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<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">In January 2022, <span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">Roche announced it is
      actively preparing to initiate a new Phase 2 study of tominersen in patients with HD. Post-hoc analyses from the GENERATION HD1 study suggested tominersen may benefit younger adult patients with lower disease burden</span>. In March 2021, Roche
    decided to discontinue dosing in the Phase 3 GENERATION HD1 study of tominersen in patients with manifest HD based on the results of a pre-planned review of data from the Phase 3 study conducted by an unblinded iDMC. We do not have any remaining
    performance obligations related to tominersen under this collaboration with Roche; however, we can still earn additional payments and royalties as Roche advances tominersen.</div>
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<div style="text-align: left; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;"><span style="background-color: #FBFBFB; font-size: 10pt; font-family: 'Times New Roman', Times, serif;">IONIS-FB-L</span><sub><span style="background-color: #FBFBFB;">Rx</span></sub><span style="background-color: #FBFBFB; font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> for Complement-Mediated Diseases</span></div>
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  <ix:continuation id="Text_94d04d6648bd4eb79b4d365680e182fc202" continuedAt="Text_94d04d6648bd4eb79b4d365680e182fc203">
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<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">In October 2018, we entered into a
      collaboration agreement with Roche to</span><span style="background-color: #FBFBFB; font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> develop IONIS-FB-L</span><sub style="color: #000000;">Rx</sub><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> for the treatment of complement-mediated diseases. We are currently conducting Phase 2 studies in </span><ix:nonFraction name="ions:NumberOfDiseaseIndications" id="Fact_748d8e6ad1bb43a384bba3995dac28ea" contextRef="c20210101to20211231_TypeOfArrangementAxis_RocheCollaborationIonisFbLForComplementMediatedDiseasesMember" unitRef="U020" decimals="INF" scale="0" format="ixt-sec:numwordsen">two</ix:nonFraction><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> disease indications for </span><span style="background-color: #FBFBFB; font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">IONIS-FB-L</span><sub style="color: #000000;">Rx</sub><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">, </span><ix:nonFraction name="ions:NumberOfDiseaseIndications" id="Fact_33191bc87cff451284262a2fbdef6e22" contextRef="c20210101to20211231_ProductOrServiceAxis_GeographicAtrophyMember_TypeOfArrangementAxis_RocheCollaborationIonisFbLForComplementMediatedDiseasesMember" unitRef="U020" decimals="INF" scale="0" format="ixt-sec:numwordsen">one</ix:nonFraction><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> for the treatment of patients with GA, the advanced stage
      of dry AMD, and a </span><span style="-sec-ix-hidden:Fact_04500eaf787641bfbd86183ba9891b89">second</span><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> for the treatment
      of patients with IgA nephropathy. </span>Roche<span style="background-color: #FBFBFB; font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> has the option to license IONIS-FB-L</span><sub style="color: #000000;"><span style="background-color: #FBFBFB;">Rx</span></sub><span style="background-color: #FBFBFB; font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> at the completion of these studies. Upon licensing, </span>Roche <span style="background-color: #FBFBFB; font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">will be responsible for global development, regulatory and commercialization activities and costs.</span></div>
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<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="background-color: #FBFBFB; font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">Under the terms of
      this agreement, we received a </span>$<ix:nonFraction name="ions:UpfrontPaymentReceived" id="Fact_dc2c32a9c1124cddb9ed5ff336ece731" contextRef="c20181001to20181231_TypeOfArrangementAxis_RocheCollaborationIonisFbLForComplementMediatedDiseasesMember" unitRef="U001" decimals="-6" scale="6" format="ixt:numdotdecimal">75</ix:nonFraction> million<span style="background-color: #FBFBFB; font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> upfront payment in the fourth quarter of 2018. We are eligible to receive more than </span>$<ix:nonFraction name="ions:MinimumAmountOfPaymentsReceivableForLicenseFeesAndMilestonePayments" id="Fact_06d83477fcf046bbabd2d4017da3a520" contextRef="c20211231_TypeOfArrangementAxis_RocheCollaborationIonisFbLForComplementMediatedDiseasesMember" unitRef="U001" decimals="-6" scale="6" format="ixt:numdotdecimal">680</ix:nonFraction> million<span style="background-color: #FBFBFB; font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> in development, regulatory and sales milestone payments and license fees. In addition, we are also eligible to receive tiered royalties
      from the high teens to </span><ix:nonFraction name="ions:RoyaltyPercentageReceivedOnNetSalesOfMedicine" id="Fact_63fb5f4decbb426a9cd241023b3ecd39" contextRef="c20210101to20211231_TypeOfArrangementAxis_RocheCollaborationIonisFbLForComplementMediatedDiseasesMember" unitRef="U003" decimals="2" scale="-2" format="ixt:numdotdecimal">20</ix:nonFraction> percent<span style="background-color: #FBFBFB; font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> on net sales. </span><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">From inception through December </span>2021<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">, we have received $</span><ix:nonFraction name="ions:CumulativePaymentsReceived" id="Fact_c786e47ad0b540fbb376640b5b6b6aba" contextRef="c20211231_TypeOfArrangementAxis_RocheCollaborationIonisFbLForComplementMediatedDiseasesMember" unitRef="U001" decimals="-6" scale="6" format="ixt:numdotdecimal">75</ix:nonFraction><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> million in upfront fees, milestone payments and license fees under this collaboration. </span><span style="background-color: #FBFBFB; font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">We will achieve the next payment of $</span><ix:nonFraction name="ions:NextPotentialPayment" id="Fact_5128247561064475b51c4c5bf62130be" contextRef="c20211231_TypeOfArrangementAxis_RocheCollaborationIonisFbLForComplementMediatedDiseasesMember" unitRef="U001" decimals="-6" scale="6" format="ixt:numdotdecimal">20</ix:nonFraction><span style="background-color: #FBFBFB; font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> million if we further advance </span>the Phase 2 study in patients with dry AMD<span style="background-color: #FBFBFB; font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">.</span></div>
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<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">At the commencement of this collaboration, we identified <ix:nonFraction name="ions:RevenueFromContractWithCustomerNumberOfSeparatePerformanceObligations" id="Fact_468a8db7e8de46a69b5ee7a0575f664d" contextRef="c20181031_TypeOfArrangementAxis_RocheCollaborationIonisFbLForComplementMediatedDiseasesMember" unitRef="U006" decimals="INF" scale="0" format="ixt-sec:numwordsen">one</ix:nonFraction> performance obligation, which was to perform R&amp;D services for Roche. We determined the transaction price to be the $<ix:nonFraction name="ions:RevenueFromContractWithCustomerTransactionPrice" id="Fact_64f9009b51e54bc8a818455d38bda2ae" contextRef="c20181031_TypeOfArrangementAxis_RocheCollaborationIonisFbLForComplementMediatedDiseasesMember" unitRef="U001" decimals="-6" scale="6" format="ixt:numdotdecimal">75</ix:nonFraction> million upfront payment we received and allocated it to our single performance obligation. We are recognizing revenue for our R&amp;D services performance obligation as we perform services
    based on our effort to satisfy our performance obligation relative to our total effort expected to satisfy our performance obligation. During the fourth quarter of 2020, we <span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">updated our estimate of the total effort we expected to expend to satisfy our performance obligation under this collaboration.</span>&#160;<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">In the
      fourth quarter of 2020, we recorded a cumulative catch up adjustment of $</span><ix:nonFraction name="us-gaap:RevenueFromContractWithCustomerExcludingAssessedTax" id="Fact_0c806f7d3c2b4f6d9c6f41c84e900bd0" contextRef="c20201001to20201231_TypeOfArrangementAxis_RocheCollaborationIonisFbLForComplementMediatedDiseasesMember" unitRef="U001" decimals="-5" scale="6" sign="-" format="ixt:numdotdecimal">9.2</ix:nonFraction><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> million to decrease revenue because we updated our total cost estimate to complete the Phase 2 study of </span><span style="background-color: #FBFBFB; font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">IONIS-FB-L</span><sub style="color: #000000;"><span style="background-color: #FBFBFB;">Rx </span></sub><span style="background-color: #FBFBFB; font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">for
      the </span><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">treatment of patients with GA. </span>We<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> currently
      estimate we will satisfy our performance obligation in </span>the fourth quarter of 2023.</div>
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<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">During the years ended December 31, 2021, 2020 and 2019, we earned the following revenue from our relationship with Roche (in millions, except percentage amounts):</div>
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          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Year Ended December 31,</div>
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    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;" colspan="1">&#160;</td>

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          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2021</div>
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    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" colspan="2">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2020</div>
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;" colspan="1">&#160;</td>

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          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2019</div>
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          <div style="text-align: left; text-indent: -27pt; margin-left: 27pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">R&amp;D revenue</div>
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          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
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    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:RevenueFromContractWithCustomerExcludingAssessedTax" id="Fact_fb8913807e664ded9db727de95b93bfc" contextRef="c20210101to20211231_ProductOrServiceAxis_ResearchAndDevelopmentRevenueUnderCollaborativeAgreementsMember_TypeOfArrangementAxis_RocheCollaborationMember" unitRef="U001" decimals="-5" scale="6" format="ixt:numdotdecimal">17.2</ix:nonFraction></div>
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    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

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          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
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          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:RevenueFromContractWithCustomerExcludingAssessedTax" id="Fact_43d5265cf6164fce9ca88f18b5897dc3" contextRef="c20200101to20201231_ProductOrServiceAxis_ResearchAndDevelopmentRevenueUnderCollaborativeAgreementsMember_TypeOfArrangementAxis_RocheCollaborationMember" unitRef="U001" decimals="-5" scale="6" format="ixt:numdotdecimal">5.9</ix:nonFraction></div>
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

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          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:RevenueFromContractWithCustomerExcludingAssessedTax" id="Fact_20872827ad6c4817bcf759078e23498f" contextRef="c20190101to20191231_ProductOrServiceAxis_ResearchAndDevelopmentRevenueUnderCollaborativeAgreementsMember_TypeOfArrangementAxis_RocheCollaborationMember" unitRef="U001" decimals="-5" scale="6" format="ixt:numdotdecimal">57.0</ix:nonFraction></div>
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          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Percentage of total revenue</div>
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    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:ConcentrationRiskPercentage1" id="Fact_50cff48cda6946bc87457fee3925e81c" contextRef="c20210101to20211231_ConcentrationRiskByBenchmarkAxis_RevenueFromContractWithCustomerMember_ConcentrationRiskByTypeAxis_CustomerConcentrationRiskMember_TypeOfArrangementAxis_RocheCollaborationMember" unitRef="U003" decimals="2" scale="-2" format="ixt:numdotdecimal">2</ix:nonFraction></div>
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          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">%</div>
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          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:ConcentrationRiskPercentage1" id="Fact_cf5ca05dc07c4448bdda2353f8ed8769" contextRef="c20200101to20201231_ConcentrationRiskByBenchmarkAxis_RevenueFromContractWithCustomerMember_ConcentrationRiskByTypeAxis_CustomerConcentrationRiskMember_TypeOfArrangementAxis_RocheCollaborationMember" unitRef="U003" decimals="2" scale="-2" format="ixt:numdotdecimal">1</ix:nonFraction></div>
        </td>

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          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">%</div>
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:ConcentrationRiskPercentage1" id="Fact_6490dfcad60e494083f50ae6646f73e4" contextRef="c20190101to20191231_ConcentrationRiskByBenchmarkAxis_RevenueFromContractWithCustomerMember_ConcentrationRiskByTypeAxis_CustomerConcentrationRiskMember_TypeOfArrangementAxis_RocheCollaborationMember" unitRef="U003" decimals="2" scale="-2" format="ixt:numdotdecimal">5</ix:nonFraction></div>
        </td>

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          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">%</div>
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<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">Our </span>consolidated balance sheet at <span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">December 31, </span>2021<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> and </span>2020<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> included deferred revenue of $</span><ix:nonFraction name="us-gaap:ContractWithCustomerLiability" id="Fact_5ff4d7b8efd14d4a81981ea0cfa0cf58" contextRef="c20211231_TypeOfArrangementAxis_RocheCollaborationMember" unitRef="U001" decimals="-5" scale="6" format="ixt:numdotdecimal">31.6</ix:nonFraction><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> million and $</span><ix:nonFraction name="us-gaap:ContractWithCustomerLiability" id="Fact_a38902f403274142aedd7c7ed42e8214" contextRef="c20201231_TypeOfArrangementAxis_RocheCollaborationMember" unitRef="U001" decimals="-5" scale="6" format="ixt:numdotdecimal">47.2</ix:nonFraction><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">
      million related to our relationship with Roche, respectively.</span></div>
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<div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Commercialization Partnerships</div>
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<div style="text-align: left; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;">Swedish Orphan Biovitrum AB (Sobi)</div>
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<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We began commercializing TEGSEDI and WAYLIVRA in Europe in January 2021 and TEGSEDI in North America in April 2021 through
    distribution agreements with Sobi. Under our agreements, we are responsible for supplying finished goods inventory to Sobi and Sobi is responsible for selling each medicine to the end customer. In exchange, we earn a distribution fee on net sales from
    Sobi for each medicine.</div>
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<div style="text-align: left; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;">PTC Therapeutics</div>
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<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">In August 2018, we entered into an exclusive
      license agreement with PTC Therapeutics to commercialize TEGSEDI and WAYLIVRA in Latin America and certain Caribbean countries. Under the license agreement, we are eligible to receive royalties from PTC in the mid-</span><ix:nonFraction name="ions:RoyaltyPercentageReceivedOnNetSalesOfEachMedicineFromCollaborationPartner" id="Fact_570d071a48d248dbb4cd460b720cd572" contextRef="c20210101to20211231_TypeOfArrangementAxis_PtcTherapeuticsCollaborationMember" unitRef="U003" decimals="2" scale="-2" format="ixt:numdotdecimal">20</ix:nonFraction> percent<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> range on net sales for each medicine. </span>In
    December 2021, we started receiving royalties from PTC for TEGSEDI sales<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">.</span></div>
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<div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Technology Enhancement Collaboration</div>
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<div style="text-align: left; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic; font-weight: bold;">Bicycle License Agreement</div>
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<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">In December 2020, we entered into a collaboration agreement with Bicycle and obtained an option to license its peptide technology to
    potentially increase the delivery capabilities of our LICA medicines. In July 2021, we paid $<ix:nonFraction name="ions:PaymentsMadeUnderCollaborationAgreement" id="Fact_5f30af4db40c410198d4adf0cf56a2ac" contextRef="c20210701to20210731_TypeOfArrangementAxis_BicycleCollaborationMember" unitRef="U001" decimals="-6" scale="6" format="ixt:numdotdecimal">42</ix:nonFraction> million when we exercised our option to license
    Bicycle&#8217;s technology, which included an equity investment in Bicycle. As part of our stock purchase, we entered into a lockup agreement with Bicycle that restricts our ability to trade our Bicycle shares for <ix:nonNumeric name="ions:LockUpAgreementTermOfTradingRestriction" id="Fact_3b6f7ff3760d482699aca63514d611a3" contextRef="c20210101to20211231_TypeOfArrangementAxis_BicycleCollaborationMember" format="ixt-sec:durwordsen">one year</ix:nonNumeric>. In 2021, we recorded a $<ix:nonFraction name="ions:InvestmentInEquitySecuritiesFvNi" id="Fact_c4984ca504f041ad810726dda263687c" contextRef="c20210101to20211231_TypeOfArrangementAxis_BicycleCollaborationMember" unitRef="U001" decimals="-5" scale="6" format="ixt:numdotdecimal">7.2</ix:nonFraction> million equity investment for the
    shares we received in Bicycle. We recognized the remaining $<ix:nonFraction name="us-gaap:ResearchAndDevelopmentExpense" id="Fact_f54d6f5ead044550b599ce90b22d6d17" contextRef="c20210101to20211231_TypeOfArrangementAxis_BicycleCollaborationMember" unitRef="U001" decimals="-5" scale="6" format="ixt:numdotdecimal">34.8</ix:nonFraction> million as R&amp;D expense in 2021. From inception through December 31, 2021, we
    have paid Bicycle $<ix:nonFraction name="ions:CumulativePaymentsMade" id="Fact_2ffb576dcfe749bd9031d801899bcdcb" contextRef="c20211231_TypeOfArrangementAxis_BicycleCollaborationMember" unitRef="U001" decimals="-5" scale="6" format="ixt:numdotdecimal">46.6</ix:nonFraction> million under this collaboration agreement.</div>
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<div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Other Agreements</div>
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<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;">Alnylam Pharmaceuticals, Inc.</div>
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<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Under the terms of our agreement with Alnylam, we co-exclusively (with ourselves) licensed to Alnylam our patent estate
      relating to antisense motifs and mechanisms and oligonucleotide chemistry for double-stranded RNAi therapeutics, with Alynylam having the exclusive right to grant platform sublicenses for double-stranded RNAi. In exchange for such rights, Alynylam
      gave us a technology access fee, participation in fees from Alnylam&#8217;s partnering programs, as well as future milestone and royalty payments from Alnylam. We retained exclusive rights to our patents for single-stranded antisense therapeutics and for a
      limited number of double-stranded RNAi therapeutic targets and all rights to single-stranded RNAi, or ssRNAi, therapeutics. In turn, Alnylam nonexclusively licensed to us its patent estate relating to antisense motifs and mechanisms and
      oligonucleotide chemistry to research, develop and commercialize single-stranded antisense therapeutics, ssRNAi therapeutics, and to research double-stranded RNAi compounds. We also received a license to develop and commercialize double-stranded RNAi
      therapeutics targeting a limited number of therapeutic targets on a nonexclusive basis. Additionally, in 2015, we and Alnylam entered into an alliance in which we cross-licensed intellectual property. Under this alliance, we and Alnylam each obtained
      exclusive license rights to four therapeutic programs. Alnylam granted us an exclusive, royalty-bearing license to its chemistry, RNA targeting mechanism and target-specific intellectual property for oligonucleotides against four targets, including
      FXI and Apo(a) and two other targets. In exchange, we granted Alnylam an exclusive, royalty-bearing license to our chemistry, RNA targeting mechanism and target-specific intellectual property for oligonucleotides against four other targets. Alnylam
      also granted us a royalty-bearing, non-exclusive license to new platform technology arising from May 2014 through April 2019 for single-stranded antisense therapeutics. In turn, we granted Alnylam a royalty-bearing, non-exclusive license to new
      platform technology arising from May 2014 through April 2019 for double-stranded RNAi therapeutics.</div>
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<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">In the fourth quarter 2020, we completed an arbitration process with Alnylam. The arbitration panel awarded us $<ix:nonFraction name="us-gaap:LitigationSettlementAmountAwardedFromOtherParty" id="Fact_dfb16bacc6b94e7989aea7d88eebed5b" contextRef="c20201001to20201231_TypeOfArrangementAxis_AlnylamCollaborationMember" unitRef="U001" decimals="-5" scale="6" format="ixt:numdotdecimal">41.2</ix:nonFraction> million for payments owed to us by Alnylam related to Alnylam&#8217;s agreement with Sanofi Genzyme. We recognized the $<ix:nonFraction name="us-gaap:RevenueFromContractWithCustomerExcludingAssessedTax" id="Fact_397eed8f6b004e30bfacdacc310446cf" contextRef="c20201001to20201231_TypeOfArrangementAxis_AlnylamCollaborationMember" unitRef="U001" decimals="-5" scale="6" format="ixt:numdotdecimal">41.2</ix:nonFraction> million payment from Alnylam as revenue in the fourth quarter of 2020 because we did not have any performance obligations for the respective payment.</div>
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<div style="display:none;"><br /></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">During the years ended December 31, <span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">2021</span>, <span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">2020</span> and <span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">2019</span>, we
      earned the following revenue from our relationship with Alnylam (in millions, except percentage amounts):</div>
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        </td>

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          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Year Ended December 31,</div>
        </td>

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    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;" colspan="1">&#160;</td>

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          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2021</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" colspan="2">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2020</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" colspan="2">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2019</div>
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          <div style="text-align: left; text-indent: -27pt; margin-left: 27pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">R&amp;D revenue</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:RevenueFromContractWithCustomerExcludingAssessedTax" id="Fact_45285d7fd8354da4a078a4a11aba04ee" contextRef="c20210101to20211231_ProductOrServiceAxis_ResearchAndDevelopmentRevenueUnderCollaborativeAgreementsMember_TypeOfArrangementAxis_AlnylamCollaborationMember" unitRef="U001" decimals="-6" scale="6" format="ixt:zerodash">&#8212;</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

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          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:RevenueFromContractWithCustomerExcludingAssessedTax" id="Fact_234485bc14344d888b7bed969bbbb34c" contextRef="c20200101to20201231_ProductOrServiceAxis_ResearchAndDevelopmentRevenueUnderCollaborativeAgreementsMember_TypeOfArrangementAxis_AlnylamCollaborationMember" unitRef="U001" decimals="-5" scale="6" format="ixt:numdotdecimal">47.9</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:RevenueFromContractWithCustomerExcludingAssessedTax" id="Fact_bce450e4b0344107ac0e55460c018791" contextRef="c20190101to20191231_ProductOrServiceAxis_ResearchAndDevelopmentRevenueUnderCollaborativeAgreementsMember_TypeOfArrangementAxis_AlnylamCollaborationMember" unitRef="U001" decimals="-5" scale="6" format="ixt:numdotdecimal">24.1</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

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    <td valign="bottom" style="vertical-align: bottom; width: 64%;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Percentage of total revenue</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:ConcentrationRiskPercentage1" id="Fact_2cfe3b7062dc4a9cb5ee360d01476480" contextRef="c20210101to20211231_ConcentrationRiskByBenchmarkAxis_RevenueFromContractWithCustomerMember_ConcentrationRiskByTypeAxis_CustomerConcentrationRiskMember_TypeOfArrangementAxis_AlnylamCollaborationMember" unitRef="U003" decimals="0" scale="-2" format="ixt:zerodash">&#8212;</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:ConcentrationRiskPercentage1" id="Fact_ab0a985934234f8bb07ff855cb4f906d" contextRef="c20200101to20201231_ConcentrationRiskByBenchmarkAxis_RevenueFromContractWithCustomerMember_ConcentrationRiskByTypeAxis_CustomerConcentrationRiskMember_TypeOfArrangementAxis_AlnylamCollaborationMember" unitRef="U003" decimals="2" scale="-2" format="ixt:numdotdecimal">7</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">%</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:ConcentrationRiskPercentage1" id="Fact_bd1c6a81db934c3e9265b1322ef276f8" contextRef="c20190101to20191231_ConcentrationRiskByBenchmarkAxis_RevenueFromContractWithCustomerMember_ConcentrationRiskByTypeAxis_CustomerConcentrationRiskMember_TypeOfArrangementAxis_AlnylamCollaborationMember" unitRef="U003" decimals="2" scale="-2" format="ixt:numdotdecimal">2</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">%</div>
        </td>

  </tr>


</table>
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  </div>
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<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We did <ix:nonFraction name="us-gaap:ContractWithCustomerLiability" id="Fact_87589be5c6de472fa7c2f37215199412" contextRef="c20201231_TypeOfArrangementAxis_AlnylamCollaborationMember" unitRef="U001" decimals="-6" scale="6" format="ixt-sec:numwordsen"><ix:nonFraction name="us-gaap:ContractWithCustomerLiability" id="Fact_12c9599416c543e7890f0ee3f45418ed" contextRef="c20211231_TypeOfArrangementAxis_AlnylamCollaborationMember" unitRef="U001" decimals="-6" scale="6" format="ixt-sec:numwordsen">no</ix:nonFraction></ix:nonFraction>t
    have any deferred revenue from our relationship with Alnylam at December 31, 2021 and 2020.</div>
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<div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">7. Akcea Merger</div>
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<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;">Purchase Price and Direct Transaction Costs Accounting for the Akcea Merger</div>
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<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">In October 2020, we reacquired the shares of Akcea&#8217;s common stock we did not own, increasing our ownership from <ix:nonFraction name="us-gaap:MinorityInterestOwnershipPercentageByParent" id="Fact_b6feac506d324b98951f0933ce40dd67" contextRef="c20200930_OwnershipAxis_AkceaTherapeuticsIncMember" unitRef="U003" decimals="2" scale="-2" format="ixt:numdotdecimal">76</ix:nonFraction> percent to <ix:nonFraction name="us-gaap:MinorityInterestOwnershipPercentageByParent" id="Fact_33b44fc190674e72a94a538abf61155f" contextRef="c20201031_OwnershipAxis_AkceaTherapeuticsIncMember" unitRef="U003" decimals="2" scale="-2" format="ixt:numdotdecimal">100</ix:nonFraction> percent. Under the purchase
    agreement, we purchased <ix:nonFraction name="ions:ConsolidationLessThanWhollyOwnedSubsidiaryParentOwnershipInterestChangesPurchaseOfInterestByParentShares" id="Fact_24aa2fc2d1384378a728edf162abb8fb" contextRef="c20201001to20201031_OwnershipAxis_AkceaTherapeuticsIncMember" unitRef="U002" decimals="-5" scale="6" format="ixt:numdotdecimal">24.8</ix:nonFraction> million shares at $<ix:nonFraction name="ions:ConsolidationLessThanWhollyOwnedSubsidiaryParentOwnershipInterestChangesPurchaseOfInterestByParentPricePerShare" id="Fact_fa704d2a69a948088d5d227df198df4e" contextRef="c20201001to20201031_OwnershipAxis_AkceaTherapeuticsIncMember" unitRef="U004" decimals="2" scale="0" format="ixt:numdotdecimal">18.15</ix:nonFraction>
    per share, resulting in a total purchase price of $<ix:nonFraction name="us-gaap:ConsolidationLessThanWhollyOwnedSubsidiaryParentOwnershipInterestChangesPurchaseOfInterestByParent" id="Fact_2e6fddec0b5647c1862613421ea983f3" contextRef="c20201001to20201031_OwnershipAxis_AkceaTherapeuticsIncMember" unitRef="U001" decimals="-5" scale="6" format="ixt:numdotdecimal">450.6</ix:nonFraction> million.</div>
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<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">To reflect our <ix:nonFraction name="us-gaap:MinorityInterestOwnershipPercentageByParent" id="Fact_43cd203825e04ef79c3027298eeb9ffa" contextRef="c20201031_OwnershipAxis_AkceaTherapeuticsIncMember" unitRef="U003" decimals="2" scale="-2" format="ixt:numdotdecimal">100</ix:nonFraction> percent
    ownership, we accounted for the increase in our ownership by eliminating the noncontrolling interest adjustment in stockholders&#8217; equity in accordance with the Consolidation accounting guidance (ASC Topic 810). We recognized the difference between the
    purchase price and the adjustment to noncontrolling interest in stockholders&#8217; equity as additional-paid-in capital. Refer to our <span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Statement of
      Stockholders&#8217; Equity</span> for detailed amounts.</div>
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  </div>
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<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We accounted for the transaction costs related to the Akcea Merger as a direct charge to stockholders&#8217; equity. We incurred
    $<ix:nonFraction name="us-gaap:BusinessAcquisitionCostOfAcquiredEntityTransactionCosts" id="Fact_0884cfbdf1684305809ccf99311b4099" contextRef="c20201231_OwnershipAxis_AkceaTherapeuticsIncMember" unitRef="U001" decimals="-5" scale="6" format="ixt:numdotdecimal">40.6</ix:nonFraction> million of direct transaction costs from the Akcea Merger, primarily comprised of banking and legal fees.</div>
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<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;">Equity Award Payouts related to the Akcea Merger</div>
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  </div>
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<div style="display:none;"><br /></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">In October 2020, as part of the Akcea Merger,
      Ionis cancelled all of Akcea&#8217;s equity awards. In exchange for the cancelled awards, if eligible under the terms of the Akcea Merger, we paid holder&#8217;s a cash payment. We paid $</span><ix:nonFraction name="ions:CashPurchasePriceOfEquityAwards" id="Fact_638c1e20e6404ff4aa52f098c6deb05d" contextRef="c20201001to20201231_OwnershipAxis_AkceaTherapeuticsIncMember" unitRef="U004" decimals="2" scale="0" format="ixt:numdotdecimal">18.15</ix:nonFraction><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> for each outstanding RSU. For each outstanding option with an exercise price less than $</span><ix:nonFraction name="ions:CashPurchasePriceOfEquityAwards" id="Fact_b89bdecf0fa14315963911cf431521b4" contextRef="c20201001to20201231_OwnershipAxis_AkceaTherapeuticsIncMember" unitRef="U004" decimals="2" scale="0" format="ixt:numdotdecimal">18.15</ix:nonFraction><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">, we paid $</span><ix:nonFraction name="ions:CashPurchasePriceOfEquityAwards" id="Fact_99ca9852ab9f4ad6ae3ea6c3a7b75b3b" contextRef="c20201001to20201231_OwnershipAxis_AkceaTherapeuticsIncMember" unitRef="U004" decimals="2" scale="0" format="ixt:numdotdecimal">18.15</ix:nonFraction><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> less the exercise price. As a result, we paid out $</span><ix:nonFraction name="ions:PaymentsForCancelledEquityAwards" id="Fact_aab524f795c14b308413d9edfc049700" contextRef="c20201001to20201231_OwnershipAxis_AkceaTherapeuticsIncMember" unitRef="U001" decimals="-5" scale="6" format="ixt:numdotdecimal">53.4</ix:nonFraction><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> million in the fourth quarter of 2020 related to Akcea&#8217;s
      cancelled equity awards. We accounted for these payments as part of the transaction costs recorded to stockholders&#8217; equity in the fourth quarter of 2020. </span>Because we did not replace the Akcea awards, we recognized all unrecognized non-cash
    stock-based compensation ($<ix:nonFraction name="us-gaap:EmployeeServiceShareBasedCompensationNonvestedAwardsTotalCompensationCostNotYetRecognizedShareBasedAwardsOtherThanOptions" id="Fact_46135659ff5e45719f62bc97882f97ae" contextRef="c20201031_OwnershipAxis_AkceaTherapeuticsIncMember" unitRef="U001" decimals="-5" scale="6" format="ixt:numdotdecimal">59.3</ix:nonFraction> million) under Akcea&#8217;s Plan in our statement of operations in the post-merger period in the fourth quarter of
    2020.</div>
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<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;">Severance and Retention Costs related to the Akcea Merger</div>
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<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">As a result of the Akcea Merger, we incurred severance and retention expenses of $<ix:nonFraction name="ions:RestructuringReserveRestructuringChargesNetOfReserveAdjustments" id="Fact_9dc8f2fc62ba4f10b141ceb5929b5e78" contextRef="c20200101to20211231_RestructuringCostAndReserveAxis_AkceaMergerMember" unitRef="U001" decimals="-5" scale="6" format="ixt:numdotdecimal">27.0</ix:nonFraction> million. During 2021 and 2020, we recorded $<ix:nonFraction name="ions:RestructuringReserveRestructuringChargesNetOfReserveAdjustments" id="Fact_17e8057efb034b5e9a107d550fa5913d" contextRef="c20210101to20211231_RestructuringCostAndReserveAxis_AkceaMergerMember" unitRef="U001" decimals="-5" scale="6" format="ixt:numdotdecimal">11.7</ix:nonFraction> million and $<ix:nonFraction name="ions:RestructuringReserveRestructuringChargesNetOfReserveAdjustments" id="Fact_c4276bcb84694590920af5733a7570a2" contextRef="c20200101to20201231_RestructuringCostAndReserveAxis_AkceaMergerMember" unitRef="U001" decimals="-5" scale="6" format="ixt:numdotdecimal">15.3</ix:nonFraction> million of severance and retention related costs in operating expenses, respectively. As of December 31, 2021, we have recognized all severance and
    retention costs related to the Akcea Merger.</div>
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  </div>
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<div style="display:none;"><br /></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">The following table summarizes the severance and retention expenses related to the Akcea Merger that we recognized for the periods indicated (in
    millions):</div>
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<div style="text-align: justify;"><br />
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    <td valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px; white-space: nowrap;" colspan="2">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Year Ended</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">December 31, 2021</div>
        </td>

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    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: top; border-bottom: #000000 solid 2px; white-space: nowrap;" colspan="2">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Year Ended</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">December 31, 2020</div>
        </td>

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    <td valign="bottom" style="vertical-align: bottom; width: 76%; background-color: #CCEEFF;">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">R&amp;D expenses</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="ions:RestructuringReserveRestructuringChargesNetOfReserveAdjustments" id="Fact_febc887acb154a2096e6c78a34299562" contextRef="c20210101to20211231_IncomeStatementLocationAxis_ResearchDevelopmentAndPatentExpensesMember_RestructuringCostAndReserveAxis_AkceaMergerMember" unitRef="U001" decimals="-5" scale="6" format="ixt:numdotdecimal">5.1</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="ions:RestructuringReserveRestructuringChargesNetOfReserveAdjustments" id="Fact_9ddf2e0188374f1daefdbbef6a522a28" contextRef="c20200101to20201231_IncomeStatementLocationAxis_ResearchDevelopmentAndPatentExpensesMember_RestructuringCostAndReserveAxis_AkceaMergerMember" unitRef="U001" decimals="-5" scale="6" format="ixt:numdotdecimal">3.9</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 76%; padding-bottom: 2px;">
          <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">SG&amp;A expenses</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="ions:RestructuringReserveRestructuringChargesNetOfReserveAdjustments" id="Fact_aa810121bcdf4228a2ff77e14b9f4c13" contextRef="c20210101to20211231_IncomeStatementLocationAxis_SellingGeneralAndAdministrativeExpensesMember_RestructuringCostAndReserveAxis_AkceaMergerMember" unitRef="U001" decimals="-5" scale="6" format="ixt:numdotdecimal">6.6</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="ions:RestructuringReserveRestructuringChargesNetOfReserveAdjustments" id="Fact_686b0ca56658464eb2900e9f087287bf" contextRef="c20200101to20201231_IncomeStatementLocationAxis_SellingGeneralAndAdministrativeExpensesMember_RestructuringCostAndReserveAxis_AkceaMergerMember" unitRef="U001" decimals="-5" scale="6" format="ixt:numdotdecimal">11.4</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 76%; padding-bottom: 4px; background-color: #CCEEFF;">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Total</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="ions:RestructuringReserveRestructuringChargesNetOfReserveAdjustments" id="Fact_5267ae8a6c9048f194b468790252e312" contextRef="c20210101to20211231_RestructuringCostAndReserveAxis_AkceaMergerMember" unitRef="U001" decimals="-5" scale="6" format="ixt:numdotdecimal">11.7</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="ions:RestructuringReserveRestructuringChargesNetOfReserveAdjustments" id="Fact_7ce28f43d950414185842f81fa633a12" contextRef="c20200101to20201231_RestructuringCostAndReserveAxis_AkceaMergerMember" unitRef="U001" decimals="-5" scale="6" format="ixt:numdotdecimal">15.3</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

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</table>
</ix:continuation></ix:continuation>
  <ix:continuation id="Text_80189c1db12b4c5cb4d361d6c7e906f221" continuedAt="Text_80189c1db12b4c5cb4d361d6c7e906f222"><ix:continuation id="Text_81f5b42511364b789485db58bad8b9393" continuedAt="Text_81f5b42511364b789485db58bad8b9394">
<div><br />
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</ix:continuation></ix:continuation>
  <ix:continuation id="Text_80189c1db12b4c5cb4d361d6c7e906f222" continuedAt="Text_80189c1db12b4c5cb4d361d6c7e906f223"><ix:continuation id="Text_81f5b42511364b789485db58bad8b9394" continuedAt="Text_81f5b42511364b789485db58bad8b9395">
<div style="display:none;"><br /></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">The following table summarizes the severance and retention reserve amounts related to the Akcea Merger that we included in
    accrued compensation for the period indicated (in millions):</div>
</ix:continuation></ix:continuation>
  <ix:continuation id="Text_80189c1db12b4c5cb4d361d6c7e906f223" continuedAt="Text_80189c1db12b4c5cb4d361d6c7e906f224"><ix:continuation id="Text_81f5b42511364b789485db58bad8b9395" continuedAt="Text_81f5b42511364b789485db58bad8b9396">
<div style="text-align: justify;"><br />
  </div>
</ix:continuation></ix:continuation>
  <ix:continuation id="Text_80189c1db12b4c5cb4d361d6c7e906f224" continuedAt="Text_80189c1db12b4c5cb4d361d6c7e906f225"><ix:continuation id="Text_81f5b42511364b789485db58bad8b9396">
<table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;" class="cfttable">


  <tr>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">

        </td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px; white-space: nowrap;" colspan="2">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Year Ended</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">December 31, 2021</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: top; width: 88%; background-color: #CCEEFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Beginning balance as of January 1, 2021</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:RestructuringReserve" id="Fact_ddb95474499a43a38b47938bf73480f8" contextRef="c20201231_RestructuringCostAndReserveAxis_AkceaMergerMember" unitRef="U001" decimals="-5" scale="6" format="ixt:numdotdecimal">14.7</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: top; width: 88%;">
          <div style="text-align: left; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Amount expensed during the year</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:RestructuringCharges" id="Fact_6349ba4bb4b4466abf67737ff5b1a129" contextRef="c20210101to20211231_RestructuringCostAndReserveAxis_AkceaMergerMember" unitRef="U001" decimals="-5" scale="6" format="ixt:numdotdecimal">13.5</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: top; width: 88%; padding-bottom: 2px; background-color: #CCEEFF;">
          <div style="text-align: left; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Reserve adjustments during the year</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:RestructuringReserveAccrualAdjustment1" id="Fact_f44ed763b00d46f8a5765bbb38fc34bb" contextRef="c20210101to20211231_RestructuringCostAndReserveAxis_AkceaMergerMember" unitRef="U001" decimals="-5" scale="6" sign="-" format="ixt:numdotdecimal">1.8</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: top; width: 88%;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Net amount expensed during the year</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="ions:RestructuringReserveRestructuringChargesNetOfReserveAdjustments" id="Fact_5fbc61de046749099f79490d5b047b01" contextRef="c20210101to20211231_RestructuringCostAndReserveAxis_AkceaMergerMember" unitRef="U001" decimals="-5" scale="6" format="ixt:numdotdecimal">11.7</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: top; width: 88%; padding-bottom: 2px; background-color: #CCEEFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Amounts paid during the year</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:PaymentsForRestructuring" id="Fact_acf2ca61eec14bb09de39ff3d9e1b693" contextRef="c20210101to20211231_RestructuringCostAndReserveAxis_AkceaMergerMember" unitRef="U001" decimals="-5" scale="6" format="ixt:numdotdecimal">26.4</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: top; width: 88%; padding-bottom: 4px;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Ending balance as of December 31, 2021</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:RestructuringReserve" id="Fact_27fe87e1582140b9aa3324f6571bc35e" contextRef="c20211231_BalanceSheetLocationAxis_EmployeeRelatedLiabilitiesCurrentMember_RestructuringCostAndReserveAxis_AkceaMergerMember" unitRef="U001" decimals="-6" scale="6" format="ixt:zerodash">&#8212;</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>


</table>
</ix:continuation></ix:continuation>
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<div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 12pt;"><br />
  </div>
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  <ix:continuation id="Text_80189c1db12b4c5cb4d361d6c7e906f226">
<div style="display:none;"><br /></div>
<div style="text-align: left; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">The reserve adjustments during the period primarily related to forfeitures of severance and retention payments as a result of employee
    terminations before they earned the amounts.</div>
</ix:continuation></div>

  <div><br />
  </div>

  <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" class="DSPFPageBreakArea">
    <div class="DSPFPageFooter">
      <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">F-<span class="DSPFPageNumber">51</span></div>

    </div>

    <div style="page-break-after:always;" class="DSPFPageBreak">
      <hr style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;" /></div>


  </div>

  <div><br />
  </div>
<div><ix:nonNumeric name="us-gaap:RestructuringAndRelatedActivitiesDisclosureTextBlock" id="Text_3f4d5297b795400889f0ddde0601a0de" contextRef="c20210101to20211231" escape="true" continuedAt="Text_aadd9af0dbf5450794adb0c1f728f2fa1">
<div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">8. Severance and Retention Costs related to our
    Restructured Operations</div>
</ix:nonNumeric>

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<div><br />
  </div>
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  <ix:continuation id="Text_aadd9af0dbf5450794adb0c1f728f2fa2" continuedAt="Text_aadd9af0dbf5450794adb0c1f728f2fa3">
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<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;">Restructured European Operations</div>
</ix:continuation>
  <ix:continuation id="Text_aadd9af0dbf5450794adb0c1f728f2fa3" continuedAt="Text_aadd9af0dbf5450794adb0c1f728f2fa4">
<div><br />
  </div>
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  <ix:continuation id="Text_aadd9af0dbf5450794adb0c1f728f2fa4" continuedAt="Text_aadd9af0dbf5450794adb0c1f728f2fa5">
<div style="display:none;"><br /></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">In the fourth quarter of 2020, </span>we
    entered into a distribution agreement with Sobi to commercialize TEGSEDI and WAYLIVRA in Europe. Under the distribution agreement, Sobi took over all material distribution operations at the end of January 2021. <span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">We remain the marketing authorization holder for TEGSEDI and WAYLIVRA in Europe. We will continue to maintain limited European operations including regulatory, manufacturing, and the
      management of relationships with key opinion leaders. We will also continue to lead the TEGSEDI and WAYLIVRA global commercial strategy.</span></div>
</ix:continuation>
  <ix:continuation id="Text_aadd9af0dbf5450794adb0c1f728f2fa5" continuedAt="Text_aadd9af0dbf5450794adb0c1f728f2fa6">
<div><br />
  </div>
</ix:continuation>
  <ix:continuation id="Text_aadd9af0dbf5450794adb0c1f728f2fa6" continuedAt="Text_aadd9af0dbf5450794adb0c1f728f2fa7">
<div style="display:none;"><br /></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">As a result of this change, we incurred severance and retention expenses of $<ix:nonFraction name="ions:RestructuringReserveRestructuringChargesNetOfReserveAdjustments" id="Fact_255deee8e5ea4dea982e26bddc094e71" contextRef="c20200101to20211231_RestructuringCostAndReserveAxis_UpdatedEuropeanDistributionModelEmployeeSeveranceAndRetentionMember" unitRef="U001" decimals="-5" scale="6" format="ixt:numdotdecimal">14.2</ix:nonFraction> million. During 2021 and 2020, we recorded $<ix:nonFraction name="ions:RestructuringReserveRestructuringChargesNetOfReserveAdjustments" id="Fact_286ef7c4c3864cf693bd0a9e320cc095" contextRef="c20210101to20211231_RestructuringCostAndReserveAxis_UpdatedEuropeanDistributionModelEmployeeSeveranceAndRetentionMember" unitRef="U001" decimals="-5" scale="6" format="ixt:numdotdecimal">1.7</ix:nonFraction> million and $<ix:nonFraction name="ions:RestructuringReserveRestructuringChargesNetOfReserveAdjustments" id="Fact_3d03331e3cbe4b0eab5e2342db5f3416" contextRef="c20200101to20201231_RestructuringCostAndReserveAxis_UpdatedEuropeanDistributionModelEmployeeSeveranceAndRetentionMember" unitRef="U001" decimals="-5" scale="6" format="ixt:numdotdecimal">12.5</ix:nonFraction> million of severance and retention related costs in operating expenses, respectively. As of December 31, 2021, we have recognized all severance and
    retention costs related to this agreement.</div>
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<div><br />
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<div style="display:none;"><br /></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">The following table summarizes the
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</ix:nonNumeric></ix:continuation>
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    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

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          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Year Ended</div>
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

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          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Year Ended</div>
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

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  <tr>

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    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

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    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

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  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 76%; padding-bottom: 2px;">
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    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="ions:RestructuringReserveRestructuringChargesNetOfReserveAdjustments" id="Fact_c7659df7d8e24a69a2a02b1e7bfbdbf0" contextRef="c20210101to20211231_IncomeStatementLocationAxis_SellingGeneralAndAdministrativeExpensesMember_RestructuringCostAndReserveAxis_UpdatedEuropeanDistributionModelEmployeeSeveranceAndRetentionMember" unitRef="U001" decimals="-5" scale="6" format="ixt:numdotdecimal">1.1</ix:nonFraction></div>
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" colspan="1">
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

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  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 76%; padding-bottom: 4px; background-color: #CCEEFF;">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Total</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" colspan="1">
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="ions:RestructuringReserveRestructuringChargesNetOfReserveAdjustments" id="Fact_a43ddb29236547c089942a095b86e34d" contextRef="c20200101to20201231_RestructuringCostAndReserveAxis_UpdatedEuropeanDistributionModelEmployeeSeveranceAndRetentionMember" unitRef="U001" decimals="-5" scale="6" format="ixt:numdotdecimal">12.5</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

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</ix:continuation></ix:continuation>
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<div><br />
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</ix:continuation></ix:continuation>
  <ix:continuation id="Text_aadd9af0dbf5450794adb0c1f728f2fa12" continuedAt="Text_aadd9af0dbf5450794adb0c1f728f2fa13"><ix:continuation id="Text_d68d6bf1dbc64f77ad4b377cf7a02ad74" continuedAt="Text_d68d6bf1dbc64f77ad4b377cf7a02ad75">
<div style="display:none;"><br /></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">The following table summarizes the severance and retention reserve amounts related to our restructured European operations
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</ix:continuation></ix:continuation>
  <ix:continuation id="Text_aadd9af0dbf5450794adb0c1f728f2fa13" continuedAt="Text_aadd9af0dbf5450794adb0c1f728f2fa14"><ix:continuation id="Text_d68d6bf1dbc64f77ad4b377cf7a02ad75" continuedAt="Text_d68d6bf1dbc64f77ad4b377cf7a02ad76">
<div style="text-align: justify;"><br />
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</ix:continuation></ix:continuation>
  <ix:continuation id="Text_aadd9af0dbf5450794adb0c1f728f2fa14" continuedAt="Text_aadd9af0dbf5450794adb0c1f728f2fa15"><ix:continuation id="Text_d68d6bf1dbc64f77ad4b377cf7a02ad76">
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  <tr>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">

        </td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px; white-space: nowrap;" colspan="2">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Year Ended</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">December 31, 2021</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: top; width: 88%; background-color: #CCEEFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Beginning balance as of January 1, 2021</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:RestructuringReserve" id="Fact_26f6f63703954ae4accd6d0e9d240582" contextRef="c20201231_RestructuringCostAndReserveAxis_UpdatedEuropeanDistributionModelEmployeeSeveranceAndRetentionMember" unitRef="U001" decimals="-5" scale="6" format="ixt:numdotdecimal">12.4</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: top; width: 88%;">
          <div style="text-align: left; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Amount expensed during the year</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:RestructuringCharges" id="Fact_12a42f612142481a9865c292163a91c0" contextRef="c20210101to20211231_RestructuringCostAndReserveAxis_UpdatedEuropeanDistributionModelEmployeeSeveranceAndRetentionMember" unitRef="U001" decimals="-5" scale="6" format="ixt:numdotdecimal">2.6</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: top; width: 88%; padding-bottom: 2px; background-color: #CCEEFF;">
          <div style="text-align: left; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Reserve adjustments during the year</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:RestructuringReserveAccrualAdjustment1" id="Fact_1717775bf90e41729ce18f3679cbed4a" contextRef="c20210101to20211231_RestructuringCostAndReserveAxis_UpdatedEuropeanDistributionModelEmployeeSeveranceAndRetentionMember" unitRef="U001" decimals="-5" scale="6" sign="-" format="ixt:numdotdecimal">0.9</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: top; width: 88%;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Net amount expensed during the year</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; white-space: nowrap;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: top; width: 88%; padding-bottom: 2px; background-color: #CCEEFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Amounts paid during the year</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:PaymentsForRestructuring" id="Fact_c38415c26dd94d25a0c0ff3efd472687" contextRef="c20210101to20211231_RestructuringCostAndReserveAxis_UpdatedEuropeanDistributionModelEmployeeSeveranceAndRetentionMember" unitRef="U001" decimals="-5" scale="6" format="ixt:numdotdecimal">14.1</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: top; width: 88%; padding-bottom: 4px;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Ending balance as of December 31, 2021</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:RestructuringReserve" id="Fact_5b05d6317d8e42bcba8d2972aebfd185" contextRef="c20211231_RestructuringCostAndReserveAxis_UpdatedEuropeanDistributionModelEmployeeSeveranceAndRetentionMember" unitRef="U001" decimals="-6" scale="6" format="ixt:zerodash">&#8212;</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>


</table>
</ix:continuation></ix:continuation>
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<div style="text-align: left;"><br />
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</ix:continuation>
  <ix:continuation id="Text_aadd9af0dbf5450794adb0c1f728f2fa16" continuedAt="Text_aadd9af0dbf5450794adb0c1f728f2fa17">
<div style="display:none;"><br /></div>
<div style="text-align: left; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">The reserve adjustments during the period primarily related to tax expense adjustments.</div>
</ix:continuation>
  <ix:continuation id="Text_aadd9af0dbf5450794adb0c1f728f2fa17" continuedAt="Text_aadd9af0dbf5450794adb0c1f728f2fa18">
<div><br />
  </div>
</ix:continuation>
  <ix:continuation id="Text_aadd9af0dbf5450794adb0c1f728f2fa18" continuedAt="Text_aadd9af0dbf5450794adb0c1f728f2fa19">
<div style="display:none;"><br /></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;">Restructured North American TEGSEDI Operations</div>
</ix:continuation>
  <ix:continuation id="Text_aadd9af0dbf5450794adb0c1f728f2fa19" continuedAt="Text_aadd9af0dbf5450794adb0c1f728f2fa20">
<div><br />
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</ix:continuation>
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<div style="display:none;"><br /></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">In April 2021, we entered into a distribution agreement with Sobi for TEGSEDI in North America. Under the terms of the
    distribution agreement, we will retain the marketing authorizations for TEGSEDI in the U.S. and Canada. We will continue to supply commercial product to Sobi and manage regulatory and manufacturing processes, as well as relationships with key opinion
    leaders. We will also continue to lead the TEGSEDI global commercial strategy. Sobi will otherwise have responsibility for commercializing TEGSEDI in the U.S. and Canada.</div>
</ix:continuation>
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  </div>
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<div style="display:none;"><br /></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">In connection with restructuring our North American TEGSEDI operations, or Restructured North American TEGSEDI Operations,
    we enacted a plan to reorganize our Akcea workforce in North America to better align with the needs of our business and to focus on our wholly owned pipeline.</div>
</ix:continuation></div>

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    </div>

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  </div>
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<div style="display:none;"><br /></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">The following table summarizes the severance expenses related to our
    Restructured North American TEGSEDI Operations that we recognized for the period indicated (in millions):</div>
</ix:nonNumeric></ix:continuation>
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<div style="text-align: justify;"><br />
  </div>
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  <tr>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">

        </td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px; white-space: nowrap;" colspan="2">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Year Ended</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">December 31, 2021</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 88%; background-color: #CCEEFF;">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">R&amp;D expenses</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:RestructuringCharges" id="Fact_af55dde53acc4ad79c91fa58bb7992ee" contextRef="c20210101to20211231_IncomeStatementLocationAxis_ResearchDevelopmentAndPatentExpensesMember_RestructuringCostAndReserveAxis_RestructuredNorthAmericanTegsediOperationsMember" unitRef="U001" decimals="-5" scale="6" format="ixt:numdotdecimal">2.3</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 88%; padding-bottom: 2px;">
          <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">SG&amp;A expenses</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:RestructuringCharges" id="Fact_125a7995b2084fc681531cbc38a2ed21" contextRef="c20210101to20211231_IncomeStatementLocationAxis_SellingGeneralAndAdministrativeExpensesMember_RestructuringCostAndReserveAxis_RestructuredNorthAmericanTegsediOperationsMember" unitRef="U001" decimals="-5" scale="6" format="ixt:numdotdecimal">7.1</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 88%; padding-bottom: 4px; background-color: #CCEEFF;">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Total</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:RestructuringCharges" id="Fact_eabbcfa223474dff907437a5eb0f17e4" contextRef="c20210101to20211231_RestructuringCostAndReserveAxis_RestructuredNorthAmericanTegsediOperationsMember" unitRef="U001" decimals="-5" scale="6" format="ixt:numdotdecimal">9.4</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>


</table>
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  </div>
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<div style="display:none;"><br /></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We recognized all severance expenses related to our Restructured North American
    TEGSEDI Operations during the three months ended June 30, 2021.</div>
</ix:continuation>
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<div><br />
  </div>
</ix:continuation>
  <ix:continuation id="Text_aadd9af0dbf5450794adb0c1f728f2fa30" continuedAt="Text_aadd9af0dbf5450794adb0c1f728f2fa31"><ix:continuation id="Text_587bee33973d4d2bb6a2d4f2f8d3d74e4" continuedAt="Text_587bee33973d4d2bb6a2d4f2f8d3d74e5">
<div style="display:none;"><br /></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">The following table summarizes the severance reserve amounts related to our
    Restructured North American TEGSEDI Operations that we included in accrued compensation for the period indicated (in millions):</div>
</ix:continuation></ix:continuation>
  <ix:continuation id="Text_aadd9af0dbf5450794adb0c1f728f2fa31" continuedAt="Text_aadd9af0dbf5450794adb0c1f728f2fa32"><ix:continuation id="Text_587bee33973d4d2bb6a2d4f2f8d3d74e5" continuedAt="Text_587bee33973d4d2bb6a2d4f2f8d3d74e6">
<div style="text-align: justify;"><br />
  </div>
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    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">

        </td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px; white-space: nowrap;" colspan="2">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Year Ended</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">December 31, 2021</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: top; width: 88%; background-color: #CCEEFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Beginning balance as of January 1, 2021</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:RestructuringReserve" id="Fact_dc999c1500104db19468603b328342c4" contextRef="c20201231_RestructuringCostAndReserveAxis_RestructuredNorthAmericanTegsediOperationsMember" unitRef="U001" decimals="-6" scale="6" format="ixt:zerodash">&#8212;</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: top; width: 88%;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Net amount expensed during the year</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:RestructuringCharges" id="Fact_0c7a5220424847c799e6df1f74c0c897" contextRef="c20210101to20211231_RestructuringCostAndReserveAxis_RestructuredNorthAmericanTegsediOperationsMember" unitRef="U001" decimals="-5" scale="6" format="ixt:numdotdecimal">9.4</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: top; width: 88%; padding-bottom: 2px; background-color: #CCEEFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Amounts paid during the year</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:PaymentsForRestructuring" id="Fact_260154de61f54ac5babc0a112b5b0236" contextRef="c20210101to20211231_RestructuringCostAndReserveAxis_RestructuredNorthAmericanTegsediOperationsMember" unitRef="U001" decimals="-5" scale="6" format="ixt:numdotdecimal">9.4</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: top; width: 88%; padding-bottom: 4px;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Ending balance as of December 31, 2021</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:RestructuringReserve" id="Fact_4723e043c9f3473a9b3b847984c59b4f" contextRef="c20211231_RestructuringCostAndReserveAxis_RestructuredNorthAmericanTegsediOperationsMember" unitRef="U001" decimals="-6" scale="6" format="ixt:zerodash">&#8212;</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>


</table>
</ix:continuation></ix:continuation></div>

  <div style="text-align: left;"><br />
  </div>

  <div><br />
  </div>
<div><ix:nonNumeric name="us-gaap:PensionAndOtherPostretirementBenefitsDisclosureTextBlock" id="Text_44a1974bfba9485682c02d2913778f03" contextRef="c20210101to20211231" escape="true" continuedAt="Text_4914fbc6ccd04c6e987ed81fd8db50701">
<div style="text-align: justify; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">9. Employment Benefits</div>
</ix:nonNumeric>

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  </div>
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<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We have employee 401(k) salary deferral plans covering all employees. Employees could make contributions by withholding a
    percentage of their salary up to the IRS annual limits of $<ix:nonFraction name="us-gaap:DefinedContributionPlanMaximumAnnualContributionsPerEmployeeAmount" id="Fact_06c142c7ec1040e0b05c4b2596dfe112" contextRef="c20210101to20211231_RangeAxis_MinimumMember" unitRef="U001" decimals="0" scale="0" format="ixt:numdotdecimal">20,500</ix:nonFraction> and $<ix:nonFraction name="us-gaap:DefinedContributionPlanMaximumAnnualContributionsPerEmployeeAmount" id="Fact_2703ad6213db4e249c38d0794a2c6418" contextRef="c20210101to20211231_RangeAxis_MaximumMember" unitRef="U001" decimals="0" scale="0" format="ixt:numdotdecimal">27,000</ix:nonFraction> in 2021 for employees under 50 years old and employees 50 years old or over,
    respectively. We made approximately $<ix:nonFraction name="us-gaap:DefinedContributionPlanCostRecognized" id="Fact_345fd7748408424580894d7cb0e0e108" contextRef="c20210101to20211231" unitRef="U001" decimals="-5" scale="6" format="ixt:numdotdecimal">5.5</ix:nonFraction> million, $<ix:nonFraction name="us-gaap:DefinedContributionPlanCostRecognized" id="Fact_47a2898dc66b4221ba3a2d92c2c0643a" contextRef="c20200101to20201231" unitRef="U001" decimals="-5" scale="6" format="ixt:numdotdecimal">5.7</ix:nonFraction>
    million and $<ix:nonFraction name="us-gaap:DefinedContributionPlanCostRecognized" id="Fact_0c0b367e1550466b886c0390a13e1e0f" contextRef="c20190101to20191231" unitRef="U001" decimals="-5" scale="6" format="ixt:numdotdecimal">6.4</ix:nonFraction> million in matching contributions for the years ended December 31, 2021, 2020 and 2019, respectively.</div>
</ix:continuation></div>

  <div><br />
  </div>
<div><ix:nonNumeric name="us-gaap:LegalMattersAndContingenciesTextBlock" id="Text_656730b2a28e4e958b751e639ff66fd5" contextRef="c20210101to20211231" escape="true" continuedAt="Text_0ed932db704c4ae993a58011a1d2fc501">
<div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">10. Legal Proceedings</div>
</ix:nonNumeric>

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  </div>
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<div style="display:none;"><br /></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">From time to time, we are involved in legal proceedings arising in the ordinary course of our business. Periodically, we
    evaluate the status of each legal matter and assess our potential financial exposure. If the potential loss from any legal proceeding is considered probable and the amount can be reasonably estimated, we accrue a liability for the estimated loss.
    Significant judgment is required to determine the probability of a loss and whether the amount of the loss is reasonably estimable. The outcome of any proceeding is not determinable in advance. As a result, the assessment of a potential liability and
    the amount of accruals recorded are based only on the information available to us at the time. As additional information becomes available, we reassess the potential liability related to the legal proceeding, and may revise our estimates.</div>
</ix:continuation>
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<div><br />
  </div>
</ix:continuation>
  <ix:continuation id="Text_0ed932db704c4ae993a58011a1d2fc504" continuedAt="Text_0ed932db704c4ae993a58011a1d2fc505">
<div style="display:none;"><br /></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">On August 5, 2021, </span><ix:nonFraction name="us-gaap:LossContingencyNumberOfPlaintiffs" id="Fact_7c35b15c9ad84e4db79ca2e02b038551" contextRef="c20210805to20210805_LitigationCaseAxis_JohnMakrisEtAlVIonisPharmaceuticalsIncEtAlMember" unitRef="U021" decimals="INF" scale="0" format="ixt-sec:numwordsen">four</ix:nonFraction><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> purported former stockholders of Akcea filed an action in the Delaware
      Court of Chancery captioned John Makris, et al. v. Ionis Pharmaceuticals, Inc., et al., C.A. No. 2021-0681, or the &#8220;Delaware Action.&#8221;&#160; The plaintiffs in the Delaware Action assert claims against (i) former members of Akcea&#8217;s board of directors; and
      (ii) Ionis, or collectively, the &#8220;Defendants.&#8221; The plaintiffs assert putatively direct claims on behalf of a purported class of former Akcea stockholders. The plaintiffs in the Delaware Action assert that the Defendants breached their fiduciary
      duties in connection with the October 2020 take-private transaction that we and Akcea entered into, in which Akcea became a wholly-owned subsidiary of Ionis. We believe that the claims asserted in the Delaware Action are without merit and filed a
      motion to dismiss the claims in November 2021. Briefing on the motion to dismiss is ongoing, and pursuant to an agreed-upon scheduling order that has been entered by the Court, argument on the motion to dismiss is expected later in the first quarter
      of 2022.</span></div>
</ix:continuation>
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<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">On January 19, 2022, a purported stockholder of Ionis filed a stockholder derivative complaint in the Delaware Court of Chancery captioned
    Leo Shumacher, et al. v. Joseph Loscalzo, et al., C.A. No. 2022-0059, or the &#8220;Action.&#8221; The complaint names as defendants the current members of Ionis&#8217; board of directors, collectively the Directors. The company is a nominal defendant. Plaintiff asserts
    a breach of fiduciary duty claim against the Directors for awarding and receiving allegedly excessive compensation. Plaintiff also asserts an unjust enrichment claim against the non-employee Directors as a result of the compensation they received. The
    complaint seeks, among other things, damages, restitution, attorneys&#8217; fees and costs, and such other relief as deemed just and proper by the court. Defendants have not yet responded to the complaint in this Action.</div>
</ix:continuation></div>

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    <div class="DSPFPageFooter">
      <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">F-<span class="DSPFPageNumber">53</span></div>

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      <hr style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;" /></div>


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<div><ix:nonNumeric name="us-gaap:QuarterlyFinancialInformationTextBlock" id="Text_4be6328593df49c295c60f8f5c9d4bc0" contextRef="c20210101to20211231" escape="true" continuedAt="Text_b62322fb4b8e47769522dc5a87bc7fb01">
<div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">11. Fourth Quarter Financial Data (Unaudited)</div>
</ix:nonNumeric>

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<div style="display:none;"><br /></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">The following financial information reflects all normal recurring adjustments, which are,
    in the opinion of management, necessary for a fair statement of the results of the interim periods. Summarized fourth quarter data for 2021
    and 2020 are as follows (in thousands, except per share data).</div>
</ix:nonNumeric></ix:continuation>
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          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Three Months Ended December 31,</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" colspan="2">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2021</div>
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;" colspan="1">&#160;</td>

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          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2020</div>
        </td>

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          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Revenue</div>
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    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:Revenues" id="Fact_284eab838adc45f1bab65fa3ed3e8a21" contextRef="c20211001to20211231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">440,006</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:Revenues" id="Fact_20e60632220f4799962c4c0ff5f00ab5" contextRef="c20201001to20201231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">290,281</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

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    <td valign="bottom" style="vertical-align: bottom; width: 76%;">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Operating expenses</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:CostsAndExpenses" id="Fact_b6f8e9fbc8074a218922e8576d906d68" contextRef="c20211001to20211231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">219,403</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:CostsAndExpenses" id="Fact_ef4a183f40c64bdd8dd30738366a5262" contextRef="c20201001to20201231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">312,945</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 76%; background-color: #CCEEFF;">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Income (loss) from operations</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:OperatingIncomeLoss" id="Fact_c3c0e5d7387e40eb92385001e70edef5" contextRef="c20211001to20211231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">220,603</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:OperatingIncomeLoss" id="Fact_e656146c3d254200b1d7c79c8135fb39" contextRef="c20201001to20201231" unitRef="U001" decimals="-3" scale="3" sign="-" format="ixt:numdotdecimal">22,664</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 76%;">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Net income (loss)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:ProfitLoss" id="Fact_64bf3d68a9a94552bd3463e1e35b0df2" contextRef="c20211001to20211231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">224,613</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:ProfitLoss" id="Fact_af25cdfae24542caac610d75303df0eb" contextRef="c20201001to20201231" unitRef="U001" decimals="-3" scale="3" sign="-" format="ixt:numdotdecimal">355,687</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 76%; background-color: #CCEEFF;">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Net income (loss) attributable to Ionis Pharmaceuticals, Inc. common stockholders</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:NetIncomeLoss" id="Fact_1e76c1964074458397b0d306a622dd8c" contextRef="c20211001to20211231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">224,613</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:NetIncomeLoss" id="Fact_7fcd3e2599a04e4e855a4af0afbf502f" contextRef="c20201001to20201231" unitRef="U001" decimals="-3" scale="3" sign="-" format="ixt:numdotdecimal">354,532</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 76%;">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Basic net income (loss) per share (1) (2)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:EarningsPerShareBasic" id="Fact_cd1a45a0547d47c59adf0ba90c1e5105" contextRef="c20211001to20211231" unitRef="U004" decimals="2" scale="0" format="ixt:numdotdecimal">1.59</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:EarningsPerShareBasic" id="Fact_bdec6ddb89aa427eb5832c982172b15b" contextRef="c20201001to20201231" unitRef="U004" decimals="2" sign="-" scale="0" format="ixt:numdotdecimal">2.54</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 76%; background-color: #CCEEFF;">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Diluted net income (loss) per share (1) (3)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:EarningsPerShareDiluted" id="Fact_a89ed465fb1d45109c8bb5281937ec8f" contextRef="c20211001to20211231" unitRef="U004" decimals="2" scale="0" format="ixt:numdotdecimal">1.41</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:EarningsPerShareDiluted" id="Fact_50ffd0d9a803420490859b8fc30d4b07" contextRef="c20201001to20201231" unitRef="U004" decimals="2" sign="-" scale="0" format="ixt:numdotdecimal">2.54</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

  </tr>


</table>
</ix:continuation></ix:continuation>
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<div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">________________</div>
</ix:continuation></ix:continuation>
  <ix:continuation id="Text_b62322fb4b8e47769522dc5a87bc7fb06" continuedAt="Text_b62322fb4b8e47769522dc5a87bc7fb07"><ix:continuation id="Text_cc36388daf204a4db4b1bfe0db12cf4b4" continuedAt="Text_cc36388daf204a4db4b1bfe0db12cf4b5">
<table cellspacing="0" cellpadding="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">


  <tr>

    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(1)</td>

    <td style="width: auto; vertical-align: top; text-align: left;">
          <div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:footnote id="Foot_260ceacf638c4b6691c7c678cfe81725" footnoteRole="http://www.xbrl.org/2003/role/footnote" xml:lang="en-US"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">We </span>compute net income (loss) per share independently for each quarter during <span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">the year.</span></ix:footnote></div>
        </td>

  </tr>


</table>
</ix:continuation></ix:continuation>
  <ix:continuation id="Text_b62322fb4b8e47769522dc5a87bc7fb07" continuedAt="Text_b62322fb4b8e47769522dc5a87bc7fb08"><ix:continuation id="Text_cc36388daf204a4db4b1bfe0db12cf4b5" continuedAt="Text_cc36388daf204a4db4b1bfe0db12cf4b6">
<div><br />
  </div>
</ix:continuation></ix:continuation>
  <ix:continuation id="Text_b62322fb4b8e47769522dc5a87bc7fb08" continuedAt="Text_b62322fb4b8e47769522dc5a87bc7fb09"><ix:continuation id="Text_cc36388daf204a4db4b1bfe0db12cf4b6" continuedAt="Text_cc36388daf204a4db4b1bfe0db12cf4b7">
<table cellspacing="0" cellpadding="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">


  <tr>

    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(2)</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:footnote id="Foot_94f9411e48574896ba56a419ae90ffb3" footnoteRole="http://www.xbrl.org/2003/role/footnote" xml:lang="en-US" continuedAt="Foot_f2b707fe28eb465e90c49a2280fff9c41">As discussed in Note 1, </ix:footnote><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;"><ix:continuation id="Foot_f2b707fe28eb465e90c49a2280fff9c41" continuedAt="Foot_f2b707fe28eb465e90c49a2280fff9c42">Organization and Significant Accounting Policies, </ix:continuation></span><ix:continuation id="Foot_f2b707fe28eb465e90c49a2280fff9c42" continuedAt="Foot_f2b707fe28eb465e90c49a2280fff9c43">we compute basic net income (loss) per share by dividing the total net income (loss)
            attributable to our common stockholders by our weighted-average number of common shares outstanding during the period. Our basic net income per share for the fourth quarter of 2021 was $<ix:nonFraction name="us-gaap:EarningsPerShareBasic" id="Fact_70151331185d48ebb0de51db51cdd7d4" contextRef="c20211001to20211231" unitRef="U004" decimals="2" scale="0" format="ixt:numdotdecimal">1.59</ix:nonFraction></ix:continuation><ix:continuation id="Foot_f2b707fe28eb465e90c49a2280fff9c43" continuedAt="Foot_f2b707fe28eb465e90c49a2280fff9c44">.</ix:continuation></div>
        </td>

  </tr>


</table>
</ix:continuation></ix:continuation>
  <ix:continuation id="Text_b62322fb4b8e47769522dc5a87bc7fb09" continuedAt="Text_b62322fb4b8e47769522dc5a87bc7fb010"><ix:continuation id="Text_cc36388daf204a4db4b1bfe0db12cf4b7" continuedAt="Text_cc36388daf204a4db4b1bfe0db12cf4b8">
<div><br />
  </div>
</ix:continuation></ix:continuation>
  <ix:continuation id="Text_b62322fb4b8e47769522dc5a87bc7fb010" continuedAt="Text_b62322fb4b8e47769522dc5a87bc7fb011"><ix:continuation id="Text_cc36388daf204a4db4b1bfe0db12cf4b8" continuedAt="Text_cc36388daf204a4db4b1bfe0db12cf4b9">
<div style="text-align: justify; margin-left: 18pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:continuation id="Foot_f2b707fe28eb465e90c49a2280fff9c44">Our basic net loss per share calculation for the fourth quarter of 2020 considered our net loss for Ionis on a stand-alone
    basis plus our share of Akcea&#8217;s net loss for the period. To calculate the portion of Akcea&#8217;s net loss attributable to our ownership, we multiplied Akcea&#8217;s loss per share by the weighted average shares we owned in Akcea during the period. As a result of
    this calculation, our total net loss available to Ionis common stockholders for the calculation of net loss per share is different than net loss attributable to Ionis Pharmaceuticals, Inc. common stockholders in the consolidated statements of
    operations.</ix:continuation></div>
</ix:continuation></ix:continuation>
  <ix:continuation id="Text_b62322fb4b8e47769522dc5a87bc7fb011" continuedAt="Text_b62322fb4b8e47769522dc5a87bc7fb012"><ix:continuation id="Text_cc36388daf204a4db4b1bfe0db12cf4b9" continuedAt="Text_cc36388daf204a4db4b1bfe0db12cf4b10">
<div><br />
  </div>
</ix:continuation></ix:continuation>
  <ix:continuation id="Text_b62322fb4b8e47769522dc5a87bc7fb012" continuedAt="Text_b62322fb4b8e47769522dc5a87bc7fb013"><ix:continuation id="Text_cc36388daf204a4db4b1bfe0db12cf4b10" continuedAt="Text_cc36388daf204a4db4b1bfe0db12cf4b11">
<div style="text-align: justify; margin-left: 18pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Our basic net loss per share for the fourth quarter of 2020 was calculated as follows (in thousands, except per share amounts):</div>
</ix:continuation></ix:continuation>
  <ix:continuation id="Text_b62322fb4b8e47769522dc5a87bc7fb013" continuedAt="Text_b62322fb4b8e47769522dc5a87bc7fb014"><ix:continuation id="Text_cc36388daf204a4db4b1bfe0db12cf4b11" continuedAt="Text_cc36388daf204a4db4b1bfe0db12cf4b12">
<div><br />
  </div>
</ix:continuation></ix:continuation>
  <ix:continuation id="Text_b62322fb4b8e47769522dc5a87bc7fb014" continuedAt="Text_b62322fb4b8e47769522dc5a87bc7fb015"><ix:continuation id="Text_cc36388daf204a4db4b1bfe0db12cf4b12" continuedAt="Text_cc36388daf204a4db4b1bfe0db12cf4b13">
<table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;" class="cfttable">


  <tr>

    <td valign="bottom" style="vertical-align: bottom; border-bottom: #000000 2px solid; white-space: nowrap;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Three Months Ended December 31, 2020</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px; white-space: nowrap;" colspan="2">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Weighted</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Average Shares</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Owned in Akcea</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px; white-space: nowrap;" colspan="2">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Akcea</span>&#8217;<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">s</span></div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Net Loss</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Per Share</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px; white-space: nowrap;" colspan="2">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Basic Net Loss</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Per Share</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Calculation</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: top; width: 64%; background-color: #CCEEFF; white-space: nowrap;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Akcea&#8217;s net loss in the pre-merger period attributable to our ownership</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="ions:WeightedAverageNumberOfSharesOwnedInSubsidiary" id="Fact_c62acc3e3ae348e4a8cf7206d5d1976c" contextRef="c20201001to20201231_OwnershipAxis_AkceaTherapeuticsIncMember" unitRef="U002" decimals="-3" scale="3" format="ixt:numdotdecimal">77,095</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
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        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:EarningsPerShareBasic" id="Fact_335e5bb93fe94df28ec77e37082c11fb" contextRef="c20201001to20201231_OwnershipAxis_AkceaTherapeuticsIncMember" unitRef="U004" decimals="2" sign="-" scale="0" format="ixt:numdotdecimal">0.05</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:NetIncomeLoss" id="Fact_9086fddb36394e5cb9bcd68266d25343" contextRef="c20201001to20201031_OwnershipAxis_AkceaTherapeuticsIncMember" unitRef="U001" decimals="-3" scale="3" sign="-" format="ixt:numdotdecimal">3,603</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: top; width: 64%; padding-bottom: 2px; white-space: nowrap;">
          <div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Akcea&#8217;s net loss in the post-merger period attributable to our ownership</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:NetIncomeLoss" id="Fact_786ac007378a49fabb7dd8870b4e9ce9" contextRef="c20201101to20201231_OwnershipAxis_AkceaTherapeuticsIncMember" unitRef="U001" decimals="-3" scale="3" sign="-" format="ixt:numdotdecimal">85,987</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: top; width: 64%; background-color: #CCEEFF; white-space: nowrap;">
          <div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Akcea&#8217;s total net loss attributable to our ownership</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:NetIncomeLoss" id="Fact_5498c6fff471441e940564d1d354691a" contextRef="c20201001to20201231_OwnershipAxis_AkceaTherapeuticsIncMember" unitRef="U001" decimals="-3" scale="3" sign="-" format="ixt:numdotdecimal">89,590</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: top; width: 64%; padding-bottom: 2px; white-space: nowrap;">
          <div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Ionis&#8217; stand-alone net loss</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:NetIncomeLoss" id="Fact_627e234811a3448ea693d89c46b16aaf" contextRef="c20201001to20201231_StatementBusinessSegmentsAxis_IonisCoreMember" unitRef="U001" decimals="-3" scale="3" sign="-" format="ixt:numdotdecimal">266,418</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: top; width: 64%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;">
          <div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Net loss available to Ionis common stockholders</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
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        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: top; width: 64%; padding-bottom: 2px; white-space: nowrap;">
          <div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Weighted average shares outstanding</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:WeightedAverageNumberOfSharesOutstandingBasic" id="Fact_36a534c150fb41e9b7c64047a8b16f6d" contextRef="c20201001to20201231" unitRef="U002" decimals="-3" scale="3" format="ixt:numdotdecimal">139,956</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: top; width: 64%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;">
          <div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Basic net loss per share</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(<ix:nonFraction name="us-gaap:EarningsPerShareBasic" id="Fact_70e31db299c04fb5b21fc6f2f0d26845" contextRef="c20201001to20201231" unitRef="U004" decimals="2" sign="-" scale="0" format="ixt:numdotdecimal">2.54</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

  </tr>


</table>
</ix:continuation></ix:continuation>
  <ix:continuation id="Text_b62322fb4b8e47769522dc5a87bc7fb015" continuedAt="Text_b62322fb4b8e47769522dc5a87bc7fb016"><ix:continuation id="Text_cc36388daf204a4db4b1bfe0db12cf4b13" continuedAt="Text_cc36388daf204a4db4b1bfe0db12cf4b14">
<div><br />
  </div>
</ix:continuation></ix:continuation>
  <ix:continuation id="Text_b62322fb4b8e47769522dc5a87bc7fb016" continuedAt="Text_b62322fb4b8e47769522dc5a87bc7fb017"><ix:continuation id="Text_cc36388daf204a4db4b1bfe0db12cf4b14" continuedAt="Text_cc36388daf204a4db4b1bfe0db12cf4b15">
<table cellspacing="0" cellpadding="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">


  <tr>

    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(3)</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:footnote id="Foot_f63ff29e56764f3485555958bff3cab9" footnoteRole="http://www.xbrl.org/2003/role/footnote" xml:lang="en-US">We had net income available
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        </td>

  </tr>


</table>
</ix:continuation></ix:continuation>
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<div><br />
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</ix:continuation></ix:continuation>
  <ix:continuation id="Text_b62322fb4b8e47769522dc5a87bc7fb018"><ix:continuation id="Text_cc36388daf204a4db4b1bfe0db12cf4b16">
<table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;" class="cfttable">


  <tr>

    <td valign="bottom" style="vertical-align: bottom; border-bottom: #000000 2px solid;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Three Months Ended December 31, 2021</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" colspan="2">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Income</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">(Numerator)</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" colspan="2">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Shares</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">(Denominator)</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" colspan="2">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Per-Share</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Amount</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: top; width: 64%; padding-bottom: 4px; background-color: #CCEEFF;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Net income available to Ionis common stockholders</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:NetIncomeLossAvailableToCommonStockholdersBasic" id="Fact_7d735a334951476ebc8e33e4897f0468" contextRef="c20211001to20211231" unitRef="U001" decimals="-3" scale="3" format="ixt:numdotdecimal">224,612</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:WeightedAverageNumberOfSharesOutstandingBasic" id="Fact_7eaba9f32f18442197a37ece9b7e3320" contextRef="c20211001to20211231" unitRef="U002" decimals="-3" scale="3" format="ixt:numdotdecimal">141,205</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:EarningsPerShareBasic" id="Fact_6de8e65be4864319852a79f01f6292c1" contextRef="c20211001to20211231" unitRef="U004" decimals="2" scale="0" format="ixt:numdotdecimal">1.59</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: top; width: 64%;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Effect of dilutive securities:</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: top; width: 64%; background-color: #CCEEFF;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 21pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Shares issuable upon exercise of stock options</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#8212;</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:IncrementalCommonSharesAttributableToShareBasedPaymentArrangements" id="Fact_a273f91bbe3848a1af35d94784e33331" contextRef="c20211001to20211231_AwardTypeAxis_EmployeeStockOptionMember" unitRef="U002" decimals="-3" scale="3" format="ixt:numdotdecimal">46</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: top; width: 64%;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 21pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Shares issuable upon restricted stock award issuance</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#8212;</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="us-gaap:IncrementalCommonSharesAttributableToShareBasedPaymentArrangements" id="Fact_4e094abc6bad4c03bc73eb42a00e39b1" contextRef="c20211001to20211231_AwardTypeAxis_RestrictedStockMember" unitRef="U002" decimals="-3" scale="3" format="ixt:numdotdecimal">1,065</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: top; width: 64%; background-color: #CCEEFF;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 21pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Shares issuable related to our ESPP</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#8212;</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonFraction name="ions:IncrementalCommonSharesAttributableToEmployeeStockPurchasePlan" id="Fact_f5840a3efd714daa9855da0b2f262c09" contextRef="c20211001to20211231" unitRef="U002" decimals="-3" scale="3" format="ixt:numdotdecimal">34</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">&#160;</td>

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    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

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    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

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    <td valign="bottom" style="vertical-align: top; width: 64%; padding-bottom: 2px;">
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" colspan="1">&#160;</td>

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    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" colspan="1">
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

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          <div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Income available to Ionis common stockholders, plus assumed conversions</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
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    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" colspan="1">
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" colspan="1">&#160;</td>

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<DOCUMENT>
<TYPE>EX-4.11
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<DESCRIPTION>EXHIBIT 4.11
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    <div>
      <div style="text-align: right; font-weight: bold;">Exhibit 4.11</div>
    </div>
    <div><font style="font-weight: bold;"> </font><br>
    </div>
    <div>
      <div style="text-align: center; font-weight: bold;">DESCRIPTION OF THE REGISTRANT&#8217;S SECURITIES</div>
      <div style="text-align: center; font-weight: bold;">REGISTERED PURSUANT TO SECTION 12 OF THE</div>
      <div style="text-align: center; font-weight: bold;">SECURITIES EXCHANGE ACT OF 1934</div>
      <div><br>
      </div>
      <div>
        <div style="text-indent: 36pt;">As of December 31, 2021, Ionis Pharmaceuticals, Inc. (the &#8220;Company&#8221;) had one class of securities, its Common Stock, registered under Section 12 of the Securities Exchange Act of 1934, as amended (the &#8220;Exchange Act&#8221;).</div>
        <div>&#160;
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      <div style="text-align: center; font-weight: bold;">Description of Common Stock</div>
      <div>&#160;</div>
      <div style="font-weight: bold;">General</div>
      <div>&#160;</div>
      <div>The following description of our Common Stock is a summary and does not purport to be complete. It is subject to and qualified in its entirety by reference to our Amended and Restated Certificate of Incorporation, as amended (the &#8220;Certificate of
        Incorporation&#8221;), and our Amended and Restated Bylaws (the &#8220;Bylaws&#8221;), each of which are incorporated by reference as an exhibit to the Annual Report on Form 10-K of which this Exhibit 4.11 is a part. We encourage you to read our Certificate of
        Incorporation, Bylaws and the applicable provisions of the General Corporation Law of Delaware (the &#8220;DGCL&#8221;) for additional information.</div>
      <div>&#160;</div>
      <div style="font-weight: bold;">Authorized Capital Stock</div>
      <div>&#160;</div>
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        <div>Our authorized capital stock consists of 300,000,000 shares of Common Stock, par value $0.001 per share, and 15,000,000 shares of Preferred Stock, par value $0.001 per share.<font style="color: rgb(0, 0, 0);"> Our board of directors has the
            authority, without stockholder approval, except as required by the listing standards of The Nasdaq Stock Market LLC, to issue additional shares of our capital stock.&#160; In addition, our board of directors has the authority, without further action
            by our stockholders, to designate the rights, preferences, privileges and restrictions of our Preferred Stock in one or more series.</font></div>
        <div>&#160;</div>
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      <div style="font-weight: bold;">Voting Rights</div>
      <div>&#160;</div>
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        <div>Holders of Common Stock are entitled to one vote per share on all matters to be voted upon by the stockholders, including the election of directors. Our Common Stock does not have cumulative voting rights.</div>
        <div>&#160;</div>
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      <div style="font-weight: bold;">Dividend Rights</div>
      <div>&#160;</div>
      <div>Subject to the preferential rights of outstanding shares of Preferred Stock, if any, the holders of Common Stock are entitled to receive dividends out of assets legally available at the times and in the amounts that our board of directors may
        determine from time to time in its discretion.</div>
      <div>&#160;</div>
      <div style="font-weight: bold;">Classification of the Board of Directors</div>
      <div>&#160;</div>
      <div>Our Certificate of Incorporation provides for classified terms for the members of our board of directors. The board of directors is divided into three classes, and each director serves a three-year term.</div>
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      <div style="font-weight: bold;">Liquidation, Dissolution or Winding Up</div>
      <div>&#160;</div>
      <div><a name="z_Hlk33602782"></a>Subject to the preferential rights of outstanding shares of Preferred Stock, if any, holders of Common Stock will share equally in all assets legally available for distribution, after payment of all liabilities, to
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      <div>&#160;</div>
      <div style="font-weight: bold;">Other Rights and Preferences</div>
      <div>&#160;</div>
      <div>Our Common Stock has no sinking fund or redemption provisions or preemptive, conversion or exchange rights.</div>
      <div>&#160;</div>
      <div style="font-weight: bold;">Anti-Takeover Provisions</div>
      <div>&#160;</div>
      <div style="font-style: italic; font-weight: bold;">Delaware Anti-takeover Law</div>
      <div>&#160;</div>
      <div>We are subject to Section 203 of the DGCL, which prohibits a Delaware corporation from engaging in any business combination with any interested stockholder for a period of three years after the date that such stockholder became an interested
        stockholder, unless:</div>
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              <div>the transaction is approved by the board of directors before the date the interested stockholder attained that status;</div>
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              <div>upon consummation of the transaction that resulted in the stockholder becoming an interested stockholder, the interested stockholder owned at least 85% of the voting stock of the corporation outstanding at the time the transaction
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              <div>on or after the date the business combination is approved by the board and authorized at a meeting of stockholders by at least 66-2/3% of the outstanding voting stock that is not owned by the interested stockholder.</div>
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      <div>&#160;</div>
      <div>A &#8220;business combination&#8221; is defined to include any merger or consolidation involving a corporation and the interested stockholder; any sale, transfer,<font style="color: rgb(0, 0, 0);"> pledge or other disposition involving the interested
          stockholder of 10% or more of the assets of the </font>corporation<font style="color: rgb(0, 0, 0);">; subject to exceptions, any transaction involving the </font>corporation <font style="color: rgb(0, 0, 0);">that has the effect of increasing
          the proportionate share of the stock of any class or series of the </font>corporation <font style="color: rgb(0, 0, 0);">beneficially owned by the interested stockholder; subject to exceptions, any transaction that results in the issuance or
          transfer by the </font>corporation <font style="color: rgb(0, 0, 0);">of any stock of the corporation to the interested stockholder; and the receipt by the interested stockholder of the benefit of any loans, advances, guarantees, pledges or
          other financial benefits provided by or through the </font>corporation<font style="color: rgb(0, 0, 0);">.</font></div>
      <div>&#160;</div>
      <div>In general, an &#8220;interested stockholder&#8221; is an entity or person who, together with affiliates and associates, owns (or within three years prior to the determination of interested stockholder status, did own) 15% or more of a corporation&#8217;s voting
        stock.</div>
      <div>&#160;</div>
      <div>The fair price provision and Section 203 of the DGCL could prohibit or delay mergers or other takeover or change in control attempts with respect to us and, accordingly, may discourage attempts to acquire us even though such a transaction may
        offer our stockholders the opportunity to sell their stock at a price above the prevailing market price.</div>
      <div>&#160;</div>
      <div style="font-style: italic; font-weight: bold;">Certificate of Incorporation and Bylaws Provisions</div>
      <div>&#160;</div>
      <div>Our Certificate of Incorporation includes a provision that requires at least 66-2/3% of our voting stockholders to approve a merger or certain other business transactions with, or proposed by, any holder of 15 percent or more of our voting
        stock, except in cases where certain directors approve the transaction or certain minimum price criteria and other procedural requirements are met.</div>
      <div>&#160;</div>
      <div>
        <div>Provisions of our Certificate of Incorporation and Bylaws may delay or discourage transactions involving an actual or potential change in our control or change in our management, including transactions in which stockholders might otherwise
          receive a premium for their shares or transactions that our stockholders might otherwise deem to be in their best interests. Therefore, these provisions could adversely affect the price of our common stock. Among other things, our Certificate of
          Incorporation and Bylaws:</div>
        <div>&#160;</div>
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              <td style="width: 18pt; vertical-align: top; color: rgb(0, 0, 0);">&#8226;</td>
              <td style="width: auto; vertical-align: top;">
                <div>permit our board of directors to issue up to 15,000,000 shares of Preferred Stock, with a<font style="color: rgb(0, 0, 0);">ny rights, preferences and privileges as they may designate;</font></div>
              </td>
            </tr>

        </table>
      </div>
      <div>
        <div><br>
        </div>
      </div>
      <div>
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            <tr>
              <td style="width: 36pt;"><br>
              </td>
              <td style="width: 18pt; vertical-align: top; color: rgb(0, 0, 0);">&#8226;</td>
              <td style="width: auto; vertical-align: top;">
                <div style="color: rgb(0, 0, 0);">provide that the authorized number of directors shall be fixed exclusively by the board of directors;</div>
              </td>
            </tr>

        </table>
      </div>
      <div>
        <div><br>
        </div>
      </div>
      <div>
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            <tr>
              <td style="width: 36pt;"><br>
              </td>
              <td style="width: 18pt; vertical-align: top; color: rgb(0, 0, 0);">&#8226;</td>
              <td style="width: auto; vertical-align: top;">
                <div style="color: rgb(0, 0, 0);">provide that the board of directors or any individual director may only be removed with cause&#160; by the affirmative vote of the holders of at least a majority of the outstanding common stock or without cause
                  by the affirmative vote of the holders of at least 66-2/3% of the voting power of all of our then outstanding common stock;</div>
              </td>
            </tr>

        </table>
        <div> <br>
        </div>
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            <tr>
              <td style="width: 36pt;"><br>
              </td>
              <td style="width: 18pt; vertical-align: top; color: rgb(0, 0, 0);">&#8226;</td>
              <td style="width: auto; vertical-align: top;">
                <div style="color: rgb(0, 0, 0);">provide that all vacancies, including newly created directorships, may, except as otherwise required by law or subject to the rights of holders of preferred stock as designated from time to time, be filled
                  by the affirmative vote of a majority of directors then in office, even if less than a quorum, unless the board of directors determines by resolution that any such vacancies or newly created directorships shall be filled by stockholders;</div>
              </td>
            </tr>

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        <div><br>
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            <tr>
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              </td>
              <td style="width: 18pt; vertical-align: top; color: rgb(0, 0, 0);">&#8226;</td>
              <td style="width: auto; vertical-align: top;">
                <div style="color: rgb(0, 0, 0);">classifies our board of directors into three classes;</div>
              </td>
            </tr>

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        <div><br>
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            <tr>
              <td style="width: 36pt;"><br>
              </td>
              <td style="width: 18pt; vertical-align: top; color: rgb(0, 0, 0);">&#8226;</td>
              <td style="width: auto; vertical-align: top;">
                <div style="color: rgb(0, 0, 0);">require that any action to be taken by our stockholders must be effected at a duly called annual or special meeting of stockholders and not be taken by written consent or electronic transmission;</div>
              </td>
            </tr>

        </table>
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      <div>
        <div><br>
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            <tr>
              <td style="width: 36pt;"><br>
              </td>
              <td style="width: 18pt; vertical-align: top; color: rgb(0, 0, 0);">&#8226;</td>
              <td style="width: auto; vertical-align: top;">
                <div style="color: rgb(0, 0, 0);">provide that stockholders seeking to present proposals before a meeting of stockholders or to nominate candidates for election as directors at a meeting of stockholders must provide notice in writing in a
                  timely manner and also specify requirements as to the form and content of a stockholder&#8217;s notice;</div>
              </td>
            </tr>

        </table>
      </div>
      <div>
        <div><br>
        </div>
      </div>
      <div>
        <table cellspacing="0" cellpadding="0" id="z4ddabe908c3b4bd49758b9d753701aba" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">

            <tr>
              <td style="width: 36pt;"><br>
              </td>
              <td style="width: 18pt; vertical-align: top; color: rgb(0, 0, 0);">&#8226;</td>
              <td style="width: auto; vertical-align: top;">
                <div style="color: rgb(0, 0, 0);">do not provide for cumulative voting rights (therefore allowing the holders of a majority of the shares of Common Stock entitled to vote in any election of directors to elect all of the directors standing
                  for election, if they should so choose); and</div>
              </td>
            </tr>

        </table>
      </div>
      <div>
        <div><br>
        </div>
      </div>
      <div>
        <table cellspacing="0" cellpadding="0" id="z36f9125fea734192a7ac5d120c81ee5f" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">

            <tr>
              <td style="width: 36pt;"><br>
              </td>
              <td style="width: 18pt; vertical-align: top;">&#8226;</td>
              <td style="width: auto; vertical-align: top;">
                <div><font style="color: rgb(0, 0, 0);">provide that special meetings of our stockholders may be called only by the Ch</font>airman of the board, our Chief Executive Officer or by the board of directors pursuant to a resolution adopted by a
                  majority of the total number of authorized directors (whether or not there exists any vacancies).</div>
              </td>
            </tr>

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      </div>
      <div>
        <div><br>
        </div>
      </div>
      <div>
        <div style="color: rgb(0, 0, 0);">The foregoing provisions may make it more difficult for our existing stockholders to replace our board of directors as well as for another party to obtain control of us by replacing our board of directors. Since
          our board of directors has the power to retain and discharge our officers, these provisions could also make it more difficult for existing stockholders or another party to effect a change in management. In addition, the authorization of
          undesignated Preferred Stock makes it possible for our board of directors to issue Preferred Stock with voting or other rights or preferences that could impede the success of any attempt to change our control.</div>
        <div>&#160;</div>
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      </div>
      <div>
        <div style="color: rgb(0, 0, 0);">These provisions are intended to enhance the likelihood of continued stability in the composition of our board of directors and its policies and to discourage certain types of transactions that may involve an
          actual or threatened acquisition of us. These provisions are also designed to reduce our vulnerability to an unsolicited acquisition proposal and to discourage certain tactics that may be used in proxy fights. However, such provisions could have
          the effect of discouraging others from making tender offers for our shares and may have the effect of deterring hostile takeovers or delaying changes in our control or management. As a consequence, these provisions also may inhibit fluctuations
          in the market price of our stock that could result from actual or rumored takeover attempts.</div>
        <div>&#160;</div>
        <div style="color: rgb(0, 0, 0); font-weight: bold;">Choice of Forum</div>
        <div>&#160;</div>
        <div><font style="color: rgb(0, 0, 0);">Our Bylaws provide that, unless we consent in writing to the selection of an alternative forum, the Court of Chancery of the State of Delaware (or, if the Court of Chancery does not have jurisdiction, another
            state court located within the State of Delaware or, if no state court located within the State of Delaware has jurisdiction, the federal district court for the District of Delaware) shall, to the fullest extent permitted by law, be the sole
            and exclusive forum for (i) any derivative claim or cause of action or proceeding brought on behalf of the Company; (ii) any claim or cause of action for breach of a fiduciary duty owed by any current or former director, officer or other
            employee of the Company to the Company or the Company&#8217;s stockholders; (iii) any claim or cause of action against the Company or any current or former director or officer or other employee of the Company arising out of or pursuant to any
            provision of the DGCL, our Certificate of Incorporation (as may be amended from time to time) or our Bylaws (as may be amended from time to time); and (iv) any action asserting a claim against the Company or any current or former director or
            officer or other employee of the Company governed by the internal affairs doctrine;</font>&#160;<font style="color: rgb(0, 0, 0);">(v) any claim or cause of action seeking to interpret, apply, enforce or determine the validity of the Bylaws or the
            Certificate of Incorporation of the corporation (as each may be amended from time to time, including any right, obligation, or remedy thereunder); and (vi) any claim or cause of action as to which the DGCL confers jurisdiction on the Court of
            Chancery of the State of Delaware, in all cases to the fullest extent permitted by law and subject to the court having personal jurisdiction over the indispensable parties named as defendants. This choice of forum provision does not apply to
            claims or causes of action brought to enforce a duty or liability created by the Securities Act of 1933, as amended, or the Exchange Act, as amended, or any other claim for which the federal courts have exclusive jurisdiction. Any person or
            entity purchasing or otherwise acquiring any interest in shares of capital stock of the Company shall be deemed to have notice of and consented to the provisions of Article XV of the Bylaws.</font></div>
        <div>&#160;</div>
        <div> <br>
        </div>
      </div>
    </div>
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      <hr noshade="noshade" align="center" style="height: 2px; color: #000000; background-color: #000000; text-align: center; margin-left: auto; margin-right: auto; border: none;"> </div>
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<DOCUMENT>
<TYPE>EX-10.19
<SEQUENCE>3
<FILENAME>exhibit10-19.htm
<DESCRIPTION>EXHIBIT 10.19
<TEXT>
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    <div style="text-align: right;"> <font style="font-weight: bold;">Exhibit 10.19</font><br>
    </div>
    <div> <br>
    </div>
    <div>
      <div style="text-align: center; font-variant: small-caps; font-weight: bold;">Ionis Pharmaceuticals, Inc.</div>
      <div style="text-align: center; font-size: 14pt; font-variant: small-caps; font-weight: bold;"><font style="font-size: 10pt;">Performance Based Restricted Stock Unit Grant Notice</font></div>
      <div style="text-align: center; font-weight: bold;">(<font style="font-variant: small-caps;">2011 Equity Incentive Plan)</font></div>
      <div>&#160;</div>
      <div>Ionis Pharmaceuticals, Inc. (the <font style="font-weight: bold; font-style: italic;">&#8220;Company&#8221;</font>), pursuant to its Amended and Restated 2011 Equity Incentive Plan (the <font style="font-weight: bold; font-style: italic;">&#8220;Plan&#8221;</font>),
        hereby awards to Participant a Performance Based Restricted Stock Unit (<font style="font-weight: bold; font-style: italic;">&#8220;PRSU&#8221;</font>) Award for the number of stock units set forth below (the <font style="font-weight: bold; font-style: italic;">&#8220;Award&#8221;</font>).&#160; The Award is subject to all of the terms and conditions as set forth herein; and in the Plan and the Performance Based Restricted Stock Unit Agreement (the <font style="font-weight: bold; font-style: italic;">&#8220;Agreement&#8221;</font>),


        both of which are attached hereto and incorporated herein in their entirety.&#160; Capitalized terms not otherwise defined herein shall have the meanings set forth in the Plan or the Agreement.&#160; In the event of any conflict between the terms in the
        Award and the Plan, the terms of the Plan shall control.</div>
      <div>&#160;</div>
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            <td style="width: 25%; vertical-align: top; padding-bottom: 2px;">
              <div style="text-align: justify;">Participant:</div>
            </td>
            <td style="width: 1%; vertical-align: top; padding-bottom: 2px;">&#160;</td>
            <td style="width: 40%; vertical-align: top; border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
            <td style="width: 34%; vertical-align: top; padding-bottom: 2px;">&#160;</td>
          </tr>
          <tr>
            <td style="width: 25%; vertical-align: top; padding-bottom: 2px;">
              <div style="text-align: justify;">Date of Grant:</div>
            </td>
            <td style="width: 1%; vertical-align: top; padding-bottom: 2px;">&#160;</td>
            <td style="width: 40%; vertical-align: top; border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
            <td style="width: 34%; vertical-align: top; padding-bottom: 2px;">&#160;</td>
          </tr>
          <tr>
            <td style="width: 25%; vertical-align: top; padding-bottom: 2px;">
              <div style="text-align: justify;">Target Number of Stock Units Subject to Award:</div>
            </td>
            <td style="width: 1%; vertical-align: top; padding-bottom: 2px;">&#160;</td>
            <td style="width: 40%; vertical-align: top; border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
            <td style="width: 34%; vertical-align: top; padding-bottom: 2px;">&#160;</td>
          </tr>
          <tr>
            <td style="vertical-align: top; white-space: nowrap; width: 25%; padding: 0px 0px 2px;">
              <div style="text-align: justify;">Maximum Number of Stock Units Subject to Award:</div>
            </td>
            <td style="width: 1%; vertical-align: top; padding-bottom: 2px;">&#160;</td>
            <td style="width: 40%; vertical-align: top; border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
            <td style="width: 34%; vertical-align: top; padding-bottom: 2px;">&#160;</td>
          </tr>
          <tr>
            <td style="width: 25%; vertical-align: top;">
              <div style="text-align: justify;">Consideration:</div>
            </td>
            <td rowspan="1" style="width: 1%; vertical-align: top;">
              <div style="text-align: justify;"><br>
              </div>
            </td>
            <td rowspan="1" style="width: 40%; vertical-align: top;">
              <div style="text-align: justify;">Participant&#8217;s Services</div>
            </td>
            <td rowspan="1" style="width: 34%; vertical-align: top;">&#160;</td>
          </tr>

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      <div style="clear: both;"><br>
      </div>
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            <td style="width: 89.1pt; vertical-align: top;"><font style="font-weight: bold;">Vesting Schedule</font>:</td>
            <td style="width: auto; vertical-align: top; text-align: justify;">
              <div>Subject to Section 4(b) of the Agreement, if Participant ceases to be a Service Provider for any or no reason before Participant vests in the PRSU, the PRSU and Participant&#8217;s right to acquire any Shares hereunder will immediately
                terminate.</div>
            </td>
          </tr>

      </table>
      <div><br>
      </div>
      <div style="text-align: justify; text-indent: 0pt; margin-left: 90pt;">Up to one third (1/3) of the maximum number of PRSUs subject to the Agreement are eligible for vesting at the end of each Performance Period depending on the Company&#8217;s relative
        Total Shareholder Return over the applicable Performance Periods, but subject to the Alternative Three Year Performance Period Vested Unit Calculation (each as more fully described in the PRSU Agreement).</div>
      <div><br>
      </div>
      <div style="text-align: justify; margin-left: 90pt;">You must accept this Award prior to the first vesting date. If you do not accept this Award by the first vest date, this Award will automatically expire.</div>
      <div><br>
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            <td style="width: 90pt; vertical-align: top; font-weight: bold;">Issuance Schedule:</td>
            <td style="width: auto; vertical-align: top; text-align: justify;">
              <div>The shares of Common Stock to be issued in respect of the Award will be issued in accordance with Section 1 of the Agreement.</div>
            </td>
          </tr>

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      <div>&#160;</div>
      <div style="text-align: justify; text-indent: -90pt; margin-left: 90pt; font-weight: bold;">Special Tax</div>
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            <td style="width: 90pt; vertical-align: top; font-weight: bold;">Withholding Right:</td>
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              <div><font style="font-style: italic;">If permitted by the Company</font>,<font style="font-weight: bold;">&#160;</font>you may direct the Company (i) to withhold, from shares otherwise issuable in respect of the Award, a portion of those shares
                with an aggregate fair market value (measured as of the delivery date) equal to the amount of the applicable withholding taxes, and (ii) to make a cash payment equal to such fair market value directly to the appropriate taxing authorities,
                as provided in Section 12 of the Agreement.</div>
            </td>
          </tr>

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      <div>&#160;</div>
      <div style="text-align: justify;"><font style="font-weight: bold;">Additional Terms/Acknowledgements:</font>&#160; The undersigned Participant acknowledges receipt of, and understands and agrees to, this Grant Notice, the Agreement and the Plan.&#160;
        Participant further acknowledges that as of the Date of Grant, this Grant Notice, the Agreement and the Plan set forth the entire understanding between Participant and the Company regarding the Award and supersede all prior oral and written
        agreements on that subject, with the exception of any employment or severance arrangement that would provide for vesting acceleration of the Award upon the terms and conditions set forth therein.</div>
      <div>&#160;</div>
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              <div style="text-indent: -7.2pt; margin-left: 7.2pt; font-variant: small-caps; font-weight: bold;">Ionis Pharmaceuticals, Inc.</div>
            </td>
            <td style="width: 2%; vertical-align: top;">&#160;</td>
            <td colspan="2" style="vertical-align: top;">
              <div style="text-indent: -7.2pt; margin-left: 7.2pt; font-variant: small-caps; font-weight: bold;">Participant:</div>
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            <td colspan="2" style="vertical-align: top;">&#160;</td>
            <td style="width: 2%; vertical-align: top;">&#160;</td>
            <td colspan="2" style="vertical-align: top;">&#160;</td>
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            <td style="width: 5%; vertical-align: top; padding-bottom: 2px;">
              <div style="text-indent: -7.2pt; margin-left: 7.2pt;">By:</div>
            </td>
            <td style="width: 45%; vertical-align: top; border-bottom: 2px solid rgb(0, 0, 0);"><br>
            </td>
            <td style="width: 2%; vertical-align: top; padding-bottom: 2px;">&#160;</td>
            <td colspan="2" rowspan="1" style="width: 5%; vertical-align: top; border-bottom: 2px solid rgb(0, 0, 0);"><br>
            </td>
          </tr>
          <tr>
            <td style="width: 5%; vertical-align: top;">&#160;</td>
            <td style="width: 45%; vertical-align: top;">
              <div style="text-align: center; text-indent: -7.2pt; margin-left: 7.2pt;">Signature</div>
            </td>
            <td style="width: 2%; vertical-align: top;">&#160;</td>
            <td style="width: 5%; vertical-align: top;">&#160;</td>
            <td style="width: 43%; vertical-align: top;">
              <div style="text-align: center; text-indent: -7.2pt; margin-left: 7.2pt;">Signature</div>
            </td>
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            <td rowspan="1" style="width: 5%; vertical-align: top;">&#160;</td>
            <td rowspan="1" style="width: 45%; vertical-align: top;">&#160;</td>
            <td rowspan="1" style="width: 2%; vertical-align: top;">&#160;</td>
            <td rowspan="1" style="width: 5%; vertical-align: top;">&#160;</td>
            <td rowspan="1" style="width: 43%; vertical-align: top;">&#160;</td>
          </tr>
          <tr>
            <td style="width: 5%; vertical-align: top; padding-bottom: 2px;">
              <div style="text-indent: -7.2pt; margin-left: 7.2pt;">Title:</div>
            </td>
            <td style="width: 45%; vertical-align: top; border-bottom: 2px solid rgb(0, 0, 0);"><br>
            </td>
            <td style="width: 2%; vertical-align: top; padding-bottom: 2px;">&#160;</td>
            <td style="width: 5%; vertical-align: top; padding-bottom: 2px;">
              <div style="text-indent: -7.2pt; margin-left: 7.2pt;">Date:</div>
            </td>
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            </td>
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            <td rowspan="1" style="width: 5%; vertical-align: top;">&#160;</td>
            <td rowspan="1" style="width: 45%; vertical-align: top;">&#160;</td>
            <td rowspan="1" style="width: 2%; vertical-align: top;">&#160;</td>
            <td rowspan="1" style="width: 5%; vertical-align: top;">&#160;</td>
            <td rowspan="1" style="width: 43%; vertical-align: top;">&#160;</td>
          </tr>
          <tr>
            <td style="width: 5%; vertical-align: top; padding-bottom: 2px;">
              <div style="text-indent: -7.2pt; margin-left: 7.2pt;">Date:</div>
            </td>
            <td style="width: 45%; vertical-align: top; border-bottom: 2px solid rgb(0, 0, 0);"><br>
            </td>
            <td style="width: 2%; vertical-align: top; padding-bottom: 2px;">&#160;</td>
            <td style="width: 5%; vertical-align: top; padding-bottom: 2px;">&#160;</td>
            <td style="width: 43%; vertical-align: top; padding-bottom: 2px;">&#160;</td>
          </tr>

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      <div><br>
      </div>
      <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: rgb(0, 0, 0);" class="DSPFListTable" id="ze91b1ba35f964b31b9b59bd98b178fa5">

          <tr>
            <td style="width: 144pt; vertical-align: top;"><font style="font-weight: bold; font-variant: small-caps;">Attachments</font>:</td>
            <td style="width: auto; vertical-align: top;">
              <div>Performance Based Restricted Stock Unit Agreement</div>
            </td>
          </tr>

      </table>
      <div><br>
      </div>
      <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
        <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-size: 8pt; color: rgb(0, 0, 0); font-weight: normal; font-style: normal;">2</font></div>
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      </div>
      <div style="text-align: center; font-variant: small-caps; font-weight: bold;">Ionis Pharmaceuticals, Inc.</div>
      <div style="text-align: center; font-variant: small-caps; font-weight: bold;">Amended &amp; Restated 2011 Equity Incentive Plan</div>
      <div>&#160;</div>
      <div style="text-align: center; font-variant: small-caps; font-weight: bold;">Performance Based Restricted Stock Unit Agreement</div>
      <div>&#160;</div>
      <div style="text-align: justify; text-indent: 36pt;">Pursuant to the Performance Based Restricted Stock Unit Grant Notice (&#8220;<font style="font-weight: bold; font-style: italic;">Grant Notice</font>&#8221;) and this Performance Based Restricted Stock Unit
        Agreement (&#8220;<font style="font-weight: bold; font-style: italic;">Agreement</font>&#8221;) and in consideration of your services, Ionis Pharmaceuticals, Inc. (the &#8220;<font style="font-weight: bold; font-style: italic;">Company</font>&#8221;) has awarded you a
        Performance Based Restricted Stock Unit Award (the &#8220;<font style="font-weight: bold; font-style: italic;">Award</font>&#8221;) under its Amended &amp; Restated 2011 Equity Incentive Plan (the &#8220;<font style="font-weight: bold; font-style: italic;">Plan</font>&#8221;).


        Your Award is granted to you effective as of the Date of Grant set forth in the Grant Notice for this Award.&#160; This Agreement will be deemed to be agreed to by the Company and you upon the earlier of (i) signing (or electronic acceptance) by you of
        the Grant Notice to which it is attached, and (ii) your receipt of shares of Common Stock under this Agreement.&#160; Capitalized terms not explicitly defined in this Agreement will have the same meanings given to them in the Plan or the Grant Notice,
        as applicable.&#160; In the event of any conflict between the terms in this Agreement and the Plan, the terms of the Plan will control.&#160; The details of your Award, in addition to those set forth in the Grant Notice and the Plan, are as follows.</div>
      <div>&#160;</div>
      <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; color: rgb(0, 0, 0);">1.</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;<font style="font-weight: bold; font-variant: small-caps;">Grant And Vesting of the Award.</font></div>
      <div>&#160;</div>
      <div style="text-indent: 72pt;"><font style="font-weight: bold; color: rgb(0, 0, 0);">(a)</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;This Award represents the right to be issued on a future date the number of shares of the Company&#8217;s Common Stock that is equal to the number of
        performance based restricted stock units (&#8220;<font style="font-size: 12pt; font-weight: bold; font-style: italic;">PRSUs</font>&#8221;) as described below. This Award was granted in consideration of your services to the Company.&#160; Except as otherwise
        provided herein, you will not be required to make any payment to the Company (other than past and future services to the Company) with respect to your receipt of the Award, the vesting of the PRSUs or the delivery of the Common Stock to be issued
        in respect of the Award. </div>
      <div>&#160;</div>
      <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold; color: rgb(0, 0, 0);">(b)</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160; One third (1/3) of the maximum number of PRSUs subject to this Agreement are eligible for vesting at the end of each
        Performance Period depending on the Company&#8217;s relative Total Shareholder Return over the applicable Performance Period, but <font style="font-size: 12pt; font-style: italic;">subject to</font> the Alternative Three Year Performance Period Vested
        Unit Calculation (each as more fully described below).</div>
      <div>&#160;</div>
      <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;">(c)</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;Following the end of each Performance Period, the Company&#8217;s Compensation Committee (the &#8220;<font style="font-size: 12pt; font-weight: bold; font-style: italic;">Committee</font>&#8221;) will certify the Company&#8217;s relative Total Shareholder Return on a percentage rank basis compared to the Comparison Group (the &#8220;<font style="font-size: 12pt; font-weight: bold; font-style: italic;">Performance


          Measure</font>&#8221;) for such Performance Period (the &#8220;<font style="font-size: 12pt; font-weight: bold; font-style: italic;">Certification</font>&#8221;). The PRSUs subject to vesting during a Performance Period will be subject to forfeiture and
        cancellation by the Company if the Company&#8217;s performance during such Performance Period does not meet or exceed the Threshold Level (as defined in the table set forth in Section 3(a)(iii)) of the Performance Measure for such Performance Period; <font style="font-size: 12pt; font-style: italic;">provided however</font>, that such forfeited shares may be subsequently granted subject to the Alternative Three Year Performance Period Vested Unit Calculation. Performance at or above the Threshold
        Level will result in PRSUs becoming vested as set forth below, and shares underlying such vested PRSUs will be promptly distributed following completion of the Certification but in no event later than March 15 of the year following the year in
        which the applicable Certification occurred.</div>
      <div style="text-align: justify; text-indent: 72pt;"> <br>
      </div>
      <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
        <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-size: 8pt; color: rgb(0, 0, 0); font-weight: normal; font-style: normal;">3</font></div>
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      </div>
      <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;">(d)</font>&#160;&#160;&#160; &#160;&#160;&#160; Notwithstanding the foregoing, following completion of the three-year period commencing on the Date of Grant and ending on the third anniversary
        of the Date of Grant (the &#8220;<font style="font-size: 12pt; font-weight: bold; font-style: italic;">Three Year Performance Period</font>&#8221;), the Committee will determine the number of PRSUs that would vest if the maximum number of PRSUs subject to the
        Award had been subject only to the Three Year Performance Period (the &#8220;<font style="font-size: 12pt; font-weight: bold; font-style: italic;">Alternative Three Year Performance Period Vested Unit Calculation</font>&#8221;). If the number of PRSUs that
        vest pursuant to the Alternative Three Year Performance Period Vested Unit Calculation is greater than the number of PRSUs that vest under this Agreement in the three Performance Periods described herein without regard to the Alternative Three Year
        Performance Period Vested Unit Calculation, then such greater number of PRSUs will vest pursuant to the Alternative Three Year Performance Period Vested Unit Calculation, reduced by the number of PRSUs previously vested.</div>
      <div>&#160;</div>
      <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; color: rgb(0, 0, 0);">2.</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;<font style="font-size: 12pt; font-weight: bold; font-variant: small-caps;">Additional Definitions</font><font style="font-size: 12pt;">.</font></div>
      <div>&#160;</div>
      <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold; color: rgb(0, 0, 0);">(a)</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160; &#8220;<font style="font-size: 12pt; font-weight: bold; font-style: italic;">Comparison Group</font>&#8221; means the companies included
        in the NASDAQ Biotechnology Index on the Date of Grant, as may be adjusted as described in Section 3(b)(iii) below.</div>
      <div>&#160;</div>
      <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold; color: rgb(0, 0, 0);">(b)</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#8220;<font style="font-size: 12pt; font-weight: bold; font-style: italic;">Performance Period</font>&#8221; means each of the
        following three periods:</div>
      <div>&#160;</div>
      <div style="text-align: justify; text-indent: 108pt;"><font style="font-weight: bold; color: rgb(0, 0, 0);">(i)</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;the one-year period commencing on the Date of Grant and ending on the first anniversary of the Date of Grant;</div>
      <div>&#160;</div>
      <div style="text-align: justify; text-indent: 108pt;"><font style="font-weight: bold; color: rgb(0, 0, 0);">(ii)</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160; the two-year period commencing on the Date of Grant and ending on the second anniversary of the Date of Grant; and</div>
      <div>&#160;</div>
      <div style="text-align: justify; text-indent: 108pt;"><font style="font-weight: bold; color: rgb(0, 0, 0);">(iii)</font>&#160;&#160;&#160;&#160;&#160;&#160; the three-year period commencing <a name="z_Hlk29813503"></a>on the Date of Grant and ending on the third anniversary of
        the Date of Grant.</div>
      <div>&#160;</div>
      <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold; color: rgb(0, 0, 0);">(c)</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#8220;<font style="font-size: 12pt; font-weight: bold; font-style: italic;">Target</font>&#8221; means the target number of shares set
        forth in the Grant Notice.&#160; The Target for each Performance Period will be one-third of the target number of shares set forth in the Grant Notice.</div>
      <div>&#160;</div>
      <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold; color: rgb(0, 0, 0);">(d)</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#8220;<font style="font-size: 12pt; font-weight: bold; font-style: italic;">Total Shareholder Return</font>&#8221; or &#8220;<font style="font-size: 12pt; font-weight: bold; font-style: italic;">TSR</font>&#8221; means total shareholder return as applied to the Company or any company in the Comparison Group, meaning stock price appreciation from the beginning to the end of the
        applicable Performance Period, plus dividends and distributions made or declared (assuming such dividends or distributions are reinvested in the common stock of the Company or any company in the Comparison Group) during the Performance Period,
        expressed as a percentage return.</div>
      <div>&#160;</div>
      <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; color: rgb(0, 0, 0);">3.</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;<font style="font-size: 12pt; font-weight: bold; font-variant: small-caps;">Calculation</font>.</div>
      <div>&#160;</div>
      <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold; color: rgb(0, 0, 0);">(a)</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160; For purposes of the Award, subject to the Negative TSR Cap set forth in Section 3(b)(i) below, the number of PRSUs earned at
        the end of each Performance Period will be calculated using the method as follows:</div>
      <div>&#160;</div>
      <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
        <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-size: 8pt; color: rgb(0, 0, 0); font-weight: normal; font-style: normal;">4</font></div>
        <div style="page-break-after: always;" id="DSPFPageBreak">
          <hr noshade="noshade" style="margin: 4px 0px; width: 100%; border-width: 0px; height: 2px; color: rgb(0, 0, 0); background-color: rgb(0, 0, 0); clear: both;"></div>
      </div>
      <div style="text-align: justify; text-indent: 108pt;"><font style="font-weight: bold; color: rgb(0, 0, 0);">(i)</font>&#160;&#160;&#160;&#160;&#160; First, for the Company and for each other company in the Comparison Group, determine the TSR for the Performance Period.</div>
      <div>&#160;</div>
      <div style="text-align: justify; text-indent: 108pt;"><font style="font-weight: bold; color: rgb(0, 0, 0);">(ii)</font>&#160;&#160;&#160;&#160;&#160;&#160; Next, rank the TSR values determined in step (i) above from low to high (with the company having the lowest TSR being ranked
        number 1, the company with the second lowest TSR ranked number 2, and so on) and determine the Company&#8217;s percentile rank based upon its position in the list by dividing the Company&#8217;s position by the total number of companies (including the Company)
        in the Comparison Group and rounding the quotient to the nearest hundredth. For example, if the Company was ranked 61 on the list out of 80 companies (including the Company), its percentile rank would be 76.25%.</div>
      <div>&#160;</div>
      <div style="text-align: justify; text-indent: 108pt;"><font style="font-weight: bold; color: rgb(0, 0, 0);">(iii)</font>&#160;&#160;&#160;&#160;&#160; Finally, plot the percentile rank for the Company determined in accordance with step (ii) above into the appropriate band in
        the left-hand column of the table below to determine the number of shares earned as a percent of the applicable Target for the applicable Performance Period, which is the figure in the right-hand column of the table below corresponding to that
        percentile rank. Use linear interpolation between points in the table below to determine the percentile rank and the corresponding share funding if the Company&#8217;s percentile rank is greater than 25% and less than 75% but not exactly one of the
        percentile ranks listed in the left-hand column.</div>
      <div>&#160;</div>
      <table cellspacing="0" cellpadding="0" border="0" align="center" style="border-collapse: collapse; width: 80%; color: rgb(0, 0, 0); font-family: 'Times New Roman'; font-size: 10pt; text-align: left;" id="zb04e9270717d4867a48882f5df5d4364">

          <tr>
            <td style="width: 25%; vertical-align: top;"><br>
            </td>
            <td colspan="1" style="width: 2%; vertical-align: top;">&#160;</td>
            <td style="width: 25%; vertical-align: bottom; text-align: center;">
              <div style="font-weight: bold;"><u>TSR Percentile Rank</u></div>
            </td>
            <td colspan="1" style="width: 2%; vertical-align: top;">&#160;</td>
            <td style="width: 30%; vertical-align: top;">
              <div style="text-align: center; font-weight: bold;"><u>Shares Earned as a</u></div>
              <div style="text-align: center; font-weight: bold;"><u>Percent of Target</u></div>
            </td>
          </tr>
          <tr>
            <td style="width: 25%; vertical-align: top;">
              <div style="text-align: justify; font-weight: bold;">Maximum Level</div>
            </td>
            <td colspan="1" style="width: 2%; vertical-align: top;">&#160;</td>
            <td style="width: 25%; vertical-align: top;">
              <div style="text-align: center;">75%</div>
            </td>
            <td colspan="1" style="width: 2%; vertical-align: top;">&#160;</td>
            <td style="width: 30%; vertical-align: top;">
              <div style="text-align: center;">150%</div>
            </td>
          </tr>
          <tr>
            <td style="width: 25%; vertical-align: top;">&#160;</td>
            <td colspan="1" style="width: 2%; vertical-align: top;">&#160;</td>
            <td style="width: 25%; vertical-align: top;">
              <div style="text-align: center;">70%</div>
            </td>
            <td colspan="1" style="width: 2%; vertical-align: top;">&#160;</td>
            <td style="width: 30%; vertical-align: top;">
              <div style="text-align: center;">140%</div>
            </td>
          </tr>
          <tr>
            <td style="width: 25%; vertical-align: top;"><br>
            </td>
            <td colspan="1" style="width: 2%; vertical-align: top;">&#160;</td>
            <td style="width: 25%; vertical-align: top;">
              <div style="text-align: center;">65%</div>
            </td>
            <td colspan="1" style="width: 2%; vertical-align: top;">&#160;</td>
            <td style="width: 30%; vertical-align: top;">
              <div style="text-align: center;">130%</div>
            </td>
          </tr>
          <tr>
            <td style="width: 25%; vertical-align: top;">&#160;</td>
            <td colspan="1" style="width: 2%; vertical-align: top;">&#160;</td>
            <td style="width: 25%; vertical-align: top;">
              <div style="text-align: center;">60%</div>
            </td>
            <td colspan="1" style="width: 2%; vertical-align: top;">&#160;</td>
            <td style="width: 30%; vertical-align: top;">
              <div style="text-align: center;">120%</div>
            </td>
          </tr>
          <tr>
            <td style="width: 25%; vertical-align: top;">&#160;</td>
            <td colspan="1" style="width: 2%; vertical-align: top;">&#160;</td>
            <td style="width: 25%; vertical-align: top;">
              <div style="text-align: center;">55%</div>
            </td>
            <td colspan="1" style="width: 2%; vertical-align: top;">&#160;</td>
            <td style="width: 30%; vertical-align: top;">
              <div style="text-align: center;">110%</div>
            </td>
          </tr>
          <tr>
            <td style="width: 25%; vertical-align: top;">
              <div style="text-align: justify; font-weight: bold;">Target Level</div>
            </td>
            <td colspan="1" style="width: 2%; vertical-align: top;">&#160;</td>
            <td style="width: 25%; vertical-align: top;">
              <div style="text-align: center;">50%</div>
            </td>
            <td colspan="1" style="width: 2%; vertical-align: top;">&#160;</td>
            <td style="width: 30%; vertical-align: top;">
              <div style="text-align: center;">100%</div>
            </td>
          </tr>
          <tr>
            <td style="width: 25%; vertical-align: top;">&#160;</td>
            <td colspan="1" style="width: 2%; vertical-align: top;">&#160;</td>
            <td style="width: 25%; vertical-align: top;">
              <div style="text-align: center;">45%</div>
            </td>
            <td colspan="1" style="width: 2%; vertical-align: top;">&#160;</td>
            <td style="width: 30%; vertical-align: top;">
              <div style="text-align: center;">90%</div>
            </td>
          </tr>
          <tr>
            <td style="width: 25%; vertical-align: top;">&#160;</td>
            <td colspan="1" style="width: 2%; vertical-align: top;">&#160;</td>
            <td style="width: 25%; vertical-align: top;">
              <div style="text-align: center;">40%</div>
            </td>
            <td colspan="1" style="width: 2%; vertical-align: top;">&#160;</td>
            <td style="width: 30%; vertical-align: top;">
              <div style="text-align: center;">80%</div>
            </td>
          </tr>
          <tr>
            <td style="width: 25%; vertical-align: top;">&#160;</td>
            <td colspan="1" style="width: 2%; vertical-align: top;">&#160;</td>
            <td style="width: 25%; vertical-align: top;">
              <div style="text-align: center;">35%</div>
            </td>
            <td colspan="1" style="width: 2%; vertical-align: top;">&#160;</td>
            <td style="width: 30%; vertical-align: top;">
              <div style="text-align: center;">70%</div>
            </td>
          </tr>
          <tr>
            <td style="width: 25%; vertical-align: top;">&#160;</td>
            <td colspan="1" style="width: 2%; vertical-align: top;">&#160;</td>
            <td style="width: 25%; vertical-align: top;">
              <div style="text-align: center;">30%</div>
            </td>
            <td colspan="1" style="width: 2%; vertical-align: top;">&#160;</td>
            <td style="width: 30%; vertical-align: top;">
              <div style="text-align: center;">60%</div>
            </td>
          </tr>
          <tr>
            <td style="width: 25%; vertical-align: top;">
              <div style="text-align: justify; font-weight: bold;">Threshold Level</div>
            </td>
            <td colspan="1" style="width: 2%; vertical-align: top;">&#160;</td>
            <td style="width: 25%; vertical-align: top;">
              <div style="text-align: center;">25%</div>
            </td>
            <td colspan="1" style="width: 2%; vertical-align: top;">&#160;</td>
            <td style="width: 30%; vertical-align: top;">
              <div style="text-align: center;">50%</div>
            </td>
          </tr>

      </table>
      <div><br>
      </div>
      <div style="text-align: justify; font-style: italic;">There is no minimum number of shares or other consideration that you will receive, and no shares will be earned, if the percentile rank is below the 25th percentile in a Performance Period.</div>
      <div><br>
      </div>
      <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold; color: rgb(0, 0, 0);">(b)</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;<font style="font-weight: bold;">Rules of Calculation:</font></div>
      <div>&#160;</div>
      <div style="text-align: justify; text-indent: 108pt;"><font style="font-weight: bold; color: rgb(0, 0, 0);">(i)</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160; If the Company&#8217;s absolute TSR is negative over the applicable Performance Period, the pay-out will not exceed 100% of Target
        for that Performance Period, even if the percentile rank exceeds the 50<sup style="vertical-align: text-top; line-height: 1; font-size: smaller;">th</sup> percentile (the &#8220;<font style="font-size: 12pt; font-weight: bold; font-style: italic;">Negative TSR Cap</font>&#8221;).</div>
      <div>&#160;</div>
      <div style="text-align: justify; text-indent: 108pt;"><font style="font-weight: bold; color: rgb(0, 0, 0);">(ii)</font>&#160;&#160;&#160;&#160;&#160;&#160; Except as modified in Section 3(b)(iii) or 3(b)(iv) below, for purposes of computing TSR, the stock price at the beginning
        of the Performance Period will be the average closing price of a share of common stock over the 20 trading days beginning on the first day of the Performance Period, and the stock price at the end of the Performance Period will be the average
        closing price of a share of common stock over the 20 trading days preceding and including the last day of the Performance Period, adjusted for changes in capital structure; <font style="font-size: 12pt; font-style: italic;">provided, however</font>,
        that TSR will be negative one hundred percent (-100%) if a company: (A) files for bankruptcy, reorganization, or liquidation under any chapter of the U.S. Bankruptcy Code; (B) is the subject of an involuntary bankruptcy proceeding that is not
        dismissed within 30 days; (C) is the subject of a stockholder approved plan of liquidation or dissolution; or (D) ceases to conduct substantial business operations.</div>
      <div>&#160;</div>
      <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
        <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-size: 8pt; color: rgb(0, 0, 0); font-weight: normal; font-style: normal;">5</font></div>
        <div style="page-break-after: always;" id="DSPFPageBreak">
          <hr noshade="noshade" style="margin: 4px 0px; width: 100%; border-width: 0px; height: 2px; color: rgb(0, 0, 0); background-color: rgb(0, 0, 0); clear: both;"></div>
      </div>
      <div style="text-align: justify; text-indent: 108pt;"><font style="font-weight: bold; color: rgb(0, 0, 0);">(iii)</font>&#160;&#160;&#160;&#160;&#160; Companies will be removed from the Comparison Group if they undergo a Specified Corporate Change. A company that is removed
        from the Comparison Group before the measurement date will not be included at all in the computation of relative TSR. A company in the Comparison Group will be deemed to have undergone a <font style="font-size: 12pt; font-weight: bold; font-style: italic;">Specified Corporate Change</font><font style="font-size: 12pt; font-style: italic;"> if </font>it (A) ceases to be a domestically domiciled publicly traded company on a national stock exchange or market system, unless such cessation of
        such listing is due to a low stock price or low trading volume; (B) has gone private; (C) has reincorporated in a foreign (e.g., non-U.S.) jurisdiction, regardless of whether it is a reporting company in that or another jurisdiction; or (D) has
        been acquired by another company (whether by a peer company or otherwise, but not including internal reorganizations), or has sold all or substantially all of its assets.</div>
      <div>&#160;</div>
      <div style="text-align: justify; text-indent: 108pt;"><font style="font-weight: bold; color: rgb(0, 0, 0);">(iv)</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160; The Company&#8217;s Compensation Committee may in its good faith discretion calculate the TSRs and TSR Percentile Rank using a
        subscription service (such as Bloomberg) provided such calculation is (A) consistently applied, (B) intended to ease the burden of administering this Award, and (C) intended to preserve the overall intent of this Award.</div>
      <div>&#160;</div>
      <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; color: rgb(0, 0, 0);">4.</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;<font style="font-weight: bold; font-variant: small-caps;">Vesting And Termination of Continuous Service.</font></div>
      <div>&#160;</div>
      <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold; color: rgb(0, 0, 0);">(a)</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160; <font style="font-size: 12pt; font-weight: bold;">In General</font>.&#160; Subject to the limitations contained herein, your
        Award will vest, if at all, in accordance with Section 1 above, provided that vesting will cease upon the termination of your Continuous Service except as set forth below.&#160; Upon termination of your Continuous Service, the PRSUs that were not vested
        on the date of such termination will be forfeited at no cost to the Company, and you will have no further right, title or interest in the PRSUs or the shares of Common Stock to be issued in respect of the Award except as set forth below.</div>
      <div>&#160;</div>
      <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold; color: rgb(0, 0, 0);">(b)</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160; <font style="font-size: 12pt; font-weight: bold;">Change in Control</font>.</div>
      <div>&#160;</div>
      <div style="text-align: justify; text-indent: 108pt;"><font style="font-weight: bold; color: rgb(0, 0, 0);">(i)</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160; If a Change in Control Termination (as such term is defined in the Company&#8217;s Severance Benefit Plan adopted October 18, 2018
        (the &#8220;<font style="font-size: 12pt; font-weight: bold; font-style: italic;">Severance Plan</font>&#8221;)) occurs during the Change in Control Protection Period (as such term is defined in the Severance Plan), the Award will pay-out at Target and the
        Target PRSUs subject to such Award that have not already vested will vest immediately upon the Change in Control Termination.</div>
      <div>&#160;</div>
      <div style="text-align: justify; text-indent: 108pt;"><font style="font-weight: bold; color: rgb(0, 0, 0);">(ii)</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160; If a Change in Control (as such term is defined in the Severance Plan) occurs and your Award will not be assumed, continued
        or substituted by the successor or acquiror entity in such Change in Control, the Award will pay-out at Target and the Target PRSUs subject to such Award that have not already vested will vest immediately upon the Change in Control.</div>
      <div>&#160;</div>
      <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
        <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-size: 8pt; color: rgb(0, 0, 0); font-weight: normal; font-style: normal;">6</font></div>
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      </div>
      <div style="text-align: justify; text-indent: 108pt;"><font style="font-weight: bold; color: rgb(0, 0, 0);">(iii)</font>&#160;&#160;&#160;&#160;&#160; If a Change in Control (as such term is defined in the Severance Plan) occurs and your Award will be assumed, continued or
        substituted by the successor or acquiror entity in such Change in Control, the PRSUs subject to such Award will automatically convert upon the Change in Control to time-vested restricted stock units (&#8220;<font style="font-size: 12pt; font-weight: bold; font-style: italic;">RSUs</font>&#8221;) at a rate of one RSU for each of the Target number of PRSUs.&#160; The RSUs will not be subject to the relative TSR performance measure described in Section 1 above and instead will vest at Target at the end of
        the applicable Performance Periods outlined in Section 2(b) above that are still remaining at the time of the Change in Control.&#160; Such RSUs will be subject to further acceleration in the case of a Change in Control Termination during the Change in
        Control Protection Period (as such term is defined in the Severance Plan).</div>
      <div>&#160;</div>
      <div style="text-align: justify; text-indent: 108pt;"><font style="font-weight: bold; color: rgb(0, 0, 0);">(iv)</font>&#160;&#160;&#160;&#160;&#160; Notwithstanding anything to the contrary in this Agreement or the Severance Plan, if you are a party to a prior written
        employment agreement, change of control agreement, or plan or other similar written agreement or plan (each, a &#8220;<font style="font-size: 12pt; font-weight: bold; font-style: italic;">Prior Agreement</font>&#8221;), that provides, in certain circumstances,
        for greater benefits regarding the accelerated vesting of equity awards (including PRSUs) following a Change in Control of the Company or similar transaction, the terms of such Prior Agreement shall control the definition of the term &#8220;<font style="font-size: 12pt; font-style: italic;">Change in Control</font>&#8221; (or any term used therein of similar import) and the terms and conditions by which the vesting of the PRSUs may be accelerated as a result of a Change in Control, as well as
        the benefits that may otherwise be available to you upon a Change in Control.</div>
      <div>&#160;</div>
      <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; color: rgb(0, 0, 0);">5.</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;<font style="font-size: 12pt; font-weight: bold; font-variant: small-caps;">Adjustments to Number of Shares</font><font style="font-size: 12pt; font-weight: bold;">.</font></div>
      <div>&#160;</div>
      <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold; color: rgb(0, 0, 0);">(a)</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160; The number of PRSUs subject to your Award may be adjusted from time to time for Capitalization Adjustments, as provided in
        the Plan.</div>
      <div>&#160;</div>
      <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold; color: rgb(0, 0, 0);">(b)</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;Any additional PRSUs that become subject to the Award pursuant to this Section 5 and Section 9, if any, will be subject, in
        a manner determined by the Board, to the same forfeiture restrictions, restrictions on transferability, and time and manner of delivery as applicable to the other PRSUs covered by your Award.</div>
      <div>&#160;</div>
      <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold; color: rgb(0, 0, 0);">(c)</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;Notwithstanding the provisions of this Section 5, no fractional shares or rights for fractional shares of Common Stock will
        be created pursuant to this Section 5.&#160; The Board will, in its discretion, determine an equivalent benefit for any fractional shares or fractional shares that might be created by the adjustments referred to in this Section 5.</div>
      <div>&#160;</div>
      <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; color: rgb(0, 0, 0);">6.</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;<font style="font-size: 12pt; font-weight: bold; font-variant: small-caps;">Securities Law Compliance</font><font style="font-size: 12pt; font-weight: bold;">.</font>&#160; You may not be issued any shares in respect of your Award unless either (i) the shares are registered under the Securities Act; or (ii) the Company has determined that such issuance would be
        exempt from the registration requirements of the Securities Act. Your Award also must comply with other applicable laws and regulations governing the Award, and you will not receive such shares if the Company determines that such receipt would not
        be in material compliance with such laws and regulations.</div>
      <div>&#160;</div>
      <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; color: rgb(0, 0, 0);">7.</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;<font style="font-size: 12pt; font-weight: bold; font-variant: small-caps;">Transfer Restrictions.</font>&#160; Prior to the time
        that shares of Common Stock have been delivered to you, you may not transfer, pledge, sell or otherwise dispose of this Award or the shares issuable in respect of your Award, except as expressly provided in this Section 7.&#160; For example, you may not
        use shares that may be issued in respect of your Award as security for a loan.&#160; The restrictions on transfer set forth herein will lapse upon delivery to you of shares in respect of your vested Award.</div>
      <div>&#160;</div>
      <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
        <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-size: 8pt; color: rgb(0, 0, 0); font-weight: normal; font-style: normal;">7</font></div>
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      </div>
      <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold; color: rgb(0, 0, 0);">(a)</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160; <font style="font-size: 12pt; font-weight: bold;">Death</font>.&#160; Your Award is transferable by will and by the laws of
        descent and distribution.&#160; In addition, upon receiving written permission from the Board or its duly authorized designee, you may, by delivering written notice to the Company, in a form provided by or otherwise satisfactory to the Company and any
        broker designated by the Company to effect transactions under the Plan, designate a third party who, in the event of your death, will thereafter be entitled to receive any distribution of Common Stock or other consideration to which you were
        entitled at the time of your death pursuant to this Agreement.&#160; In the absence of such a designation, your executor or administrator of your estate will be entitled to receive, on behalf of your estate, such Common Stock or other consideration.</div>
      <div>&#160;</div>
      <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold; color: rgb(0, 0, 0);">(b)</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160; <font style="font-size: 12pt; font-weight: bold;">Certain Trusts.</font>&#160; Upon receiving written permission from the Board
        or its duly authorized designee, you may transfer your Award to a trust if you are considered to be the sole beneficial owner (determined under Section 671 of the Code and applicable state law) while the Award is held in the trust, provided that
        you and the trustee enter into transfer and other agreements required by the Company.</div>
      <div>&#160;</div>
      <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold; color: rgb(0, 0, 0);">(c)</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;<font style="font-size: 12pt; font-weight: bold;">Domestic Relations Orders.</font>&#160; Upon receiving written permission from
        the Board or its duly authorized designee, and provided that you and the designated transferee enter into transfer and other agreements required by the Company, you may transfer your Award or your right to receive the distribution of Common Stock
        or other consideration thereunder, pursuant to a domestic relations order that contains the information required by the Company to effectuate the transfer.&#160; You are encouraged to discuss the proposed terms of any division of this Award with the
        Company prior to finalizing the domestic relations order to help ensure the required information is contained within the domestic relations order.</div>
      <div>&#160;</div>
      <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; color: rgb(0, 0, 0);">8.</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;<font style="font-weight: bold; font-variant: small-caps;">Date of Issuance.</font></div>
      <div>&#160;</div>
      <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold; color: rgb(0, 0, 0);">(a)</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;If the Award is exempt from application of Section 409A of the Code and the regulations and other guidance thereunder and
        any state law of similar effect (collectively <font style="font-size: 12pt; font-weight: bold;">&#8220;</font><font style="font-size: 12pt; font-weight: bold; font-style: italic;">Section</font>&#160;<font style="font-size: 12pt; font-weight: bold; font-style: italic;">409A</font><font style="font-size: 12pt; font-weight: bold;">&#8221;</font>), the Company will deliver to you a number of shares of the Company&#8217;s Common Stock equal to the number of vested PRSUs subject to your Award, including any
        additional PRSUs received pursuant to Section 5 above that relate to those vested PRSUs on the applicable vesting date(s).&#160; However, if a scheduled delivery date falls on a date that is not a business day, such delivery date will instead fall on
        the next following business day.&#160; Notwithstanding the foregoing, in the event that (i) you are subject to the Company&#8217;s policy permitting officers and directors to sell shares only during certain &#8220;window&#8221; periods, in effect from time to time (the &#8220;<font style="font-size: 12pt; font-weight: bold; font-style: italic;">Policy</font>&#8221;) or you are otherwise prohibited from selling shares of the Company&#8217;s Common Stock in the public market and any shares covered by your Award are scheduled to be
        delivered on a day (the &#8220;<font style="font-size: 12pt; font-weight: bold; font-style: italic;">Original Distribution Date</font>&#8221;) that does not occur during an open &#8220;window period&#8221; applicable to you or a day on which you are permitted to sell
        shares of the Company&#8217;s Common Stock pursuant to a written plan that meets the requirements of Rule 10b5-1 under the Exchange Act, in each case as determined by the Company in accordance with the Policy, or does not occur on a date when you are
        otherwise permitted to sell shares of the Company&#8217;s Common Stock on the open market, and (ii) the Company elects not to satisfy its tax withholding obligations (if any) by withholding shares from your distribution, then such shares will not be
        delivered on such Original Distribution Date and will instead be delivered on the first business day of the next occurring open &#8220;window period&#8221; applicable to you pursuant to such policy (regardless of whether you are still providing Continuous
        Services at such time) or the next business day when you are not prohibited from selling shares of the Company&#8217;s Common Stock in the open market, but in no event later than the fifteenth day of the third calendar month of the calendar year
        following the calendar year in which the shares covered by the Award vest.&#160; Delivery of the shares pursuant to the provisions of this Section 8(a) is intended to comply with the requirements for the short-term deferral exemption available under
        Treasury Regulation 1.409A-1(b)(4) and will be construed and administered in such manner.&#160; The form of such delivery of the shares (<font style="font-size: 12pt; font-style: italic;">e.g.</font>, a stock certificate or electronic entry evidencing
        such shares) will be determined by the Company.</div>
      <div>&#160;</div>
      <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
        <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-size: 8pt; color: rgb(0, 0, 0); font-weight: normal; font-style: normal;">8</font></div>
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      </div>
      <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold; color: rgb(0, 0, 0);">(b)</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;The provisions of this Section 8(b) are intended to apply if the Award is subject to Section 409A because of the terms of a
        severance arrangement or other agreement between you and the Company that provides for acceleration of vesting of the Award upon your separation from service (as such term is defined in section 409A(a)(2)(A)(i) of the Code and applicable guidance
        thereunder (&#8220;<font style="font-size: 12pt; font-weight: bold; font-style: italic;">Separation From Service</font>&#8221;) and such severance benefit does not satisfy the requirements for an exemption from application of Section 409A provided under
        Treasury Regulations Sections 1.409A-1(b)(4) or 1.409A-1(b)(9) (&#8220;<font style="font-size: 12pt; font-weight: bold; font-style: italic;">Non-Exempt Severance Arrangement</font>&#8221;).&#160; If the Award is subject to and not exempt from application of Section
        409A due to application of a Non-Exempt Severance Arrangement, the following provisions in this Section 8(b) will supersede anything to the contrary in Section 8(a).</div>
      <div>&#160;</div>
      <div style="text-align: justify; text-indent: 108pt;"><font style="font-weight: bold; color: rgb(0, 0, 0);">(i)</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160; If the Award vests in ordinary course during your Continuous Service in accordance with the vesting schedule set forth in
        the Grant Notice, in no event will the shares to be issued in respect of your Award be issued any later than the later of: (A) December 31<sup style="vertical-align: text-top; line-height: 1; font-size: smaller;">st</sup> of the calendar year that includes the applicable vesting date, or (B) the 60<sup style="vertical-align: text-top; line-height: 1; font-size: smaller;">th</sup> day
        that follows the applicable vesting date.</div>
      <div>&#160;</div>
      <div style="text-align: justify; text-indent: 108pt;"><font style="font-weight: bold; color: rgb(0, 0, 0);">(ii)</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160; If the Award accelerates vesting under the terms of your Non-Exempt Severance Arrangement in connection with your
        Separation From Service, and such vesting acceleration provisions of your Non-Exempt Severance Arrangement were in effect as of the Date of Grant of the Award and therefore part of the terms of the Award as of the Date of Grant, then the shares
        will be earlier issued in respect of your Award upon your Separation From Service in accordance with the terms of the Non-Exempt Severance Arrangement, but in no event later than the 60<sup style="vertical-align: text-top; line-height: 1; font-size: smaller;">th</sup> day that follows the date of your Separation From
        Service.&#160; However, if at the time the shares would otherwise be issued you are subject to the distribution limitations contained in section 409A of the Code applicable to &#8220;specified employees&#8221; as defined in section 409A(a)(2)(B)(i) of the Code and
        applicable guidance thereunder, such share issuances will not be made before the date which is six months following the date of your Separation From Service, or, if earlier, the date of your death that occurs within such six month period.</div>
      <div>&#160;</div>
      <div style="text-align: justify; text-indent: 108pt;"><font style="font-weight: bold; color: rgb(0, 0, 0);">(iii)</font>&#160;&#160;&#160;&#160;&#160;&#160; If the Award accelerates vesting under the terms of your Non-Exempt Severance Arrangement in connection with your
        Separation From Service, and such vesting acceleration provisions of your Non-Exempt Severance Arrangement were not in effect as of the Date of Grant of the Award and therefore not a part of the terms of the Award on the Date of Grant, then such
        acceleration of vesting of the Award will not accelerate the issuance date of the shares, but the shares will instead be issued on the same schedule as set forth on the Grant Notice as if they had vested in ordinary course during your Continuous
        Service, notwithstanding the vesting acceleration of the Award.&#160; Such issuance schedule is intended to satisfy the requirements of payment on a specified date or pursuant to a fixed schedule, as provided under Treas. Reg. 1.409A-3(a)(4).</div>
      <div>&#160;</div>
      <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
        <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-size: 8pt; color: rgb(0, 0, 0); font-weight: normal; font-style: normal;">9</font></div>
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      </div>
      <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold; color: rgb(0, 0, 0);">(c)</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;The provisions in this Agreement for delivery of the shares in respect of the Award are intended either to comply with the
        requirements of Section 409A or to provide a basis for exemption from such requirements so that the delivery of the shares will not trigger the additional tax imposed under Section 409A, and any ambiguities herein will be so interpreted.</div>
      <div>&#160;</div>
      <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; color: rgb(0, 0, 0);">9.</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160; <font style="font-size: 12pt; font-weight: bold; font-variant: small-caps;">Dividends.</font><font style="font-size: 12pt; font-weight: bold;">&#160; </font>You will be entitled to receive payments equal to any cash dividends and other distributions paid with respect to a corresponding number of shares to be issued in respect of the PRSUs covered by your Award, provided
        that if any such dividends or distributions are paid in shares, the Fair Market Value of such shares will be converted into additional PRSUs covered by the Award, and further provided that such additional PRSUs will be subject to the same
        forfeiture restrictions and restrictions on transferability as apply to the PRSUs subject to the Award with respect to which they relate.</div>
      <div>&#160;</div>
      <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; color: rgb(0, 0, 0);">10.</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160; <font style="font-size: 12pt; font-weight: bold; font-variant: small-caps;">Restrictive Legends.</font>&#160; The shares issued
        in respect of your Award will be endorsed with appropriate legends determined by the Company.</div>
      <div>&#160;</div>
      <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; color: rgb(0, 0, 0);">11.</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160; <font style="font-size: 12pt; font-weight: bold; font-variant: small-caps;">Award not a Service Contract</font><font style="font-size: 12pt; font-weight: bold;">.</font></div>
      <div>&#160;</div>
      <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold; color: rgb(0, 0, 0);">(a)</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;Your Continuous Service with the Company or an Affiliate is not for any specified term and may be terminated by you or by
        the Company or an Affiliate at any time, for any reason, with or without cause and with or without notice.&#160; Nothing in this Agreement (including, but not limited to, the vesting of your Award pursuant to Section 1 herein or the issuance of the
        shares in respect of your Award), the Plan or any covenant of good faith and fair dealing that may be found implicit in this Agreement or the Plan will:&#160; (i) confer upon you any right to continue in the employ of, or affiliation with, the Company
        or an Affiliate; (ii) constitute any promise or commitment by the Company or an Affiliate regarding the fact or nature of future positions, future work assignments, future compensation or any other term or condition of employment or affiliation;
        (iii) confer any right or benefit under this Agreement or the Plan unless such right or benefit has specifically accrued under the terms of this Agreement or Plan; or (iv) deprive the Company of the right to terminate you at will and without regard
        to any future vesting opportunity that you may have.</div>
      <div>&#160;</div>
      <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold; color: rgb(0, 0, 0);">(b)</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;By accepting this Award, you acknowledge and agree that the right to continue vesting in the Award pursuant to Section 1 is
        earned only by continuing as an employee, director or consultant at the will of the Company (not through the act of being hired, being granted this Award or any other award or benefit) and that the Company has the right to reorganize, sell,
        spin-out or otherwise restructure one or more of its businesses or Affiliates at any time or from time to time, as it deems appropriate (a &#8220;reorganization&#8221;).&#160; You further acknowledge and agree that such a reorganization could result in the
        termination of your Continuous Service, or the termination of Affiliate status of your employer and the loss of benefits available to you under this Agreement, including but not limited to, the termination of the right to continue vesting in the
        Award.&#160; You further acknowledge and agree that this Agreement, the Plan, the transactions contemplated hereunder and the vesting schedule set forth herein or any covenant of good faith and fair dealing that may be found implicit in any of them do
        not constitute an express or implied promise of continued engagement as an employee or consultant for the term of this Agreement, for any period, or at all, and will not interfere in any way with your right or the Company&#8217;s right to terminate your
        Continuous Service at any time, with or without cause and with or without notice.</div>
      <div>&#160;</div>
      <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
        <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-size: 8pt; color: rgb(0, 0, 0); font-weight: normal; font-style: normal;">10</font></div>
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      </div>
      <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; color: rgb(0, 0, 0);">12.</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160; <font style="font-weight: bold; font-variant: small-caps;">Withholding Obligations.</font></div>
      <div>&#160;</div>
      <div style="text-align: justify; text-indent: 72pt;"><a name="OLE_LINK5"></a><a name="OLE_LINK6"></a><font style="font-weight: bold; color: rgb(0, 0, 0);">(a)</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;On or before the time you receive a distribution of shares subject to your
        Award, or at any time thereafter as requested by the Company, you hereby authorize any required withholding (if any) from the Common Stock issuable to you and/or otherwise agree to make adequate provision in cash for any sums required to satisfy
        the federal, state, local and foreign tax withholding obligations (if any) of the Company or any Affiliate which arise in connection with your Award (the &#8220;<font style="font-size: 12pt; font-weight: bold; font-style: italic;">Withholding Taxes</font>&#8221;).&#160;

        Additionally, the Company may, in its sole discretion, satisfy all or any portion of the Withholding Taxes obligation relating to your Award by any of the following means or by a combination of such means: (i) withholding from any compensation
        otherwise payable to you by the Company; (ii) causing you to tender a cash payment; or (iii) withholding shares of Common Stock from the shares of Common Stock issued or otherwise issuable to you in connection with the Award with a Fair Market
        Value (measured as of the date shares of Common Stock are issued pursuant to Section 8) equal to the amount of such Withholding Taxes; provided, however, that the number of such shares of Common Stock so withheld will not exceed the amount
        necessary to satisfy the Company&#8217;s required tax withholding obligations using the minimum statutory withholding rates for federal, state, local and foreign tax purposes, including payroll taxes, that are applicable to supplemental taxable income.</div>
      <div>&#160;</div>
      <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold; color: rgb(0, 0, 0);">(b)</font>&#160;&#160;&#160;&#160;&#160;&#160; Unless the tax withholding obligations of the Company and/or any Affiliate are satisfied, the Company will have no obligation
        to deliver to you any Common Stock.</div>
      <div>&#160;</div>
      <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold; color: rgb(0, 0, 0);">(c)</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;In the event the Company&#8217;s obligation to withhold arises prior to the delivery to you of Common Stock or it is determined
        after the delivery of Common Stock to you that the amount of the Company&#8217;s withholding obligation was greater than the amount withheld by the Company, you agree to indemnify and hold the Company harmless from any failure by the Company to withhold
        the proper amount.</div>
      <div>&#160;</div>
      <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold; color: rgb(0, 0, 0);">(d)</font>&#160;&#160;&#160;&#160;&#160;&#160; If specified in your Grant Notice and permitted by the Company, you may direct the Company to withhold shares of Common Stock
        with a Fair Market Value (measured as of the date shares of Common Stock are issued pursuant to Section 8) equal to the amount of such Withholding Taxes; provided, however, that the number of such shares of Common Stock so withheld will not exceed
        the amount necessary to satisfy the Company&#8217;s required tax withholding obligations using the minimum statutory withholding rates for federal, state, local and foreign tax purposes, including payroll taxes, that are applicable to supplemental
        taxable income.</div>
      <div>&#160;</div>
      <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; color: rgb(0, 0, 0);">13.</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;<font style="font-size: 12pt; font-weight: bold; font-variant: small-caps;">Unsecured Obligation.</font>&#160; Your Award is
        unfunded, and as a holder of a vested Award, you will be considered an unsecured creditor of the Company with respect to the Company&#8217;s obligation, if any, to issue shares pursuant to this Agreement.&#160; You will not have voting or any other rights as
        a stockholder of the Company with respect to the shares to be issued pursuant to this Agreement until such shares are issued to you pursuant to Section 8 of this Agreement.&#160;&#160; Upon such issuance, you will obtain full voting and other rights as a
        stockholder of the Company.&#160; Nothing contained in this Agreement, and no action taken pursuant to its provisions, will create or be construed to create a trust of any kind or a fiduciary relationship between you and the Company or any other person.</div>
      <div>&#160;</div>
      <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
        <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-size: 8pt; color: rgb(0, 0, 0); font-weight: normal; font-style: normal;">11</font></div>
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      <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; color: rgb(0, 0, 0);">14.</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160; <font style="font-size: 12pt; font-weight: bold; font-variant: small-caps;">Other Documents</font><font style="font-size: 12pt; font-variant: small-caps;">.</font>&#160; You hereby acknowledge receipt or the right to receive a document providing the information required by Rule 428(b)(1) promulgated under the Securities Act, which includes the Plan prospectus.&#160; In
        addition, you acknowledge receipt of the Company&#8217;s insider-trading policy and agree that you may sell shares only in compliance with such policy, in effect from time to time.</div>
      <div>&#160;</div>
      <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; color: rgb(0, 0, 0);">15.</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160; <font style="font-size: 12pt; font-weight: bold; font-variant: small-caps;">Notices</font><font style="font-size: 12pt; font-weight: bold;">.</font>&#160; Any notices provided for in your Award or the Plan will be given in writing and will be deemed effectively given upon receipt or, in the case of notices delivered by the Company to you, five days after deposit in the
        United States mail, postage prepaid, addressed to you at the last address you provided to the Company.&#160; Notwithstanding the foregoing, the Company may, in its sole discretion, decide to deliver any documents related to participation in the Plan and
        this Award by electronic means or to request your consent to participate in the Plan by electronic means.&#160; You hereby consent to receive such documents by electronic delivery and, if requested, to agree to participate in the Plan through an on-line
        or electronic system established and maintained by the Company or another third party designated by the Company.</div>
      <div>&#160;</div>
      <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; color: rgb(0, 0, 0);">16.</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160; <font style="font-weight: bold;"><font style="font-variant: small-caps;">Miscellaneous</font>.</font></div>
      <div>&#160;</div>
      <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold; color: rgb(0, 0, 0);">(a)</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160; The rights and obligations of the Company under your Award will be transferable to any one or more persons or entities, and
        all covenants and agreements hereunder will inure to the benefit of, and be enforceable by the Company&#8217;s successors and assigns. Your rights and obligations under your Award may only be assigned with the prior written consent of the Company.</div>
      <div>&#160;</div>
      <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold; color: rgb(0, 0, 0);">(b)</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160; You agree upon request to execute any further documents or instruments necessary or desirable in the sole determination of
        the Company to carry out the purposes or intent of your Award.</div>
      <div>&#160;</div>
      <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold; color: rgb(0, 0, 0);">(c)</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160; You acknowledge and agree that you have reviewed your Award in its entirety, have had an opportunity to obtain the advice of
        counsel prior to executing and accepting your Award, and fully understand all provisions of your Award.</div>
      <div>&#160;</div>
      <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold; color: rgb(0, 0, 0);">(d)</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160; This Agreement will be subject to all applicable laws, rules, and regulations, and to such approvals by any governmental
        agencies or national securities exchanges as may be required.</div>
      <div>&#160;</div>
      <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold; color: rgb(0, 0, 0);">(e)</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160; All obligations of the Company under the Plan and this Agreement will be binding on any successor to the Company, whether the
        existence of such successor is the result of a direct or indirect purchase, merger, consolidation, or otherwise, of all or substantially all of the business and/or assets of the Company.</div>
      <div>&#160;</div>
      <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; color: rgb(0, 0, 0);">17.</font>&#160;&#160;&#160;&#160;&#160;&#160; <font style="font-size: 12pt; font-weight: bold; font-variant: small-caps;">Governing Plan Document</font><font style="font-size: 12pt; font-weight: bold;">.</font>&#160; Your Award is subject to all the provisions of the Plan, the provisions of which are hereby made a part of your Award, and is further subject to all interpretations, amendments, rules and
        regulations which may from time to time be promulgated and adopted pursuant to the Plan.&#160; Except as expressly provided herein, in the event of any conflict between the provisions of your Award and those of the Plan, the provisions of the Plan will
        control.</div>
      <div>&#160;</div>
      <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
        <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-size: 8pt; color: rgb(0, 0, 0); font-weight: normal; font-style: normal;">12</font></div>
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      </div>
      <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; color: rgb(0, 0, 0);">18.</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160; <font style="font-size: 12pt; font-weight: bold; font-variant: small-caps;">Severability.</font>&#160; If all or any part of this
        Agreement or the Plan is declared by any court or governmental authority to be unlawful or invalid, such unlawfulness or invalidity will not invalidate any portion of this Agreement or the Plan not declared to be unlawful or invalid. Any Section of
        this Agreement (or part of such a Section) so declared to be unlawful or invalid will, if possible, be construed in a manner which will give effect to the terms of such Section or part of a Section to the fullest extent possible while remaining
        lawful and valid.</div>
      <div>&#160;</div>
      <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; color: rgb(0, 0, 0);">19.</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160; <font style="font-size: 12pt; font-weight: bold; font-variant: small-caps;">Effect on Other Employee Benefit Plans</font><font style="font-size: 12pt; font-weight: bold;">. </font>The value of the Award subject to this Agreement shall not be included as compensation, earnings, salaries, or other similar terms used when calculating your benefits under any employee
        benefit plan sponsored by the Company or any Affiliate, except as such plan otherwise expressly provides. The Company expressly reserves its rights to amend, modify, or terminate any of the Company&#8217;s or any Affiliate&#8217;s employee benefit plans.</div>
      <div>&#160;</div>
      <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; color: rgb(0, 0, 0);">20.</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160; <font style="font-size: 12pt; font-weight: bold; font-variant: small-caps;">Choice of Law</font><font style="font-size: 12pt; font-weight: bold;">.</font>&#160; The interpretation, performance and enforcement of this Agreement will be governed by the law of the state of California without regard to such state&#8217;s conflicts of laws rules.</div>
      <div>&#160;</div>
      <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; color: rgb(0, 0, 0);">21.</font>&#160;&#160;&#160;&#160;&#160;&#160; <font style="font-size: 12pt; font-weight: bold; font-variant: small-caps;">Amendment.</font>&#160; This Agreement may not be
        modified, amended or terminated except by an instrument in writing, signed by you and by a duly authorized representative of the Company. Notwithstanding the foregoing, this Agreement may be amended solely by the Board by a writing which
        specifically states that it is amending this Agreement, so long as a copy of such amendment is delivered to you, and provided that no such amendment adversely affecting your rights hereunder may be made without your written consent. Without
        limiting the foregoing, the Board reserves the right to change, by written notice to you, the provisions of this Agreement in any way it may deem necessary or advisable to carry out the purpose of the grant as a result of any change in applicable
        laws or regulations or any future law, regulation, ruling, or judicial decision, provided that any such change will be applicable only to rights relating to that portion of the Award which is then subject to restrictions as provided herein.</div>
      <div>&#160;</div>
      <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; color: rgb(0, 0, 0);">22.</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160; <font style="font-size: 12pt; font-weight: bold; font-variant: small-caps;">Discretion of the Committee.</font> Unless
        otherwise explicitly provided herein, the Compensation Committee of the Board of Directors of the Company, or an authorized successor committee thereto, shall make all determinations required to be made hereunder, including but not limited to
        determinations relating to the achievement of any thresholds or the vesting of any PRSUs hereunder, and shall interpret all provisions of this PRSU Award Agreement and the underlying PRSUs, as it deems necessary or desirable, in its sole and
        absolute discretion. Such determinations and interpretations shall be binding on and conclusive to the Company and you. Without limiting the foregoing, the Company may, in its sole and absolute discretion, delay payments hereunder or make such
        other modifications with respect to the issuance of stock hereunder as it reasonably deems necessary to the extent that (a) audited financials are not complete for any applicable period during the Performance Period and/or (b) the Company has not
        had an adequate opportunity to review the audited financials or confirm the applicable TSR Percentile Ranks.</div>
      <div>&#160;</div>
    </div>
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<DOCUMENT>
<TYPE>EX-10.60
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<FILENAME>exhibit10-60.htm
<DESCRIPTION>EXHIBIT 10.60
<TEXT>
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    <div style="text-align: right;"> <font style="font-weight: bold;">Exhibit 10.60</font><br>
    </div>
    <div>
      <div style="text-align: center; font-weight: bold;">IONIS PHARMACEUTICALS, INC.</div>
      <div><br>
      </div>
      <div style="text-align: center; font-weight: bold;">FOURTH AMENDED AND RESTATED</div>
      <div style="text-align: center; font-weight: bold;">STRATEGIC ADVISORY SERVICES AGREEMENT (&#8220;<font style="font-style: italic;">SUMMARY PAGE</font>&#8221;)</div>
      <div><br>
      </div>
      <div style="text-align: justify;">This Fourth Amended and Restated Strategic Advisory Services Agreement is entered into by and between Lyme Pinnacle Consulting Inc., for the services of B. Lynne Parshall, and is made effective as of February 22,
        2022, and amends and restates the Strategic Advisory Service Agreement dated January 15, 2018, as amended on March 22, 2019, January 9, 2020 and February 22, 2021, by and between B. Lynne Parshall and Ionis Pharmaceuticals, Inc. (&#8220;<font style="font-weight: bold; font-style: italic;">Ionis</font>&#8221;).</div>
      <div><br>
      </div>
      <table cellspacing="0" cellpadding="0" border="0" id="z9f5b274917b3432fa81e4c8d8fedd392" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; border-collapse: collapse; text-align: left; color: #000000;">

          <tr>
            <td style="width: 50%; vertical-align: top;">
              <div style="margin-left: 2.8pt;">Date of Fourth Amended and Restated Strategic Advisory Services Agreement: (&#8220;<font style="font-weight: bold; font-style: italic;">Agreement</font>&#8221;)</div>
            </td>
            <td style="width: 50%; vertical-align: bottom; border-bottom: 2px solid rgb(0, 0, 0);">
              <div style="margin-left: 4.45pt;">February 22, 2022 (&#8220;4<sup style="vertical-align: text-top; line-height: 1; font-size: smaller;">th</sup><font style="font-weight: bold; font-style: italic;"> A&amp;R Effective Date</font>&#8221;).</div>
            </td>
          </tr>
          <tr>
            <td style="width: 50%; vertical-align: bottom;">
              <div style="margin-left: 2.8pt;">Name of Strategic Advisor:</div>
            </td>
            <td style="width: 50%; vertical-align: bottom; border-bottom: 2px solid rgb(0, 0, 0);">
              <div style="margin-right: 0.05pt; margin-left: 4.45pt;">B. Lynne Parshall (hereinafter &#8220;<font style="font-weight: bold; font-style: italic;">Strategic Advisor</font>&#8221;).</div>
            </td>
          </tr>
          <tr>
            <td style="width: 50%; vertical-align: bottom;">
              <div style="margin-left: 2.8pt;">Scope of Strategic Advisory Services:</div>
            </td>
            <td style="width: 50%; vertical-align: bottom; border-bottom: 2px solid rgb(0, 0, 0);">
              <div style="margin-right: 0.05pt; margin-left: 4.45pt;">Provide advisory services to Ionis on projects as directed by the CEO.</div>
            </td>
          </tr>
          <tr>
            <td style="width: 50%; vertical-align: bottom;">
              <div style="margin-left: 2.8pt;">Duration of Strategic Advisory Services (the &#8220;<font style="font-weight: bold; font-style: italic;">Strategic Advisory Period</font>&#8221;):</div>
            </td>
            <td style="width: 50%; vertical-align: bottom; border-bottom: 2px solid rgb(0, 0, 0);">
              <div style="margin-left: 4.45pt;">Commencing January 1, 2022 and continuing through December 31, 2022.</div>
            </td>
          </tr>
          <tr>
            <td style="width: 50%; vertical-align: top;">
              <div style="margin-right: 18.7pt; margin-left: 2.9pt;">Consideration for Strategic Advisory Services:</div>
            </td>
            <td style="width: 50%; vertical-align: bottom; border-bottom: 2px solid rgb(0, 0, 0);">
              <div style="margin-right: 0.05pt; margin-left: 4.45pt;">Annual fee of $225,000 to be paid quarterly.</div>
            </td>
          </tr>

      </table>
      <div><br>
      </div>
      <div style="text-align: justify;">In addition to such compensation, Ionis will reimburse Strategic Advisor for Ionis directed travel, lodging and related expenses or reasonable rate equivalents for lodging, car and meals that Strategic Advisor&#160;
        incurs in the course of performing Strategic Advisory Services under this Agreement.&#160; All such reimbursements will be in accordance with Ionis&#8217; travel policy and Strategic Advisor will provide Ionis with reasonably acceptable supporting
        documentation.</div>
      <div><br>
      </div>
      <div style="text-align: justify;">Strategic Advisor agrees to provide Ionis with Strategic Advisory Services on the terms described above and according to the additional terms attached hereto as Exhibit A. In this Agreement references to Ionis will
        include Ionis&#8217; affiliate companies where applicable.</div>
      <div><br>
      </div>
      <table cellspacing="0" cellpadding="0" border="0" id="z18a62b3ce28749f7a3a9b7e40cbc444e" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; border-collapse: collapse; text-align: left; color: #000000;">

          <tr>
            <td style="width: 15%; vertical-align: top; border-right: 2px solid rgb(0, 0, 0);">&#160;</td>
            <td style="width: 40%; vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0);">
              <div style="font-weight: bold;">Lyme Pinnacle Consulting Inc.</div>
            </td>
            <td style="width: 2%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0);">&#160;</td>
            <td style="width: 43%; vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0);">
              <div style="font-weight: bold;">Ionis Pharmaceuticals, Inc.</div>
            </td>
          </tr>
          <tr>
            <td style="width: 15%; vertical-align: bottom; padding-bottom: 2px;">
              <div>By (Signature):</div>
            </td>
            <td style="width: 40%; vertical-align: bottom; border-bottom: 2px solid rgb(0, 0, 0);">
              <div>/s/B. Lynne Parshall</div>
            </td>
            <td style="width: 2%; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
            <td style="width: 43%; vertical-align: bottom; border-bottom: 2px solid rgb(0, 0, 0);">
              <div>/s/Brett Monia</div>
            </td>
          </tr>
          <tr>
            <td style="width: 15%; vertical-align: bottom;">
              <div>Date:</div>
            </td>
            <td style="width: 40%; vertical-align: bottom; border-bottom: 2px solid rgb(0, 0, 0);">
              <div>February 23, 2022</div>
            </td>
            <td style="width: 2%; vertical-align: bottom;">&#160;</td>
            <td style="width: 43%; vertical-align: bottom; border-bottom: 2px solid rgb(0, 0, 0);">
              <div>February 22, 2022</div>
            </td>
          </tr>
          <tr>
            <td style="width: 15%; vertical-align: top;">
              <div>Printed Name:</div>
            </td>
            <td style="width: 40%; vertical-align: bottom; border-bottom: 2px solid rgb(0, 0, 0);">
              <div>B. Lynne Parshall, for Lyme Pinnacle Consulting Inc.</div>
            </td>
            <td style="width: 2%; vertical-align: bottom;">&#160;</td>
            <td style="width: 43%; vertical-align: bottom; border-bottom: 2px solid rgb(0, 0, 0);">
              <div>Brett Monia</div>
            </td>
          </tr>

      </table>
      <div><br>
      </div>
      <div style="text-align: justify; font-weight: bold;">Social Security or Employer Tax ID Number to be provided separately via W-9 form or foreign equivalent.</div>
      <div style="text-align: justify; font-weight: bold;"> <br>
      </div>
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      <div style="text-align: center; font-weight: bold;">EXHIBIT A</div>
      <div><br>
      </div>
      <div style="text-align: center; font-weight: bold;">TERMS OF STRATEGIC ADVISORY AGREEMENT</div>
      <div><br>
      </div>
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          <tr>
            <td style="width: 36pt; vertical-align: top; font-weight: bold;">1.</td>
            <td style="width: auto; vertical-align: top;">
              <div style="font-weight: bold;"><u>Engagement of Services</u></div>
            </td>
          </tr>

      </table>
      <div><br>
      </div>
      <div style="text-align: justify;">Strategic Advisor is retained to perform certain services, as needed and requested by Ionis (&#8220;<font style="font-weight: bold; font-style: italic;">Strategic Advisory Services</font>&#8221;). Strategic Advisor will perform
        such Strategic Advisory Services to the best of Strategic Advisor&#8217;s talent and ability.</div>
      <div><br>
      </div>
      <table cellspacing="0" cellpadding="0" id="z7425e01827a546a0bb97b30f8461a28d" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">

          <tr>
            <td style="width: 36pt; vertical-align: top; font-weight: bold;">2.</td>
            <td style="width: auto; vertical-align: top;">
              <div style="font-weight: bold;"><u>Compensation</u></div>
            </td>
          </tr>

      </table>
      <div><br>
      </div>
      <div style="text-align: justify;">(a)&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160; As full and complete compensation for Strategic Advisory Services and for the discharge of all of Strategic Advisor&#8217;s obligations hereunder, Ionis will pay Strategic Advisor at the annual rate of $225,000
        to be paid quarterly in calendar year 2022. Strategic Advisor will submit reimbursable expenses to Ionis electronically, and Ionis, upon its approval, will pay all undisputed fees and expenses within 30 days after Ionis&#8217; receipt of the
        reimbursement request.</div>
      <div><br>
      </div>
      <div style="text-align: justify;">(b)&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;<font style="font-style: italic;">Ionis Stock Awards:</font></div>
      <div><br>
      </div>
      <div style="text-align: justify; text-indent: 36pt;">(i) Since you transitioned seamlessly from an Ionis employee to a nonemployee director, the stock options and RSUs you received for your previous service as an Ionis employee will continue to vest
        so long as your Continuous Service (as defined in the applicable equity plan) continues.</div>
      <div><br>
      </div>
      <div style="text-align: justify; text-indent: 36pt;">(ii) Once you are no longer serving on the Ionis board and no longer providing Strategic Advisory Services, to the extent permitted by the terms of the applicable stock option agreement, your
        vested stock options will not terminate until the earlier of 18 months following your retirement or the expiration of the original term of such stock option.</div>
      <div><br>
      </div>
      <div style="text-align: justify; text-indent: 36pt;">(iii) For the 18 months following the end of your Ionis board of directors services, if you are eligible for continued health coverage under COBRA, Ionis will pay your COBRA premium payments
        sufficient to continue your coverage at your then current level, or if COBRA is not available, Ionis will pay you an amount equal to the cost of comparable replacement coverage.</div>
      <div><br>
      </div>
      <div style="text-indent: 36pt;">(c) While you are providing Strategic Advisory Services, Ionis will make an appropriate level of administrative and technical personnel available to facilitate your performance of Advisory Services at no cost to you,
        including, without limitation IT support and access to Ionis&#8217; electronic calendar and IT systems that are necessary to perform your duties.</div>
      <div><br>
      </div>
      <table cellspacing="0" cellpadding="0" id="zc351d46777774dd4ae704d2cf952287b" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">

          <tr>
            <td style="width: 36pt; vertical-align: top; font-weight: bold;">3.</td>
            <td style="width: auto; vertical-align: top;">
              <div style="font-weight: bold;"><u>Independent Contractor</u></div>
            </td>
          </tr>

      </table>
      <div><br>
      </div>
      <div style="text-align: justify;">Strategic Advisor is an independent contractor and not an employee of Ionis. Strategic Advisor has no authority to obligate Ionis by contract or otherwise. Strategic Advisor will not be eligible for any employee
        benefits. Taxes will be the sole responsibility of Strategic Advisor.</div>
      <div><br>
      </div>
      <table cellspacing="0" cellpadding="0" id="za10340e9dec949e78aaa1ae43d0bf20b" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">

          <tr>
            <td style="width: 36pt; vertical-align: top; font-weight: bold;">4.</td>
            <td style="width: auto; vertical-align: top;">
              <div style="font-weight: bold;"><u>Additional Activities</u></div>
            </td>
          </tr>

      </table>
      <div><br>
      </div>
      <div style="text-align: justify;">(a)&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160; Strategic Advisor agrees that during the Strategic Advisory Period and for one year thereafter, Strategic Advisor will not attempt to induce any employee or employees of Ionis to terminate their
        employment with, or otherwise cease their relationship with Ionis.</div>
      <div style="text-align: justify;"> <br>
      </div>
      <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
        <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-size: 8pt; color: #000000; font-weight: normal; font-style: normal;" id="DSPFPageNumber">2 of 7</font></div>
        <div id="DSPFPageBreak" style="page-break-after:always;">
          <hr noshade="noshade" style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;"></div>
      </div>
      <div style="text-align: justify;">(b)&#160;&#160;&#160;&#160;&#160;&#160;&#160; Strategic Advisor acknowledges that Ionis has developed, through an extensive acquisition process, valuable information regarding actual or prospective partners, licensors, licensees, clients, customers
        and accounts of Ionis (&#8220;<font style="font-weight: bold; font-style: italic;">Trade Secret Information</font>&#8221;). Strategic Advisor acknowledges that Strategic Advisor&#8217;s use of such Trade Secret Information after the termination of the Strategic
        Advisory Period would cause Ionis irreparable harm. Therefore, Strategic Advisor also agrees that Strategic Advisor will not utilize any Trade Secret Information to solicit the business relationship or patronage of any of the actual or prospective
        partners, licensors, licensees, clients, customers or accounts of Ionis.</div>
      <div><br>
      </div>
      <div style="text-align: justify;">(c)&#160;&#160;&#160;&#160;&#160; &#160;&#160; The restrictions set forth in this Section 4 are considered by the parties to be reasonable for the purposes of protecting Ionis&#8217; business. However, if any such restriction is found by a court of
        competent jurisdiction to be unenforceable because it extends for too long a period of time or over too great a range of activities or in too broad a geographic area, it will be interpreted to extend only over the maximum period of time, range of
        activities or geographic areas as to which it may be enforceable.</div>
      <div><br>
      </div>
      <table cellspacing="0" cellpadding="0" id="zcbde70c8d499426c9d1daed043bc761a" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">

          <tr>
            <td style="width: 36pt; vertical-align: top; font-weight: bold;">5.</td>
            <td style="width: auto; vertical-align: top;">
              <div style="font-weight: bold;"><u>Confidential Information</u></div>
            </td>
          </tr>

      </table>
      <div><br>
      </div>
      <div style="text-align: justify;">(a)&#160;&#160;&#160;&#160;&#160;&#160; Ionis possesses confidential information that has been created, discovered, developed by, or otherwise become known to Ionis (including, without limitation, information created, discovered, developed or
        made known by Strategic Advisor arising from the Strategic Advisory Services).</div>
      <div><br>
      </div>
      <div style="text-align: justify;">(i)&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160; All such information is hereinafter referred to as &#8220;<font style="font-weight: bold; font-style: italic;">Confidential Information</font>.&#8221; By way of illustration, but not limitation, Confidential
        Information includes: (A) inventions, developments, designs, improvements, trade secrets, ideas, formulas, source and object codes, programs, other works of authorship, organisms, plasmids, expression vectors, know-how, processes, cell lines,
        discoveries, techniques, data and documentation systems (hereinafter collectively referred to as &#8220;<font style="font-weight: bold; font-style: italic;">Inventions</font>&#8221;); and (B) information regarding plans for research, development, new products,
        clinical data, pre-clinical product data, clinical trial patient data, marketing and selling, business plans, budgets and unpublished financial statements, licenses, prices and costs, as well as information regarding the skills and compensation of
        employees of Ionis.</div>
      <div><br>
      </div>
      <div style="text-align: justify;">(ii)&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160; All Confidential Information will be the sole property of Ionis and its assigns, and Ionis and its assigns will be the sole owner of all patents, copyrights and other rights in connection with such
        Confidential Information. At all times, both during the term of this Agreement and for five years after its termination, Strategic Advisor will keep in confidence and trust all Confidential Information and will not use, disclose, lecture upon or
        publish any Confidential Information or anything related to such information without Ionis&#8217; prior written consent. Any permitted disclosures will be made in strict compliance with the Ionis publication and presentation clearance policy.</div>
      <div><br>
      </div>
      <div style="text-align: justify;">(b)&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160; Strategic Advisor also understands that Ionis has received and in the future, will receive valuable information from third parties that is confidential or proprietary (&#8220;<font style="font-weight: bold; font-style: italic;">Third-Party Information</font>&#8221;) subject to a duty on the part of Ionis to maintain the confidentiality of such information and to use it only for certain limited purposes. During the term of this Agreement and for five years
        thereafter, Strategic Advisor will hold Third-Party Information in the strictest confidence and will not disclose or use Third-Party Information except as permitted by the agreement between Ionis and such third party, unless expressly authorized to
        act otherwise by an officer of Ionis in writing. Any permitted disclosures will be made in strict compliance with Ionis publication and presentation clearance policy.</div>
      <div><br>
      </div>
      <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
        <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-size: 8pt; color: #000000; font-weight: normal; font-style: normal;" id="DSPFPageNumber">3 of 7</font></div>
        <div id="DSPFPageBreak" style="page-break-after:always;">
          <hr noshade="noshade" style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;"></div>
      </div>
      <div style="text-align: justify;">(c)&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160; The obligations of Section 5 will not apply to information that Strategic Advisor can establish by written records: (i) was known by Strategic Advisor prior to the receipt of Confidential Information;
        (ii) was disclosed to Strategic Advisor by a third party having the right to do so; (iii) was, or subsequently became, in the public domain through no fault of Strategic Advisor, its officers, directors, affiliates employees or agents; (iv) was
        independently developed by Strategic Advisor without use of Confidential Information; or (v) was disclosed by Strategic Advisor pursuant to any judicial, governmental or stock exchange request, requirement or order, so long as Strategic Advisor
        provided Ionis with sufficient prior notice in order to allow Ionis to contest such request, requirement or order.</div>
      <div><br>
      </div>
      <table cellspacing="0" cellpadding="0" id="z0796b61ef2a04f0ea9e0e5f4628c0246" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">

          <tr>
            <td style="width: 36pt; vertical-align: top; font-weight: bold;">6.</td>
            <td style="width: auto; vertical-align: top;">
              <div style="font-weight: bold;"><u>Inventions</u></div>
            </td>
          </tr>

      </table>
      <div><br>
      </div>
      <div style="text-align: justify;">In the course of performing Strategic Advisory Services for Ionis, Strategic Advisor may develop new ideas or Inventions or make other contributions of value to Ionis.</div>
      <div><br>
      </div>
      <div style="text-align: justify;">(a)&#160;&#160;&#160;&#160;&#160;&#160;&#160; Strategic Advisor hereby assigns to Ionis Strategic Advisor&#8217;s entire right, title and interest in and to any and all Inventions (and all patent rights, copyrights, and all other rights in connection
        therewith, hereinafter referred to as &#8220;<font style="font-weight: bold; font-style: italic;">Proprietary Rights</font>&#8221;) whether or not patentable or registrable under patent, copyright or similar statutes, made or conceived of or reduced to
        practice or learned by Strategic Advisor, either alone or jointly with others, as a result of performing Strategic Advisory Services hereunder. All Inventions assigned to Ionis pursuant to this section will be known as &#8220;<font style="font-weight: bold; font-style: italic;">Company Inventions</font>&#8221;. Strategic Advisor agrees that all Proprietary Rights and Company Inventions are Ionis&#8217; sole property. Strategic Advisor agrees, upon request, to execute, verify and deliver assignments of
        such Proprietary Rights to Ionis or its designee. Strategic Advisor understands that, to the extent this Agreement will be construed in accordance with the laws of any state which precludes a requirement in an agreement to assign certain classes of
        inventions made by an individual acting as a Strategic Advisor, this section will be interpreted not to apply to any inventions that a court rules and/or Ionis agrees falls within such classes.</div>
      <div><br>
      </div>
      <div style="text-align: justify;">(b)&#160;&#160;&#160;&#160;&#160;&#160;&#160; Strategic Advisor further agrees to assist Ionis in every proper way to obtain, from time to time, and to enforce United States and foreign Proprietary Rights relating to Company Inventions in any and all
        countries. To that end Strategic Advisor will execute, verify and deliver such documents and perform such other acts (including appearances as a witness) as Ionis may reasonably request for use in applying for, obtaining, sustaining and enforcing
        such Proprietary Rights relating to Company Inventions. Strategic Advisor&#8217;s obligation to assist Ionis in obtaining and enforcing Proprietary Rights relating to Company Inventions in any and all countries will continue beyond the termination of
        this Agreement, but Ionis will compensate Strategic Advisor at a reasonable rate after such termination for the time actually spent by Strategic Advisor at Ionis&#8217; request in connection with such assistance. If Ionis is unable, after reasonable
        effort, to secure Strategic Advisor&#8217;s signature on any document needed to apply for or prosecute any Proprietary Rights relating to a Company Invention, Strategic Advisor hereby irrevocably designates and appoints Ionis and its duly authorized
        officers and agents as her agent and attorney in fact, to act for and on Strategic Advisor&#8217;s behalf to execute, verify and file any such applications and to do all other lawfully permitted acts to further the prosecution and issuance of any such
        Proprietary Rights with the same legal force and effect as if executed by Strategic Advisor.</div>
      <div><br>
      </div>
      <div style="text-align: justify;">(c)&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160; During the term of this Agreement, Strategic Advisor will promptly disclose to Ionis, or&#160;&#160; any persons designated by it, fully and in writing and will hold in trust for the sole right and benefit of Ionis
        any and all Company Inventions, whether or not patentable or protectable by copyright. At the time of each such disclosure, Strategic Advisor will advise Ionis in writing of any Inventions that Strategic Advisor believes are not subject to the
        assignment provisions of Section 6(a) above, and Strategic Advisor will at that time provide to Ionis in writing all evidence necessary to substantiate that belief. Strategic Advisor will not be obligated to disclose information received by
        Strategic Advisor from others under a contract of confidentiality. In addition, after termination of this Agreement, Strategic Advisor will disclose to Ionis all patent applications filed by Strategic Advisor relating to any Company Inventions or
        relating to any work performed by Strategic Advisor on behalf of Ionis.</div>
      <div><br>
      </div>
      <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
        <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-size: 8pt; color: #000000; font-weight: normal; font-style: normal;" id="DSPFPageNumber">4 of 7</font></div>
        <div id="DSPFPageBreak" style="page-break-after:always;">
          <hr noshade="noshade" style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;"></div>
      </div>
      <table cellspacing="0" cellpadding="0" id="z631e853067fc4abc8fe9572c3e03c985" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">

          <tr>
            <td style="width: 36pt; vertical-align: top; font-weight: bold;">7.</td>
            <td style="width: auto; vertical-align: top;">
              <div style="font-weight: bold;"><u>Previous Strategic Advisory Relationships</u></div>
            </td>
          </tr>

      </table>
      <div><br>
      </div>
      <div style="text-align: justify;">Strategic Advisor represents that Strategic Advisor&#8217;s performance of Strategic Advisory Services, as well as Strategic Advisor&#8217;s performance of the rest of Strategic Advisor&#8217;s obligations under the terms of this
        Agreement, will not breach any agreement to keep in confidence any proprietary information acquired by Strategic Advisor in confidence or in trust from another entity prior to the date of this Agreement. Strategic Advisor agrees not to bring to
        Ionis or to use in the performance of Strategic Advisory Services for Ionis any materials or documents of a present or former employer or client of Strategic Advisor, or any materials or documents obtained by Strategic Advisor under a
        confidentiality agreement imposed by reason of another of Strategic Advisor&#8217;s Strategic Advisory relationships, unless such materials or documents are generally available to the public or Strategic Advisor has authorization from such present or
        former employer or client for the possession and unrestricted use of such materials.</div>
      <div><br>
      </div>
      <table cellspacing="0" cellpadding="0" id="z57e099b7c2674879ae910fae2a57e00d" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">

          <tr>
            <td style="width: 36pt; vertical-align: top; font-weight: bold;">8.</td>
            <td style="width: auto; vertical-align: top;">
              <div style="font-weight: bold;"><u>Termination; Survival</u></div>
            </td>
          </tr>

      </table>
      <div><br>
      </div>
      <div style="text-align: justify;">(a)&#160;&#160;&#160;&#160;&#160;&#160;&#160; The term of this Agreement will begin on January 15, 2018 and will end when terminated by either Ionis or Strategic Advisor. Ionis may terminate this Agreement at any time for any reason by providing
        Strategic Advisor at least 90 days advance written notice. Strategic Advisor may terminate this Agreement at any time for any reason by providing Ionis at least 90 days advance written notice; <font style="font-style: italic;">provided</font>,
        once Strategic Advisor delivers such a termination notice, Ionis may elect to accelerate the effective date of such termination. Upon any termination, Ionis will pay Strategic Advisor for any Strategic Advisory Services appropriately rendered and
        for any out of pocket expenses reasonably incurred on behalf of Ionis, up to and including the termination date.</div>
      <div><br>
      </div>
      <div style="text-align: justify;">(b)&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160; Sections 2(b)(ii) and 2(b)(iii), 9 and 10, will survive termination of this Agreement. In addition, upon expiration or termination of this Agreement, each party will be released from all obligations and
        liabilities to the other occurring or arising after the date of such expiration or termination, except that any termination or expiration of this Agreement will not relieve Strategic Advisor of Strategic Advisor&#8217;s obligations under Sections 4, 5,
        6, 7, 9, 10 and 11 hereof, nor will any such expiration or termination relieve Strategic Advisor or Ionis from any liability arising from any breach of this Agreement. Upon expiration or termination of this Agreement for any reason whatsoever,
        Strategic Advisor will promptly surrender and deliver to Ionis any and all notes, business records, memoranda, specifications, devices, formulas, molecules, cells, storage media, including calculations, sequences, data and other materials of any
        nature pertaining to Strategic Advisory Services for Ionis, as well as any documents or data of any description (or any reproduction of any documents or data) containing or pertaining to any Trade Secret Information, Ionis&#8217; Confidential Information
        or Third Party Information.</div>
      <div><br>
      </div>
      <table cellspacing="0" cellpadding="0" id="z5bbf0669623746b39bc3c259e6091160" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">

          <tr>
            <td style="width: 36pt; vertical-align: top; font-weight: bold;">9.</td>
            <td style="width: auto; vertical-align: top;">
              <div style="font-weight: bold;"><u>Arbitration</u></div>
            </td>
          </tr>

      </table>
      <div><br>
      </div>
      <div style="text-align: justify;">(a)&#160;&#160;&#160;&#160;&#160;&#160;&#160; Ionis and Strategic Advisor agree to resolve by arbitration all disputes, claims or controversies (&#8220;<font style="font-weight: bold; font-style: italic;">Claims</font>&#8221;), past, present or future, whether or
        not arising out of this Agreement or its termination, that Ionis may have against Strategic Advisor or that Strategic Advisor may have against any of the following (i) Ionis; (ii) Ionis officers, directors; employees or agents; (iii) Ionis&#8217;
        subsidiary or affiliated entities, joint ventures, or joint employers; (iv) Ionis&#8217; benefit plans or the plans&#8217; sponsors, fiduciaries, administrators, affiliates and agents; and/or (v) all successors and assigns of any of the foregoing. The Claims
        covered by this Agreement include all disputes that Ionis or Strategic Advisor could otherwise pursue in state or federal court including, but not limited to, Claims based on any state, federal, or local statute, regulation or ordinance (including
        Claims for discrimination, retaliation, harassment, unpaid wages or violation of state or federal wage and hour laws), as well as common law Claims (including Claims for breach of contract, breach of the implied covenant of good faith and fair
        dealing, wrongful discharge, defamation, misrepresentation, fraud, or infliction of emotional distress). Ionis and Strategic Advisor anticipates that this Section 9 provides the benefits of a speedy, less formal, impartial, final and binding
        dispute resolution procedure.</div>
      <div><br>
      </div>
      <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
        <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-size: 8pt; color: #000000; font-weight: normal; font-style: normal;" id="DSPFPageNumber">5 of 7</font></div>
        <div id="DSPFPageBreak" style="page-break-after:always;">
          <hr noshade="noshade" style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;"></div>
      </div>
      <div style="text-align: justify;">(b)&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160; To the maximum extent permitted by law, Strategic Advisor hereby waives any right to bring on behalf of persons other than Strategic Advisor, or to otherwise participate with other persons in, any class,
        collective or representative action (i.e. a type of lawsuit in which one or several persons sue on behalf of a larger group of persons).</div>
      <div><br>
      </div>
      <div style="text-align: justify;">(c)&#160;&#160;&#160;&#160;&#160;&#160;&#160; The arbitration will be conducted by a single neutral arbitrator in accordance with the then- current Commercial Arbitration and Mediation Procedures of the American Arbitration Association (&#8220;<font style="font-weight: bold; font-style: italic;">AAA</font>&#8221;). The arbitration will take place in San Diego, California. Ionis will pay the arbitrator&#8217;s fee and will bear all administrative charges by AAA. All parties will be entitled to engage in
        reasonable pre-hearing discovery to obtain information to prosecute or defend the asserted claims. Any disputes between the parties regarding the nature or scope of discovery will be decided by the arbitrator. The arbitrator will hear and issue a
        written ruling upon any dispositive motions brought by either party, including but not limited to, motions for summary judgment or summary adjudication of issues. After the hearing, the arbitrator will issue a written decision setting forth the
        award, if any, and explaining the basis therefore. The arbitrator will have the power to award any type of relief that would be available in court. The arbitrator&#8217;s award will be final and binding upon the parties and may be entered as a judgment
        in any court of competent jurisdiction. If there is conflict in the arbitration procedures set forth in this Agreement and the AAA rules specified above, the AAA rules will control. Notwithstanding the foregoing, and regardless of what is provided
        by the AAA rules, the arbitrator will not have authority or jurisdiction to consolidate claims of different individuals or entities into one proceeding, nor will the arbitrator have authority or jurisdiction to hear the arbitration as a class
        action. As noted above, Strategic Advisor has agreed to waive any right to bring any class, collective or representative action. To the extent that the class, collective or representative action waiver described above is not enforceable, the issue
        of whether to certify any alleged or putative class for a class action proceeding must be decided by a court of competent jurisdiction. The arbitrator will not have authority or jurisdiction to decide class certification, collective or
        representative action issues. Until any class certification, collective, or representative action issues are decided by the court, all arbitration proceedings will be stayed, and the arbitrator will take no action with respect to the matter.
        However, once any issues regarding class certification, collective, or representative action have been decided by the court, the arbitrator will have authority to decide the substantive claims.</div>
      <div><br>
      </div>
      <table cellspacing="0" cellpadding="0" id="z364ee6f4d7cd45dcb8e0d627637ee964" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">

          <tr>
            <td style="width: 36pt; vertical-align: top; font-weight: bold;">10.</td>
            <td style="width: auto; vertical-align: top;">
              <div style="font-weight: bold;"><u>Indemnification</u></div>
            </td>
          </tr>

      </table>
      <div><br>
      </div>
      <div style="text-align: justify;">(a)&#160;&#160;&#160;&#160;&#160; &#160;&#160; Ionis will indemnify, defend and hold Strategic Advisor harmless against any and all losses, costs, expenses and damages (including reasonable attorney&#8217;s fees) (&#8220;Loss(es)&#8221;) incurred as a result of any
        third party claims, suits, actions, demands or proceedings resulting or arising from the performance of Strategic Advisory Services as specifically directed by Ionis in accordance with the Agreement to the extent such Loss(es) are not the result of
        Strategic Advisor&#8217;s gross negligence, intentional misconduct or material breach of this Agreement.</div>
      <div><br>
      </div>
      <div style="text-align: justify;">(b)&#160;&#160;&#160;&#160;&#160;&#160;&#160; Ionis&#8217; agreement to indemnify, defend and hold Strategic Advisor harmless is conditioned upon the Strategic Advisor (i) providing written notice to Ionis of any claim, demand or action arising out of the
        indemnified activities within thirty (30) days after Strategic Advisor has knowledge of such claim, demand or action, <font style="font-style: italic;">provided </font>that the failure to so notify Ionis shall not relieve Ionis of its obligations
        hereunder except to the extent such failure shall have actually materially prejudiced Ionis; (ii) permitting Ionis to assume full responsibility to investigate, prepare for and defend against any such claim or demand; (iii) assisting Ionis, at
        Ionis&#8217; reasonable expense, in the investigation of, preparation of and defense of any such claim or demand; (iv) undertaking reasonable steps to mitigate any loss, damage or expense with respect to the applicable claim or demand; and (v) not
        settling such claim or demand without Ionis&#8217; prior written consent.</div>
      <div><br>
      </div>
      <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
        <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-size: 8pt; color: #000000; font-weight: normal; font-style: normal;" id="DSPFPageNumber">6 of 7</font></div>
        <div id="DSPFPageBreak" style="page-break-after:always;">
          <hr noshade="noshade" style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;"></div>
      </div>
      <div style="text-align: justify;">(c)&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;Ionis will endeavor to include Strategic Advisor as a covered attorney on its insurance policy for attorneys who advise Ionis.</div>
      <div><br>
      </div>
      <table cellspacing="0" cellpadding="0" id="zc02174282ce8471c90e67cd8bf74ff3a" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">

          <tr>
            <td style="width: 36pt; vertical-align: top; font-weight: bold;">11.</td>
            <td style="width: auto; vertical-align: top;">
              <div style="font-weight: bold;"><u>Miscellaneous</u></div>
            </td>
          </tr>

      </table>
      <div><br>
      </div>
      <div style="text-align: justify;">(a)&#160;&#160;&#160;&#160; &#160;&#160; The rights and liabilities of the parties hereto will bind and inure to the benefit of their respective successors, heirs, executors and administrators, as the case may be; <font style="font-style: italic;">provided that</font>, as Ionis has specifically contracted for Strategic Advisor&#8217;s services, Strategic Advisor may not assign or delegate Strategic Advisor&#8217;s obligations under this Agreement either in whole or in part without Ionis&#8217;
        prior written consent.</div>
      <div><br>
      </div>
      <div style="text-align: justify;">(b)&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160; Because Strategic Advisor&#8217;s services are personal and unique and because Strategic Advisor has access to and become acquainted with Ionis&#8217; Confidential Information, the parties agree that in the event of
        a threatened or actual material breach of this Agreement by Strategic Advisor injunctive relief would be appropriate. As such, Ionis has the right to enforce this Agreement and any of its provisions by injunction, specific performance or other
        equitable relief without prejudice to any other rights and remedies that Ionis may have for a breach of this Agreement.</div>
      <div><br>
      </div>
      <div style="text-align: justify;">(c)&#160;&#160;&#160;&#160;&#160;&#160;&#160; This Agreement will be governed by and construed according to the laws of the State of California as such laws are applied to contracts entered into and performed entirely within such State. If any
        provision of this Agreement is held to be or becomes invalid, illegal or unenforceable, such provision will be validly reformed to approximate as nearly as possible the intent of the parties and the remainder of this Agreement will not be affected
        thereby and will remain valid and enforceable to the greatest extent permitted by law.</div>
      <div><br>
      </div>
      <div style="text-align: justify;">(d)&#160;&#160;&#160;&#160;&#160;&#160;&#160; This Agreement, and all other documents mentioned herein, constitute the final, exclusive and complete understanding and agreement of the parties hereto and supersedes all prior understandings and
        agreements. Any waiver, modification or amendment of any provision of this Agreement will be effective only if in writing and signed by the parties hereto.</div>
      <div><br>
      </div>
      <div style="text-align: justify;">(e)&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160; Any notices required or permitted hereunder will be given to the appropriate party at the address specified on the Summary Page or at such other address as the party will specify in writing. Such notice
        will be deemed given upon personal delivery to the appropriate address, or by facsimile transmission (receipt verified and with confirmation copy followed by another permitted method), sent by express courier service, or, if sent by certified or
        registered mail, three (3) days after the date of mailing.</div>
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<DOCUMENT>
<TYPE>EX-10.83
<SEQUENCE>5
<FILENAME>exhibit10-83.htm
<DESCRIPTION>EXHIBIT 10.83
<TEXT>
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    <div style="text-align: right;"><font style="font-weight: bold;">Exhibit 10.83</font><br>
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        <table style="font-family: 'Times New Roman'; font-size: 10pt; color: #000000; width: 100%;" id="z541f105ea88f442796de00f96b1c6b2e" border="0" cellpadding="0" cellspacing="0">

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                <div style="text-align: left; color: rgb(0, 0, 0); font-family: 'Times New Roman',Times,serif; font-weight: bold;">CONFIDENTIAL</div>
              </td>
              <td style="width: 50%;">
                <div style="text-align: right; color: rgb(0, 0, 0); font-family: 'Times New Roman',Times,serif; font-weight: bold;">Execution Version</div>
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      </div>
      <div style="font-family: 'Times New Roman', Times, serif; font-weight: bold;">CERTAIN IDENTIFIED INFORMATION HAS BEEN EXCLUDED FROM THE EXHIBIT BECAUSE IT IS BOTH (I) NOT MATERIAL AND (II) WOULD BE COMPETITIVELY HARMFUL IF PUBLICLY DISCLOSED.&#160; SUCH
        EXCLUDED INFORMATION HAS BEEN MARKED WITH &#8220;[***]&#8221;.</div>
      <div><br>
      </div>
      <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-weight: bold;">AMENDMENT NO. 1 TO COLLABORATION AND LICENSE AGREEMENT</div>
      <div>&#160;</div>
      <div style="text-align: justify; text-indent: 10.5pt; font-family: 'Times New Roman', Times, serif;"><font style="font-weight: bold; font-variant: small-caps;">This Amendment No. 1 to Collaboration and License Agreement </font>(&#8220;<font style="font-weight: bold;">First Amendment</font>&#8221;)<font style="font-variant: small-caps;">&#160;</font>is made and entered into effective as of December 17, 2021 (&#8220;<font style="font-weight: bold;">First Amendment Effective Date</font>&#8221;) by and
        between <font style="font-weight: bold;">BicycleTx Limited</font>, a company incorporated in England and Wales with a place of business at Building 900, Babraham Research Campus, Cambridge CB22 3AT, UK (&#8220;<font style="font-weight: bold;">BicycleTx</font>&#8221;),
        and Ionis Pharmaceuticals, Inc., a Delaware corporation with a principal place of business at 2855 Gazelle Court, Carlsbad, California 92010, USA (&#8220;<font style="font-weight: bold;">Ionis</font>&#8221;).&#160; BicycleTx and Ionis are referred to herein
        individually as a &#8220;<font style="font-weight: bold;">Party</font>&#8221; and collectively as the &#8220;<font style="font-weight: bold;">Parties</font>&#8221;.</div>
      <div>&#160;</div>
      <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-weight: bold;"><a name="z_Toc169423637"></a>BACKGROUND</div>
      <div>&#160;</div>
      <div style="text-align: justify; font-family: 'Times New Roman', Times, serif;"><font style="font-weight: bold;">WHEREAS</font>, BicycleTx and Ionis entered into that certain Collaboration and License Agreement dated as of July 9, 2021 (the &#8220;<font style="font-weight: bold;">Agreement</font>&#8221;), pursuant to which the Parties agreed to collaborate in the research and development of products incorporating TfR1 Bicycles directed against certain Targets;</div>
      <div>&#160;</div>
      <div style="text-align: justify; font-family: 'Times New Roman', Times, serif;"><font style="font-weight: bold;">WHEREAS</font>, the Agreement provides for BicycleTx to perform the Research Activities, subject to certain terms and conditions,
        including <font style="font-weight: bold;">[***]</font> at BicycleTx&#8217;s cost, with additional BicycleTx work requested by Ionis over and above such <font style="font-weight: bold;">[***]</font> annually to be discussed in good faith and mutually
        agreed by the Parties;</div>
      <div>&#160;</div>
      <div style="text-align: justify; font-family: 'Times New Roman', Times, serif;"><font style="font-weight: bold;">WHEREAS</font>, the Parties now seek to conduct certain additional activities to evaluate the potential for TfR1 Bicycles <font style="font-weight: bold;">[***]</font>, and the Parties thus desire to amend the Agreement to provide for BicycleTx to perform such additional activities at Ionis&#8217; cost, as further set forth in this First Amendment; and</div>
      <div>&#160;</div>
      <div style="text-align: justify; font-family: 'Times New Roman', Times, serif;"><font style="font-weight: bold;">WHEREAS</font>, <u>Section 12.3</u> of the Agreement provides that the Agreement may only be modified by a written instrument duly
        executed by authorized representatives of each Party.</div>
      <div>&#160;</div>
      <div style="text-align: justify; font-family: 'Times New Roman', Times, serif;"><font style="font-weight: bold;">NOW, THEREFORE</font>, the Parties desire, for good and valuable consideration, the receipt and sufficiency of which is hereby
        acknowledged, to amend the Agreement as set forth in this First Amendment.</div>
      <div>&#160;</div>
      <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-weight: bold;"><a name="z_Toc169423638"></a><a name="z_Toc169490328"></a><a name="z_Toc211050904"></a><a name="z_Ref169428728"></a>ARTICLE 1</div>
      <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-weight: bold;">DEFINITIONS<a name="z_Toc279745085"></a></div>
      <div>&#160;</div>
      <div style="text-align: justify;"><font style="font-family: 'Times New Roman', Times, serif; color: #000000;">1.1</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160; <font style="font-family: 'Times New Roman', Times, serif;"><font style="font-weight: bold;">Capitalized Terms. </font>
          Capitalized terms used in this First Amendment shall have the meanings set forth in the Agreement, unless otherwise defined in in this First Amendment.&#160; Section references set forth in this First Amendment shall refer to section references in
          this First Amendment, unless expressly stated to refer to sections of the Agreement.</font></div>
      <div>&#160;</div>
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        <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">1</font></div>
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      <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-weight: bold;"><a name="z_Toc169423707"></a><a name="z_Toc169490397"></a><a name="z_Toc169423724"></a><a name="z_Toc169490414"></a><a name="z_Toc169423750"></a><a name="z_Toc169490440"></a><a name="z_Toc169423754"></a><a name="z_Toc169490444"></a><a name="z_Hlk53084538"></a></div>
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        <div>
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                  <div style="text-align: left; color: rgb(0, 0, 0); font-family: 'Times New Roman',Times,serif; font-weight: bold;">CONFIDENTIAL</div>
                </td>
                <td style="width: 50%;">
                  <div style="text-align: right; color: rgb(0, 0, 0); font-family: 'Times New Roman',Times,serif; font-weight: bold;">Execution Version</div>
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      <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-weight: bold;"> <br>
      </div>
      <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-weight: bold;">ARTICLE 2</div>
      <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-weight: bold;">AMENDMENT</div>
      <div>&#160;</div>
      <div style="text-align: justify;"><a name="z_Ref168457302"></a><a name="z_Toc169490446"></a><font style="font-family: 'Times New Roman',Times,serif;">2.1</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160; <font style="font-family: 'Times New Roman', Times, serif;"><font style="font-family: 'Times New Roman',Times,serif; font-weight: bold;">Additional Activities</font><font style="font-family: 'Times New Roman',Times,serif;">.&#160; BicycleTx will perform the research activities set forth on </font><u><font style="font-family: 'Times New Roman',Times,serif;">Schedule 1</font></u><font style="font-family: 'Times New Roman',Times,serif;"> attached hereto (the &#8220;</font><font style="font-family: 'Times New Roman',Times,serif; font-weight: bold;">Additional
            Activities</font><font style="font-family: 'Times New Roman',Times,serif;">&#8221;) during the period beginning on </font>[***]<font style="font-family: 'Times New Roman',Times,serif;">&#160;and continuing until the first anniversary of such date (the &#8220;</font><font style="font-family: 'Times New Roman',Times,serif; font-weight: bold;">Additional Research Period</font><font style="font-family: 'Times New Roman',Times,serif;">&#8221;)</font> in accordance with Section 4.5.1(a) of the Agreement<font style="font-family: 'Times New Roman',Times,serif;">.&#160; The Additional Activities shall be deemed Research Activities under the Agreement, pursuant to </font><u><font style="font-family: 'Times New Roman',Times,serif;">Section 4.2.2</font></u><font style="font-family: 'Times New Roman',Times,serif;"> thereof, subject to the terms and conditions of this First Amendment.&#160; </font>Ionis shall use Commercially Reasonable Efforts to perform the Additional Activities allocated to it at its sole
          cost and expense.</font></div>
      <div>&#160;</div>
      <div style="text-align: justify;"><font style="font-family: 'Times New Roman',Times,serif;">2.2</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;<font style="font-family: 'Times New Roman', Times, serif;"><font style="font-family: 'Times New Roman',Times,serif; font-weight: bold;">Amendment
            of the Research Plan</font><font style="font-family: 'Times New Roman',Times,serif;">.&#160; The Research Plan shall be deemed amended pursuant to </font><u><font style="font-family: 'Times New Roman',Times,serif;">Section 4.2.3</font></u><font style="font-family: 'Times New Roman',Times,serif;"> of the Agreement as of the First Amendment Effective Date to incorporate the Additional Activities, without the requirement for a separate written agreement by the JSC.</font></font></div>
      <div>&#160;</div>
      <div style="text-align: justify;"><font style="font-family: 'Times New Roman',Times,serif;">2.3</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160; <font style="font-family: 'Times New Roman', Times, serif;"><font style="font-family: 'Times New Roman',Times,serif; font-weight: bold;">Level
            of Effort; Payment</font><font style="font-family: 'Times New Roman',Times,serif;">.&#160; BicycleTx shall allocate </font>[***]<font style="font-family: 'Times New Roman',Times,serif;">.&#160; Within </font>[***]<font style="font-family: 'Times New Roman',Times,serif;"> Business Days after the First Amendment Effective Date, Ionis shall pay to BicycleTx the sum of $1,560,000, of which $780,000 is in consideration of the signing of this First Amendment, and the remaining $780,000 is</font><font style="font-style: italic;">&#160;</font><font style="font-family: 'Times New Roman',Times,serif;">in consideration of the performance by BicycleTx of the Additional Activities for the duration of the Additional Research Period (such total amount,
            the &#8220;</font><font style="font-family: 'Times New Roman',Times,serif; font-weight: bold;">Additional Activities Fee</font><font style="font-family: 'Times New Roman',Times,serif;">&#8221;).</font></font></div>
      <div>&#160;</div>
      <div style="text-align: justify;"><font style="font-family: 'Times New Roman',Times,serif;">2.4</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;<font style="font-family: 'Times New Roman', Times, serif;"><font style="font-family: 'Times New Roman',Times,serif; font-weight: bold;">Initial
            Period</font><font style="font-family: 'Times New Roman',Times,serif;">.</font></font></div>
      <div>&#160;</div>
      <div style="text-align: justify; text-indent: 36pt;"><font style="font-family: 'Times New Roman',Times,serif;">2.4.1</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;<font style="font-family: 'Times New Roman', Times, serif;"><font style="font-weight: bold;">Determination of Success
            Criteria and Initial Data Package</font>.&#160; During the first six-month period of the Additional Research Period (the &#8220;<font style="font-weight: bold;">Initial Period</font>&#8221;), the Parties, through the JSC, shall discuss in good faith and
          mutually agree upon (a) the success criteria by which the Parties will determine whether the initial goals of the Additional Activities have been achieved, and whether the Parties should continue to perform such Additional Activities for the
          remainder of the Additional Research Period (the &#8220;<font style="font-weight: bold;">Success Criteria</font>&#8221;) and (b) <a name="z_Hlk87338863"></a>the nature and scope of the data generated by BicycleTx in the course of performing the Additional
          Activities during the Initial Period, which data BicycleTx will deliver to the JSC pursuant to <u>Section 2.4.2</u> (the &#8220;<font style="font-weight: bold;">Initial</font>&#160;<font style="font-weight: bold;">Data Package</font>&#8221;).</font></div>
      <div>&#160;</div>
      <div style="text-align: justify; text-indent: 36pt;"><font style="font-family: 'Times New Roman',Times,serif;">2.4.2</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160; <font style="font-family: 'Times New Roman', Times, serif;"><font style="font-weight: bold;">Data Sharing</font>.&#160; No
          later than the date that is <font style="font-family: 'Times New Roman',Times,serif;">[***] </font>prior to the expiration of the Initial Period, BicycleTx shall deliver to the JSC the Initial Data Package.&#160; The Parties shall review and discuss
          the Initial Data Package and, prior to the expiration of the Initial Period, shall mutually determine in good faith whether the Success Criteria have been achieved.</font></div>
      <div>&#160;</div>
      <div style="text-align: justify; text-indent: 36pt;"><font style="font-family: 'Times New Roman',Times,serif;">2.4.3</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;<font style="font-family: 'Times New Roman', Times, serif;"><font style="font-weight: bold;">Decisions by Consensus</font>.&#160;
          The Parties&#8217; agreement upon the Success Criteria pursuant to <u>Section 2.4.1</u> and determination of whether the Success Criteria have been achieved pursuant to <u>Section 2.4.2</u> shall not be subject to the final decision-making authority
          of either Party and shall be made by the Parties by consensus only.&#160; If the Parties are unable to agree upon the Success Criteria or their achievement, then <u>Section 2.5.2</u> shall apply.</font></div>
    </div>
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      <table style="font-family: 'Times New Roman'; font-size: 10pt; color: #000000; width: 100%;" id="z5b365dcfddb044af8c68384c9b063ade" border="0" cellpadding="0" cellspacing="0">

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            <td style="width: 50.00%;">
              <div style="text-align: left; color: rgb(0, 0, 0); font-family: 'Times New Roman',Times,serif; font-weight: bold;">CONFIDENTIAL</div>
            </td>
            <td style="width: 50.00%;">
              <div style="text-align: right; color: rgb(0, 0, 0); font-family: 'Times New Roman',Times,serif; font-weight: bold;">Execution Version</div>
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      </table>
      <div style="text-align: justify;"><font style="font-family: 'Times New Roman',Times,serif;"> <br>
        </font></div>
      <div style="text-align: justify;"><font style="font-family: 'Times New Roman',Times,serif;">2.5</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;<font style="font-family: 'Times New Roman', Times, serif;"><font style="font-family: 'Times New Roman',Times,serif; font-weight: bold;">Follow-On
            Period; Termination of Additional Activities</font><font style="font-family: 'Times New Roman',Times,serif;">.</font></font></div>
      <div>&#160;</div>
      <div style="text-align: justify; text-indent: 36pt;"><font style="font-family: 'Times New Roman',Times,serif;">2.5.1</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160; <font style="font-family: 'Times New Roman', Times, serif;"><font style="font-weight: bold;">Follow-On Period</font>.&#160;
          If the Parties mutually agree upon the Success Criteria and mutually determine that the Success Criteria have been achieved, then BicycleTx shall continue to perform the Additional Activities for the remainder of the Additional Research Period
          (the &#8220;<font style="font-weight: bold;">Follow-On Period</font>&#8221;), and BicycleTx shall be entitled to retain the entire Additional Activities Fee.&#160; The Parties, through the JSC, shall discuss in good faith and mutually agree upon the nature and
          scope of the data generated by BicycleTx in the course of performing the Additional Activities during the Follow-On Period, which data BicycleTx will deliver to the JSC pursuant to this <u>Section 2.5.1</u> (the &#8220;<font style="font-weight: bold;">Follow-On
            Data Package</font>&#8221;).&#160; Promptly following the expiration of the Follow-On Period, BicycleTx shall deliver to the JSC the Follow-On Data Package.&#160; Upon expiration of the Follow-On Period, BicycleTx shall have no further obligation to perform
          any Additional Activities, unless the Parties mutually agree upon an extension to the Additional Research Period and the <font style="font-family: 'Times New Roman',Times,serif;">[***]</font>.</font></div>
      <div>&#160;</div>
      <div style="text-align: justify; text-indent: 36pt;"><font style="font-family: 'Times New Roman',Times,serif;">2.5.2</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160; <font style="font-family: 'Times New Roman', Times, serif;"><font style="font-weight: bold;">Termination of
            Additional Activities</font>.&#160; If (a) the Parties cannot agree upon (i) the Success Criteria prior to the end of the Initial Period, or (ii) whether the Success Criteria have been achieved prior to the end of the Initial Period, or (b) the
          Parties agree upon the Success Criteria but do not agree that the Success Criteria have been achieved by the end of the Initial Period, then in each case ((a) and (b)), BicycleTx (A) shall have no further obligation to perform any Additional
          Activities, (B) shall be entitled to retain $780,000 of the Additional Activities Fee as consideration for signing of this First Amendment, (C) shall refund to Ionis the remaining $780,000 of the Additional Activities Fee, and (D) the Additional
          Research Period shall be deemed terminated upon the expiration of the Initial Period.</font></div>
      <div>&#160;</div>
      <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-weight: bold;"><a name="z_Toc279745256"></a>ARTICLE 3</div>
      <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-weight: bold;">MISCELLANEOUS</div>
      <div>&#160;</div>
      <div style="text-align: justify;"><font style="font-family: 'Times New Roman', Times, serif;">3.1</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;<font style="font-family: 'Times New Roman', Times, serif;"><font style="font-weight: bold;">No Waiver</font>.&#160; Nothing in this First
          Amendment is intended to operate as a waiver of any claims either Party may have against the other Party arising prior to the date of this First Amendment under the Agreement.&#160; Any term or condition of this Agreement may be waived at any time by
          the Party that is entitled to the benefit thereof, but no such waiver shall be effective unless it is in writing and signed by the Party waiving such term or condition.&#160; The waiver by either Party hereto of any right hereunder or of a breach by
          the other Party shall not be deemed a waiver of any other right hereunder or of any other breach by such other Party whether of a similar nature or otherwise.</font></div>
      <div>&#160;</div>
      <div style="text-align: justify;"><font style="font-family: 'Times New Roman', Times, serif;">3.2</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;<font style="font-family: 'Times New Roman', Times, serif;"><font style="font-weight: bold;">Miscellaneous.</font>&#160; This First Amendment
          and the performance, enforcement, breach, and termination hereof shall be interpreted, governed by, and construed in accordance with the laws of the State of New York, United States excluding any conflicts or choice of law rule or principle that
          might otherwise refer construction or interpretation of this First Amendment to the substantive law of another jurisdiction.&#160; Any dispute arising from or relating to this First Amendment will be subject to resolution in accordance with <u>Section
            12.2</u> of the Agreement.&#160; Except as specifically amended by this First Amendment, the terms and conditions of the Agreement shall remain in full force and effect.&#160; Except to the extent expressly provided herein, the Agreement, as amended by
          this First Amendment, including all appendices, exhibits and schedules to each of the foregoing, sets forth the entire agreement and understanding between the Parties with respect to the subject matter of the Agreement (as amended) and <a name="z_cp_text_2_2504"></a><a name="z_cp_text_2_2505"></a>all prior agreements, understandings, promises, and representations, whether written or oral, with respect thereto are superseded hereby.&#160; This First Amendment may be executed in two or
          more counterparts in original, facsimile, PDF, or other electronic format, each of which shall be an original, and all of which together shall constitute one instrument.</font></div>
      <div>&#160;</div>
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        <table style="font-family: 'Times New Roman'; font-size: 10pt; color: #000000; width: 100%;" id="z81467f32870544a59edac0c1c87e91c8" border="0" cellpadding="0" cellspacing="0">

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                <div style="text-align: left; color: rgb(0, 0, 0); font-family: 'Times New Roman',Times,serif; font-weight: bold;">CONFIDENTIAL</div>
              </td>
              <td style="width: 50.00%;">
                <div style="text-align: right; color: rgb(0, 0, 0); font-family: 'Times New Roman',Times,serif; font-weight: bold;">Execution Version</div>
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      </div>
      <div style="text-align: justify; font-family: 'Times New Roman', Times, serif;"><font style="font-weight: bold;"> <br>
        </font></div>
      <div style="text-align: justify; font-family: 'Times New Roman', Times, serif;"><font style="font-weight: bold;">THIS AMENDMENT NO. 1 TO COLLABORATION AND LICENSE AGREEMENT </font>is executed by the authorized representatives of the Parties as of
        the First Amendment Effective Date.</div>
      <div><br>
      </div>
      <div>&#160;</div>
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              <div style="font-family: 'Times New Roman',Times,serif; font-weight: bold;">BICYCLETX LIMITED</div>
            </td>
            <td style="vertical-align: top;" colspan="2">
              <div style="font-family: 'Times New Roman',Times,serif; font-weight: bold;">IONIS<a name="z_cp_text_1_303"></a> PHARMACEUTICALS, INC.</div>
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            <td style="vertical-align: top;" colspan="2"><br>
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            </td>
            <td style="width: 47%; vertical-align: top;"><br>
            </td>
            <td style="width: 3%; vertical-align: top;"><br>
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            <td style="width: 47%; vertical-align: top;"><br>
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          <tr>
            <td style="width: 5%; vertical-align: top;">
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              <div style="font-family: 'Times New Roman',Times,serif;"><u>Michael Skynner</u></div>
            </td>
            <td style="width: 5%; vertical-align: top;">
              <div style="font-family: 'Times New Roman',Times,serif;">Name:</div>
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          <tr>
            <td style="width: 5%; vertical-align: top;"><br>
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            <td style="width: 45%; vertical-align: top;"><br>
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            <td style="width: 5%; vertical-align: top;"><br>
            </td>
            <td style="width: 45%; vertical-align: top;"><br>
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              <td style="width: 50%; text-align: center; font-weight: bold;">CONFIDENTIAL<br>
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      <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Schedule 1</div>
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<DOCUMENT>
<TYPE>EX-10.84
<SEQUENCE>6
<FILENAME>exhibit10-84.htm
<DESCRIPTION>EXHIBIT 10.84
<TEXT>
<html>
  <head>
    <title></title>
    <!-- Licensed to: Ionis Pharmaceuticals
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         Copyright 1995 - 2022 Broadridge -->
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<body bgcolor="#ffffff" style="font-family: 'Times New Roman'; font-size: 9pt; text-align: left; color: rgb(0, 0, 0);">
  <font style="font-size: 10pt;"> </font>
  <div>
    <hr noshade="noshade" align="center" style="height: 4px; color: #000000; background-color: #000000; text-align: center; margin-left: auto; margin-right: auto; border: none;">
    <div style="text-align: right;"><font style="font-weight: bold;"> Exhibit 10.84<br>
      </font></div>
    <div><font style="font-weight: bold;"> <br>
      </font></div>
    <div><font style="font-weight: bold;">CERTAIN IDENTIFIED INFORMATION HAS BEEN EXCLUDED FROM THE EXHIBIT BECAUSE IT IS BOTH (I) NOT MATERIAL AND (II) WOULD BE COMPETITIVELY HARMFUL IF PUBLICLY</font><font style="font-weight: bold; font-size: 10pt;">
        DISCLOSED.&#160; SUCH EXCLUDED INFORMATION HAS BEEN MARKED WITH &#8220;[***]&#8221; </font></div>
    <font style="font-size: 10pt;"><br>
    </font>
    <div>
      <div style="font-size: 10pt; font-weight: bold; text-align: center;">COLLABORATION AND LICENSE AGREEMENT</div>
      <div style="font-size: 10pt; font-weight: bold; text-align: center;"> <br>
      </div>
      <div style="font-size: 10pt; font-weight: bold; text-align: center;">by and between</div>
      <div style="font-size: 10pt; font-weight: bold; text-align: center;"> <br>
      </div>
      <div style="font-size: 10pt; font-weight: bold; text-align: center;">Akcea Therapeutics, Inc.</div>
      <div style="font-size: 10pt; font-weight: bold; text-align: center;"> <br>
      </div>
      <div style="font-size: 10pt; font-weight: bold; text-align: center;">and</div>
      <div style="font-size: 10pt; font-weight: bold; text-align: center;"> <br>
      </div>
      <div style="font-size: 10pt; font-weight: bold; text-align: center;">AstraZeneca<font style="font-style: italic;">&#160;</font>AB</div>
      <div style="font-size: 10pt; font-weight: bold; text-align: center;"> <br>
      </div>
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      <!--PROfilePageNumberReset%LCR%1%%%-->
      <div style="text-align: center; font-size: 10pt; font-weight: bold;">TABLE OF CONTENTS<a name="TABLEOFCONTENTS"><!--Anchor--></a></div>
      <div style="text-align: center; font-size: 10pt;"> <br>
      </div>
      <table cellspacing="0" cellpadding="0" border="0" id="z229b4a6daee747b299e2d6dfd3322037" style="font-family: 'Times New Roman'; font-size: 9pt; width: 100%; border-collapse: collapse; text-align: left; color: rgb(0, 0, 0);">

          <tr>
            <td style="width: 8%; vertical-align: top; font-size: 10pt;">&#160;</td>
            <td style="width: 87%; vertical-align: top; font-size: 10pt;">&#160;</td>
            <td style="width: 5%; vertical-align: top; font-size: 10pt;">
              <div style="text-align: right; font-weight: bold;">Page</div>
            </td>
          </tr>
          <tr>
            <td style="vertical-align: top; font-size: 10pt; color: rgb(0, 0, 0);" colspan="2" rowspan="1">&#160;</td>
            <td style="width: 5%; vertical-align: top; font-size: 10pt; text-align: right;" rowspan="1">&#160;</td>
          </tr>
          <tr>
            <td style="vertical-align: top; font-size: 10pt; background-color: rgb(204, 238, 255);" colspan="2">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">ARTICLE 1 OVERVIEW</div>
            </td>
            <td style="width: 5%; vertical-align: top; font-size: 10pt; background-color: rgb(204, 238, 255);">
              <div style="text-align: right;">1</div>
            </td>
          </tr>
          <tr>
            <td style="width: 8%; vertical-align: top; font-size: 10pt;">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">1.1</div>
            </td>
            <td style="width: 87%; vertical-align: top; font-size: 10pt;">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">Development and Commercialization</div>
            </td>
            <td style="width: 5%; vertical-align: top; font-size: 10pt; text-align: right;">1<br>
            </td>
          </tr>
          <tr>
            <td style="width: 8%; vertical-align: top; font-size: 10pt; background-color: rgb(204, 238, 255);">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">1.2</div>
            </td>
            <td style="width: 87%; vertical-align: top; font-size: 10pt; background-color: rgb(204, 238, 255);">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">Governance</div>
            </td>
            <td style="width: 5%; vertical-align: top; font-size: 10pt; background-color: rgb(204, 238, 255);">
              <div style="text-align: right;">2</div>
            </td>
          </tr>
          <tr>
            <td style="width: 8%; vertical-align: top; font-size: 10pt;">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">1.3</div>
            </td>
            <td style="width: 87%; vertical-align: top; font-size: 10pt;">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">Purpose</div>
            </td>
            <td style="width: 5%; vertical-align: top; font-size: 10pt;">
              <div style="text-align: right;">2</div>
            </td>
          </tr>
          <tr>
            <td style="vertical-align: top; font-size: 10pt; background-color: rgb(204, 238, 255);" colspan="2">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">ARTICLE 2 DEVELOPMENT</div>
            </td>
            <td style="width: 5%; vertical-align: top; font-size: 10pt; background-color: rgb(204, 238, 255);">
              <div style="text-align: right;">2</div>
            </td>
          </tr>
          <tr>
            <td style="width: 8%; vertical-align: top; font-size: 10pt;">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">2.1</div>
            </td>
            <td style="width: 87%; vertical-align: top; font-size: 10pt;">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">Development Diligence</div>
            </td>
            <td style="width: 5%; vertical-align: top; font-size: 10pt;">
              <div style="text-align: right;">2</div>
            </td>
          </tr>
          <tr>
            <td style="width: 8%; vertical-align: top; font-size: 10pt; background-color: rgb(204, 238, 255);">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">2.2</div>
            </td>
            <td style="width: 87%; vertical-align: top; font-size: 10pt; background-color: rgb(204, 238, 255);">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">Development Plan and Budget and Updates</div>
            </td>
            <td style="width: 5%; vertical-align: top; font-size: 10pt; background-color: rgb(204, 238, 255);">
              <div style="text-align: right;">2</div>
            </td>
          </tr>
          <tr>
            <td style="width: 8%; vertical-align: top; font-size: 10pt;">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">2.3</div>
            </td>
            <td style="width: 87%; vertical-align: top; font-size: 10pt;">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">Development Activities Prior to Closing Date</div>
            </td>
            <td style="width: 5%; vertical-align: top; font-size: 10pt;">
              <div style="text-align: right;">3</div>
            </td>
          </tr>
          <tr>
            <td style="width: 8%; vertical-align: top; font-size: 10pt; background-color: rgb(204, 238, 255);">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">2.4</div>
            </td>
            <td style="width: 87%; vertical-align: top; font-size: 10pt; background-color: rgb(204, 238, 255);">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">Development Costs</div>
            </td>
            <td style="width: 5%; vertical-align: top; font-size: 10pt; text-align: right; background-color: rgb(204, 238, 255);">3</td>
          </tr>
          <tr>
            <td style="width: 8%; vertical-align: top; font-size: 10pt;">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">2.5</div>
            </td>
            <td style="width: 87%; vertical-align: top; font-size: 10pt;">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">Additional Development</div>
            </td>
            <td style="width: 5%; vertical-align: top; font-size: 10pt; text-align: right;">5</td>
          </tr>
          <tr>
            <td style="width: 8%; vertical-align: top; font-size: 10pt; background-color: rgb(204, 238, 255);">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">2.6</div>
            </td>
            <td style="width: 87%; vertical-align: top; font-size: 10pt; background-color: rgb(204, 238, 255);">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">Records</div>
            </td>
            <td style="width: 5%; vertical-align: top; font-size: 10pt; text-align: right; background-color: rgb(204, 238, 255);">7</td>
          </tr>
          <tr>
            <td style="width: 8%; vertical-align: top; font-size: 10pt;">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">2.7</div>
            </td>
            <td style="width: 87%; vertical-align: top; font-size: 10pt;">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">Disclosure of Results</div>
            </td>
            <td style="width: 5%; vertical-align: top; font-size: 10pt; text-align: right;">7</td>
          </tr>
          <tr>
            <td style="vertical-align: top; font-size: 10pt; background-color: rgb(204, 238, 255);" colspan="2">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">ARTICLE 3 COMMERCIALIZATION AND MEDICAL AFFAIRS</div>
            </td>
            <td style="width: 5%; vertical-align: top; font-size: 10pt; text-align: right; background-color: rgb(204, 238, 255);">7</td>
          </tr>
          <tr>
            <td style="width: 8%; vertical-align: top; font-size: 10pt;">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">3.1</div>
            </td>
            <td style="width: 87%; vertical-align: top; font-size: 10pt;">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">Commercialization Generally</div>
            </td>
            <td style="width: 5%; vertical-align: top; font-size: 10pt; text-align: right;">7</td>
          </tr>
          <tr>
            <td style="width: 8%; vertical-align: top; font-size: 10pt; background-color: rgb(204, 238, 255);">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">3.2</div>
            </td>
            <td style="width: 87%; vertical-align: top; font-size: 10pt; background-color: rgb(204, 238, 255);">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">U.S. Commercialization Plan and Budget, U.S. Medical Affairs Plan and Budget and Updates</div>
            </td>
            <td style="width: 5%; vertical-align: top; font-size: 10pt; text-align: right; background-color: rgb(204, 238, 255);">8</td>
          </tr>
          <tr>
            <td style="width: 8%; vertical-align: top; font-size: 10pt;">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">3.3</div>
            </td>
            <td style="width: 87%; vertical-align: top; font-size: 10pt;">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">ROW Commercialization Plan and Updates</div>
            </td>
            <td style="width: 5%; vertical-align: top; font-size: 10pt; text-align: right;">12</td>
          </tr>
          <tr>
            <td style="width: 8%; vertical-align: top; font-size: 10pt; background-color: rgb(204, 238, 255);">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">3.4</div>
            </td>
            <td style="width: 87%; vertical-align: top; font-size: 10pt; background-color: rgb(204, 238, 255);">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">Commercialization and Medical Affairs Costs</div>
            </td>
            <td style="width: 5%; vertical-align: top; font-size: 10pt; text-align: right; background-color: rgb(204, 238, 255);">12</td>
          </tr>
          <tr>
            <td style="width: 8%; vertical-align: top; font-size: 10pt;">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">3.5</div>
            </td>
            <td style="width: 87%; vertical-align: top; font-size: 10pt;">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">Commercialization and Medical Affairs Reporting</div>
            </td>
            <td style="width: 5%; vertical-align: top; font-size: 10pt; text-align: right;">13</td>
          </tr>
          <tr>
            <td style="width: 8%; vertical-align: top; font-size: 10pt; background-color: rgb(204, 238, 255);">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">3.6</div>
            </td>
            <td style="width: 87%; vertical-align: top; font-size: 10pt; background-color: rgb(204, 238, 255);">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">Akcea Opt-Out Right</div>
            </td>
            <td style="width: 5%; vertical-align: top; font-size: 10pt; text-align: right; background-color: rgb(204, 238, 255);">14</td>
          </tr>
          <tr>
            <td style="vertical-align: top; font-size: 10pt;" colspan="2">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">ARTICLE 4 REGULATORY</div>
            </td>
            <td style="width: 5%; vertical-align: top; font-size: 10pt; text-align: right;">17</td>
          </tr>
          <tr>
            <td style="width: 8%; vertical-align: top; font-size: 10pt; background-color: rgb(204, 238, 255);">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">4.1</div>
            </td>
            <td style="width: 87%; vertical-align: top; font-size: 10pt; background-color: rgb(204, 238, 255);">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">Regulatory Strategy</div>
            </td>
            <td style="width: 5%; vertical-align: top; font-size: 10pt; text-align: right; background-color: rgb(204, 238, 255);">17</td>
          </tr>
          <tr>
            <td style="width: 8%; vertical-align: top; font-size: 10pt;">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">4.2</div>
            </td>
            <td style="width: 87%; vertical-align: top; font-size: 10pt;">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">Responsibility for Regulatory Filings and Ownership of Regulatory Materials</div>
            </td>
            <td style="width: 5%; vertical-align: top; font-size: 10pt; text-align: right;">17</td>
          </tr>
          <tr>
            <td style="width: 8%; vertical-align: top; font-size: 10pt; background-color: rgb(204, 238, 255);">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">4.3</div>
            </td>
            <td style="width: 87%; vertical-align: top; font-size: 10pt; background-color: rgb(204, 238, 255);">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">Regulatory Cooperation</div>
            </td>
            <td style="width: 5%; vertical-align: top; font-size: 10pt; text-align: right; background-color: rgb(204, 238, 255);">19</td>
          </tr>
          <tr>
            <td style="width: 8%; vertical-align: top; font-size: 10pt;">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">4.4</div>
            </td>
            <td style="width: 87%; vertical-align: top; font-size: 10pt;">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">Class Generic Claims for the Licensed Product</div>
            </td>
            <td style="width: 5%; vertical-align: top; font-size: 10pt;">
              <div style="text-align: right;">20</div>
            </td>
          </tr>
          <tr>
            <td style="width: 8%; vertical-align: top; font-size: 10pt; background-color: rgb(204, 238, 255);">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">4.5</div>
            </td>
            <td style="width: 87%; vertical-align: top; font-size: 10pt; background-color: rgb(204, 238, 255);">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">Recalls</div>
            </td>
            <td style="width: 5%; vertical-align: top; font-size: 10pt; text-align: right; background-color: rgb(204, 238, 255);">20<br>
            </td>
          </tr>
          <tr>
            <td style="width: 8%; vertical-align: top; font-size: 10pt;">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">4.6</div>
            </td>
            <td style="width: 87%; vertical-align: top; font-size: 10pt;">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">Adverse Event Reporting; Global Safety Database</div>
            </td>
            <td style="width: 5%; vertical-align: top; font-size: 10pt; text-align: right;">20<br>
            </td>
          </tr>
          <tr>
            <td style="vertical-align: top; font-size: 10pt; background-color: rgb(204, 238, 255);" colspan="2">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">ARTICLE 5 MANUFACTURING AND SUPPLY</div>
            </td>
            <td style="width: 5%; vertical-align: top; font-size: 10pt; text-align: right; background-color: rgb(204, 238, 255);">22</td>
          </tr>
          <tr>
            <td style="width: 8%; vertical-align: top; font-size: 10pt;">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">5.1</div>
            </td>
            <td style="width: 87%; vertical-align: top; font-size: 10pt;">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">Supply of the Licensed Products</div>
            </td>
            <td style="width: 5%; vertical-align: top; font-size: 10pt; text-align: right;">22</td>
          </tr>
          <tr>
            <td style="width: 8%; vertical-align: top; font-size: 10pt; background-color: rgb(204, 238, 255);">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">5.2</div>
            </td>
            <td style="width: 87%; vertical-align: top; font-size: 10pt; background-color: rgb(204, 238, 255);">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">Manufacturing Transition Plan</div>
            </td>
            <td style="width: 5%; vertical-align: top; font-size: 10pt; text-align: right; background-color: rgb(204, 238, 255);">22</td>
          </tr>
          <tr>
            <td style="width: 8%; vertical-align: top; font-size: 10pt;">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">5.3</div>
            </td>
            <td style="width: 87%; vertical-align: top; font-size: 10pt;">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">Manufacturing Improvements.</div>
            </td>
            <td style="width: 5%; vertical-align: top; font-size: 10pt; text-align: right;">23</td>
          </tr>

      </table>
      <div style="font-size: 10pt;"><br>
      </div>
      <div id="DSPFPageBreakArea" style="clear: both; margin-top: 9pt; margin-bottom: 9pt;">
        <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">i</font></div>
        <div id="DSPFPageBreak" style="page-break-after:always;">
          <hr noshade="noshade" style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;"></div>
      </div>
      <table cellspacing="0" cellpadding="0" id="z3f09d33beab14085a27c9e162aa6b1ff" style="font-family: 'Times New Roman'; font-size: 9pt; width: 100%; border-collapse: collapse; text-align: left; color: rgb(0, 0, 0);">

          <tr>
            <td style="width: 8%; vertical-align: top; font-size: 10pt; background-color: rgb(204, 238, 255);">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">5.4</div>
            </td>
            <td style="width: 87%; vertical-align: top; font-size: 10pt; background-color: rgb(204, 238, 255);">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">Capital Expenditures</div>
            </td>
            <td style="width: 5%; vertical-align: top; font-size: 10pt; text-align: right; background-color: rgb(204, 238, 255);">25</td>
          </tr>
          <tr>
            <td style="vertical-align: top; font-size: 10pt;" colspan="2">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">ARTICLE 6 GOVERNANCE</div>
            </td>
            <td style="width: 5%; vertical-align: top; font-size: 10pt; text-align: right;">26</td>
          </tr>
          <tr>
            <td style="width: 8%; vertical-align: top; font-size: 10pt; background-color: rgb(204, 238, 255);">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">6.1</div>
            </td>
            <td style="width: 87%; vertical-align: top; font-size: 10pt; background-color: rgb(204, 238, 255);">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">Joint Steering Committee</div>
            </td>
            <td style="width: 5%; vertical-align: top; font-size: 10pt; text-align: right; background-color: rgb(204, 238, 255);">26</td>
          </tr>
          <tr>
            <td style="width: 8%; vertical-align: top; font-size: 10pt;">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">6.2</div>
            </td>
            <td style="width: 87%; vertical-align: top; font-size: 10pt;">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">Subcommittees</div>
            </td>
            <td style="width: 5%; vertical-align: top; font-size: 10pt; text-align: right;">27</td>
          </tr>
          <tr>
            <td style="width: 8%; vertical-align: top; font-size: 10pt; background-color: rgb(204, 238, 255);">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">6.3</div>
            </td>
            <td style="width: 87%; vertical-align: top; font-size: 10pt; background-color: rgb(204, 238, 255);">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">Joint Development Committee</div>
            </td>
            <td style="width: 5%; vertical-align: top; font-size: 10pt; text-align: right; background-color: rgb(204, 238, 255);">27<br>
            </td>
          </tr>
          <tr>
            <td style="width: 8%; vertical-align: top; font-size: 10pt;">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">6.4</div>
            </td>
            <td style="width: 87%; vertical-align: top; font-size: 10pt;">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">Joint Commercialization and Medical Committee</div>
            </td>
            <td style="width: 5%; vertical-align: top; font-size: 10pt; text-align: right;">29</td>
          </tr>
          <tr>
            <td style="width: 8%; vertical-align: top; font-size: 10pt; background-color: rgb(204, 238, 255);">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">6.5</div>
            </td>
            <td style="width: 87%; vertical-align: top; font-size: 10pt; background-color: rgb(204, 238, 255);">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">Regulatory Working Group</div>
            </td>
            <td style="width: 5%; vertical-align: top; font-size: 10pt; text-align: right; background-color: rgb(204, 238, 255);">30</td>
          </tr>
          <tr>
            <td style="width: 8%; vertical-align: top; font-size: 10pt;">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">6.6</div>
            </td>
            <td style="width: 87%; vertical-align: top; font-size: 10pt;">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">Decision-Making</div>
            </td>
            <td style="width: 5%; vertical-align: top; font-size: 10pt; text-align: right;">31</td>
          </tr>
          <tr>
            <td style="width: 8%; vertical-align: top; font-size: 10pt; background-color: rgb(204, 238, 255);">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">6.7</div>
            </td>
            <td style="width: 87%; vertical-align: top; font-size: 10pt; background-color: rgb(204, 238, 255);">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">Discontinuation</div>
            </td>
            <td style="width: 5%; vertical-align: top; font-size: 10pt; text-align: right; background-color: rgb(204, 238, 255);">33</td>
          </tr>
          <tr>
            <td style="width: 8%; vertical-align: top; font-size: 10pt;">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">6.8</div>
            </td>
            <td style="width: 87%; vertical-align: top; font-size: 10pt;">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">Alliance Managers</div>
            </td>
            <td style="width: 5%; vertical-align: top; font-size: 10pt;">
              <div style="text-align: right;">34</div>
            </td>
          </tr>
          <tr>
            <td style="width: 8%; vertical-align: top; font-size: 10pt; background-color: rgb(204, 238, 255);">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">6.9</div>
            </td>
            <td style="width: 87%; vertical-align: top; font-size: 10pt; background-color: rgb(204, 238, 255);">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">Annual Review</div>
            </td>
            <td style="width: 5%; vertical-align: top; font-size: 10pt; text-align: right; background-color: rgb(204, 238, 255);">34</td>
          </tr>
          <tr>
            <td style="vertical-align: top; font-size: 10pt;" colspan="2">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">ARTICLE 7 GENERAL PROVISIONS RELATING TO THE PROGRAM</div>
            </td>
            <td style="width: 5%; vertical-align: top; font-size: 10pt; text-align: right;">34</td>
          </tr>
          <tr>
            <td style="width: 8%; vertical-align: top; font-size: 10pt; background-color: rgb(204, 238, 255);">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">7.1</div>
            </td>
            <td style="width: 87%; vertical-align: top; font-size: 10pt; background-color: rgb(204, 238, 255);">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">Compliance</div>
            </td>
            <td style="width: 5%; vertical-align: top; font-size: 10pt; text-align: right; background-color: rgb(204, 238, 255);">34</td>
          </tr>
          <tr>
            <td style="width: 8%; vertical-align: top; font-size: 10pt;">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">7.2</div>
            </td>
            <td style="width: 87%; vertical-align: top; font-size: 10pt;">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">Subcontracting Rights</div>
            </td>
            <td style="width: 5%; vertical-align: top; font-size: 10pt; text-align: right;">35</td>
          </tr>
          <tr>
            <td style="width: 8%; vertical-align: top; font-size: 10pt; background-color: rgb(204, 238, 255);">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">7.3</div>
            </td>
            <td style="width: 87%; vertical-align: top; font-size: 10pt; background-color: rgb(204, 238, 255);">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">Materials Transfer</div>
            </td>
            <td style="width: 5%; vertical-align: top; font-size: 10pt; text-align: right; background-color: rgb(204, 238, 255);">35</td>
          </tr>
          <tr>
            <td style="vertical-align: top; font-size: 10pt;" colspan="2">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">ARTICLE 8 LICENSE GRANTS</div>
            </td>
            <td style="width: 5%; vertical-align: top; font-size: 10pt; text-align: right;">36</td>
          </tr>
          <tr>
            <td style="width: 8%; vertical-align: top; font-size: 10pt; background-color: rgb(204, 238, 255);">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">8.1</div>
            </td>
            <td style="width: 87%; vertical-align: top; font-size: 10pt; background-color: rgb(204, 238, 255);">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">License Grant to AstraZeneca</div>
            </td>
            <td style="width: 5%; vertical-align: top; font-size: 10pt; text-align: right; background-color: rgb(204, 238, 255);">36</td>
          </tr>
          <tr>
            <td style="width: 8%; vertical-align: top; font-size: 10pt;">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">8.2</div>
            </td>
            <td style="width: 87%; vertical-align: top; font-size: 10pt;">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">License Grants to Akcea</div>
            </td>
            <td style="width: 5%; vertical-align: top; font-size: 10pt; text-align: right;">36</td>
          </tr>
          <tr>
            <td style="width: 8%; vertical-align: top; font-size: 10pt; background-color: rgb(204, 238, 255);">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">8.3</div>
            </td>
            <td style="width: 87%; vertical-align: top; font-size: 10pt; background-color: rgb(204, 238, 255);">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">AstraZeneca&#8217;s Sublicensing Rights</div>
            </td>
            <td style="width: 5%; vertical-align: top; font-size: 10pt; text-align: right; background-color: rgb(204, 238, 255);">37</td>
          </tr>
          <tr>
            <td style="width: 8%; vertical-align: top; font-size: 10pt;">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">8.4</div>
            </td>
            <td style="width: 87%; vertical-align: top; font-size: 10pt;">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">Sublicense Conditions</div>
            </td>
            <td style="width: 5%; vertical-align: top; font-size: 10pt; text-align: right;">37</td>
          </tr>
          <tr>
            <td style="width: 8%; vertical-align: top; font-size: 10pt; background-color: rgb(204, 238, 255);">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">8.5</div>
            </td>
            <td style="width: 87%; vertical-align: top; font-size: 10pt; background-color: rgb(204, 238, 255);">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">Effect of Termination on Sublicenses</div>
            </td>
            <td style="width: 5%; vertical-align: top; font-size: 10pt; text-align: right; background-color: rgb(204, 238, 255);">38</td>
          </tr>
          <tr>
            <td style="width: 8%; vertical-align: top; font-size: 10pt;">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">8.6</div>
            </td>
            <td style="width: 87%; vertical-align: top; font-size: 10pt;">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">Technology Transfer</div>
            </td>
            <td style="width: 5%; vertical-align: top; font-size: 10pt; text-align: right;">38</td>
          </tr>
          <tr>
            <td style="width: 8%; vertical-align: top; font-size: 10pt; background-color: rgb(204, 238, 255);">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">8.7</div>
            </td>
            <td style="width: 87%; vertical-align: top; font-size: 10pt; background-color: rgb(204, 238, 255);">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">Consequence of Natural Expiration of this Agreement</div>
            </td>
            <td style="width: 5%; vertical-align: top; font-size: 10pt; text-align: right; background-color: rgb(204, 238, 255);">38</td>
          </tr>
          <tr>
            <td style="width: 8%; vertical-align: top; font-size: 10pt;">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">8.8</div>
            </td>
            <td style="width: 87%; vertical-align: top; font-size: 10pt;">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">No Other Rights and Retained Rights</div>
            </td>
            <td style="width: 5%; vertical-align: top; font-size: 10pt; text-align: right;">38</td>
          </tr>
          <tr>
            <td style="width: 8%; vertical-align: top; font-size: 10pt; background-color: rgb(204, 238, 255);">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">8.9</div>
            </td>
            <td style="width: 87%; vertical-align: top; font-size: 10pt; background-color: rgb(204, 238, 255);">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">Section 365(n) of the Bankruptcy Code</div>
            </td>
            <td style="width: 5%; vertical-align: top; font-size: 10pt; text-align: right; background-color: rgb(204, 238, 255);">39</td>
          </tr>
          <tr>
            <td style="width: 8%; vertical-align: top; font-size: 10pt;">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">8.10</div>
            </td>
            <td style="width: 87%; vertical-align: top; font-size: 10pt;">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">License Conditions; Limitations</div>
            </td>
            <td style="width: 5%; vertical-align: top; font-size: 10pt; text-align: right;">39</td>
          </tr>
          <tr>
            <td style="vertical-align: top; font-size: 10pt; background-color: rgb(204, 238, 255);" colspan="2">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">ARTICLE 9 ROFN AND EXCLUSIVITY PROVISIONS</div>
            </td>
            <td style="width: 5%; vertical-align: top; font-size: 10pt; text-align: right; background-color: rgb(204, 238, 255);">39<br>
            </td>
          </tr>
          <tr>
            <td style="width: 8%; vertical-align: top; font-size: 10pt;">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">9.1</div>
            </td>
            <td style="width: 87%; vertical-align: top; font-size: 10pt;">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">ROFN for [***]</div>
            </td>
            <td style="width: 5%; vertical-align: top; font-size: 10pt; text-align: right;">39<br>
            </td>
          </tr>
          <tr>
            <td style="width: 8%; vertical-align: top; font-size: 10pt; background-color: rgb(204, 238, 255);">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">9.2</div>
            </td>
            <td style="width: 87%; vertical-align: top; font-size: 10pt; background-color: rgb(204, 238, 255);">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">Exclusivity Covenants</div>
            </td>
            <td style="width: 5%; vertical-align: top; font-size: 10pt; text-align: right; background-color: rgb(204, 238, 255);">40</td>
          </tr>
          <tr>
            <td style="width: 8%; vertical-align: top; font-size: 10pt;">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">9.3</div>
            </td>
            <td style="width: 87%; vertical-align: top; font-size: 10pt;">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">Limitations and Exceptions to Akcea&#8217;s Exclusivity Covenants</div>
            </td>
            <td style="width: 5%; vertical-align: top; font-size: 10pt; text-align: right;">40</td>
          </tr>
          <tr>
            <td style="width: 8%; vertical-align: top; font-size: 10pt; background-color: rgb(204, 238, 255);">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">9.4</div>
            </td>
            <td style="width: 87%; vertical-align: top; font-size: 10pt; background-color: rgb(204, 238, 255);">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">Competitive Oligo Transactions</div>
            </td>
            <td style="width: 5%; vertical-align: top; font-size: 10pt; text-align: right; background-color: rgb(204, 238, 255);">40</td>
          </tr>
          <tr>
            <td style="vertical-align: top; font-size: 10pt;" colspan="2">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">ARTICLE 10 CLOSING</div>
            </td>
            <td style="width: 5%; vertical-align: top; font-size: 10pt; text-align: right;">41</td>
          </tr>
          <tr>
            <td style="width: 8%; vertical-align: top; font-size: 10pt; background-color: rgb(204, 238, 255);">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">10.1</div>
            </td>
            <td style="width: 87%; vertical-align: top; font-size: 10pt; background-color: rgb(204, 238, 255);">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">Closing</div>
            </td>
            <td style="width: 5%; vertical-align: top; font-size: 10pt; text-align: right; background-color: rgb(204, 238, 255);">41</td>
          </tr>
          <tr>
            <td style="width: 8%; vertical-align: top; font-size: 10pt;">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">10.2</div>
            </td>
            <td style="width: 87%; vertical-align: top; font-size: 10pt;">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">Antitrust Filings</div>
            </td>
            <td style="width: 5%; vertical-align: top; font-size: 10pt; text-align: right;">42</td>
          </tr>

      </table>
      <div style="font-size: 10pt;"><br>
      </div>
      <div id="DSPFPageBreakArea" style="clear: both; margin-top: 9pt; margin-bottom: 9pt;">
        <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">ii</font></div>
        <div id="DSPFPageBreak" style="page-break-after:always;">
          <hr noshade="noshade" style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;"></div>
      </div>
      <table cellspacing="0" cellpadding="0" id="z61edbd06a43646f38762877240fd28e5" style="font-family: 'Times New Roman'; font-size: 9pt; width: 100%; border-collapse: collapse; text-align: left; color: rgb(0, 0, 0);">

          <tr>
            <td style="width: 8%; vertical-align: top; font-size: 10pt; background-color: rgb(204, 238, 255);">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">10.3</div>
            </td>
            <td style="width: 87%; vertical-align: top; font-size: 10pt; background-color: rgb(204, 238, 255);">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">Covenants between Signing and Closing</div>
            </td>
            <td style="width: 5%; vertical-align: top; font-size: 10pt; text-align: right; background-color: rgb(204, 238, 255);">43</td>
          </tr>
          <tr>
            <td style="vertical-align: top; font-size: 10pt;" colspan="2">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">ARTICLE 11 UPFRONT FEE; MILESTONES AND ROYALTIES; REIMBURSEMENTS; PAYMENTS</div>
            </td>
            <td style="width: 5%; vertical-align: top; font-size: 10pt; text-align: right;">43</td>
          </tr>
          <tr>
            <td style="width: 8%; vertical-align: top; font-size: 10pt; background-color: rgb(204, 238, 255);">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">11.1</div>
            </td>
            <td style="width: 87%; vertical-align: top; font-size: 10pt; background-color: rgb(204, 238, 255);">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">Upfront Fees</div>
            </td>
            <td style="width: 5%; vertical-align: top; font-size: 10pt; text-align: right; background-color: rgb(204, 238, 255);">43</td>
          </tr>
          <tr>
            <td style="width: 8%; vertical-align: top; font-size: 10pt;">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">11.2</div>
            </td>
            <td style="width: 87%; vertical-align: top; font-size: 10pt;">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">Development and Regulatory Milestone Payments</div>
            </td>
            <td style="width: 5%; vertical-align: top; font-size: 10pt; text-align: right;">43</td>
          </tr>
          <tr>
            <td style="width: 8%; vertical-align: top; font-size: 10pt; background-color: rgb(204, 238, 255);">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">11.3</div>
            </td>
            <td style="width: 87%; vertical-align: top; font-size: 10pt; background-color: rgb(204, 238, 255);">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">Sales Milestone Payments</div>
            </td>
            <td style="width: 5%; vertical-align: top; font-size: 10pt; text-align: right; background-color: rgb(204, 238, 255);">44</td>
          </tr>
          <tr>
            <td style="width: 8%; vertical-align: top; font-size: 10pt;">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">11.4</div>
            </td>
            <td style="width: 87%; vertical-align: top; font-size: 10pt;">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">Limitations on Milestone Payments; Exceptions; Notice</div>
            </td>
            <td style="width: 5%; vertical-align: top; font-size: 10pt; text-align: right;">45</td>
          </tr>
          <tr>
            <td style="width: 8%; vertical-align: top; font-size: 10pt; background-color: rgb(204, 238, 255);">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">11.5</div>
            </td>
            <td style="width: 87%; vertical-align: top; font-size: 10pt; background-color: rgb(204, 238, 255);">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">U.S. Royalties</div>
            </td>
            <td style="width: 5%; vertical-align: top; font-size: 10pt; text-align: right; background-color: rgb(204, 238, 255);">46</td>
          </tr>
          <tr>
            <td style="width: 8%; vertical-align: top; font-size: 10pt;">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">11.6</div>
            </td>
            <td style="width: 87%; vertical-align: top; font-size: 10pt;">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">ROW Royalties</div>
            </td>
            <td style="width: 5%; vertical-align: top; font-size: 10pt; text-align: right;">47</td>
          </tr>
          <tr>
            <td style="width: 8%; vertical-align: top; font-size: 10pt; background-color: rgb(204, 238, 255);">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">11.7</div>
            </td>
            <td style="width: 87%; vertical-align: top; font-size: 10pt; background-color: rgb(204, 238, 255);">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">Royalty Reports; Payment of Royalties</div>
            </td>
            <td style="width: 5%; vertical-align: top; font-size: 10pt; text-align: right; background-color: rgb(204, 238, 255);">49</td>
          </tr>
          <tr>
            <td style="width: 8%; vertical-align: top; font-size: 10pt;">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">11.8</div>
            </td>
            <td style="width: 87%; vertical-align: top; font-size: 10pt;">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">Third Party Licenses</div>
            </td>
            <td style="width: 5%; vertical-align: top; font-size: 10pt; text-align: right;">49</td>
          </tr>
          <tr>
            <td style="width: 8%; vertical-align: top; font-size: 10pt; background-color: rgb(204, 238, 255);">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">11.9</div>
            </td>
            <td style="width: 87%; vertical-align: top; font-size: 10pt; background-color: rgb(204, 238, 255);">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">Minimum Payments</div>
            </td>
            <td style="width: 5%; vertical-align: top; font-size: 10pt; text-align: right; background-color: rgb(204, 238, 255);">51</td>
          </tr>
          <tr>
            <td style="width: 8%; vertical-align: top; font-size: 10pt;">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">11.10</div>
            </td>
            <td style="width: 87%; vertical-align: top; font-size: 10pt;">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">Other Operating Expenses</div>
            </td>
            <td style="width: 5%; vertical-align: top; font-size: 10pt; text-align: right;">51</td>
          </tr>
          <tr>
            <td style="width: 8%; vertical-align: top; font-size: 10pt; background-color: rgb(204, 238, 255);">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">11.11</div>
            </td>
            <td style="width: 87%; vertical-align: top; font-size: 10pt; background-color: rgb(204, 238, 255);">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">Accounting</div>
            </td>
            <td style="width: 5%; vertical-align: top; font-size: 10pt; text-align: right; background-color: rgb(204, 238, 255);">51</td>
          </tr>
          <tr>
            <td style="width: 8%; vertical-align: top; font-size: 10pt;">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">11.12</div>
            </td>
            <td style="width: 87%; vertical-align: top; font-size: 10pt;">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">Methods of Payments</div>
            </td>
            <td style="width: 5%; vertical-align: top; font-size: 10pt; text-align: right;">53</td>
          </tr>
          <tr>
            <td style="width: 8%; vertical-align: top; font-size: 10pt; background-color: rgb(204, 238, 255);">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">11.13</div>
            </td>
            <td style="width: 87%; vertical-align: top; font-size: 10pt; background-color: rgb(204, 238, 255);">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">Taxes</div>
            </td>
            <td style="width: 5%; vertical-align: top; font-size: 10pt; text-align: right; background-color: rgb(204, 238, 255);">53</td>
          </tr>
          <tr>
            <td style="width: 8%; vertical-align: top; font-size: 10pt;">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">11.14</div>
            </td>
            <td style="width: 87%; vertical-align: top; font-size: 10pt;">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">Currency Exchange</div>
            </td>
            <td style="width: 5%; vertical-align: top; font-size: 10pt; text-align: right;">55</td>
          </tr>
          <tr>
            <td style="width: 8%; vertical-align: top; font-size: 10pt; background-color: rgb(204, 238, 255);">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">11.15</div>
            </td>
            <td style="width: 87%; vertical-align: top; font-size: 10pt; background-color: rgb(204, 238, 255);">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">Interest</div>
            </td>
            <td style="width: 5%; vertical-align: top; font-size: 10pt; text-align: right; background-color: rgb(204, 238, 255);">55</td>
          </tr>
          <tr>
            <td style="vertical-align: top; font-size: 10pt;" colspan="2">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">ARTICLE 12 INTELLECTUAL PROPERTY</div>
            </td>
            <td style="width: 5%; vertical-align: top; font-size: 10pt; text-align: right;">55</td>
          </tr>
          <tr>
            <td style="width: 8%; vertical-align: top; font-size: 10pt; background-color: rgb(204, 238, 255);">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">12.1</div>
            </td>
            <td style="width: 87%; vertical-align: top; font-size: 10pt; background-color: rgb(204, 238, 255);">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">Ownership of Inventions; Disclosure; Cross-License</div>
            </td>
            <td style="width: 5%; vertical-align: top; font-size: 10pt; text-align: right; background-color: rgb(204, 238, 255);">55</td>
          </tr>
          <tr>
            <td style="width: 8%; vertical-align: top; font-size: 10pt;">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">12.2</div>
            </td>
            <td style="width: 87%; vertical-align: top; font-size: 10pt;">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">Filing, Prosecution and Maintenance of Patents</div>
            </td>
            <td style="width: 5%; vertical-align: top; font-size: 10pt; text-align: right;">57</td>
          </tr>
          <tr>
            <td style="width: 8%; vertical-align: top; font-size: 10pt; background-color: rgb(204, 238, 255);">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">12.3</div>
            </td>
            <td style="width: 87%; vertical-align: top; font-size: 10pt; background-color: rgb(204, 238, 255);">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">Defense of Claims Brought by Third Parties; Oppositions</div>
            </td>
            <td style="width: 5%; vertical-align: top; font-size: 10pt; text-align: right; background-color: rgb(204, 238, 255);">59</td>
          </tr>
          <tr>
            <td style="width: 8%; vertical-align: top; font-size: 10pt;">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">12.4</div>
            </td>
            <td style="width: 87%; vertical-align: top; font-size: 10pt;">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">Enforcement of Patents Against Competitive Infringement</div>
            </td>
            <td style="width: 5%; vertical-align: top; font-size: 10pt; text-align: right;">60</td>
          </tr>
          <tr>
            <td style="width: 8%; vertical-align: top; font-size: 10pt; background-color: rgb(204, 238, 255);">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">12.5</div>
            </td>
            <td style="width: 87%; vertical-align: top; font-size: 10pt; background-color: rgb(204, 238, 255);">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">Settlement</div>
            </td>
            <td style="width: 5%; vertical-align: top; font-size: 10pt; text-align: right; background-color: rgb(204, 238, 255);">62</td>
          </tr>
          <tr>
            <td style="width: 8%; vertical-align: top; font-size: 10pt;">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">12.6</div>
            </td>
            <td style="width: 87%; vertical-align: top; font-size: 10pt;">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">Patent Listing</div>
            </td>
            <td style="width: 5%; vertical-align: top; font-size: 10pt; text-align: right;">62</td>
          </tr>
          <tr>
            <td style="width: 8%; vertical-align: top; font-size: 10pt; background-color: rgb(204, 238, 255);">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">12.7</div>
            </td>
            <td style="width: 87%; vertical-align: top; font-size: 10pt; background-color: rgb(204, 238, 255);">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">Joint Research Agreement under the Leahy-Smith America Invents Act</div>
            </td>
            <td style="width: 5%; vertical-align: top; font-size: 10pt; text-align: right; background-color: rgb(204, 238, 255);">62</td>
          </tr>
          <tr>
            <td style="width: 8%; vertical-align: top; font-size: 10pt;">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">12.8</div>
            </td>
            <td style="width: 87%; vertical-align: top; font-size: 10pt;">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">Additional Rights and Exceptions</div>
            </td>
            <td style="width: 5%; vertical-align: top; font-size: 10pt; text-align: right;">63</td>
          </tr>
          <tr>
            <td style="width: 8%; vertical-align: top; font-size: 10pt; background-color: rgb(204, 238, 255);">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">12.9</div>
            </td>
            <td style="width: 87%; vertical-align: top; font-size: 10pt; background-color: rgb(204, 238, 255);">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">Patent Term Extension</div>
            </td>
            <td style="width: 5%; vertical-align: top; font-size: 10pt; text-align: right; background-color: rgb(204, 238, 255);">63</td>
          </tr>
          <tr>
            <td style="width: 8%; vertical-align: top; font-size: 10pt;">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">12.10</div>
            </td>
            <td style="width: 87%; vertical-align: top; font-size: 10pt;">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">UPC</div>
            </td>
            <td style="width: 5%; vertical-align: top; font-size: 10pt; text-align: right;">63</td>
          </tr>
          <tr>
            <td style="vertical-align: top; font-size: 10pt; background-color: rgb(204, 238, 255);" colspan="2">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">ARTICLE 13 CONFIDENTIALITY</div>
            </td>
            <td style="width: 5%; vertical-align: top; font-size: 10pt; text-align: right; background-color: rgb(204, 238, 255);">63</td>
          </tr>
          <tr>
            <td style="width: 8%; vertical-align: top; font-size: 10pt;">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">13.1</div>
            </td>
            <td style="width: 87%; vertical-align: top; font-size: 10pt;">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">Confidentiality; Exceptions</div>
            </td>
            <td style="width: 5%; vertical-align: top; font-size: 10pt; text-align: right;">63</td>
          </tr>
          <tr>
            <td style="width: 8%; vertical-align: top; font-size: 10pt; background-color: rgb(204, 238, 255);">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">13.2</div>
            </td>
            <td style="width: 87%; vertical-align: top; font-size: 10pt; background-color: rgb(204, 238, 255);">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">Prior Confidentiality Agreement Superseded</div>
            </td>
            <td style="width: 5%; vertical-align: top; font-size: 10pt; text-align: right; background-color: rgb(204, 238, 255);">64</td>
          </tr>
          <tr>
            <td style="width: 8%; vertical-align: top; font-size: 10pt;">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">13.3</div>
            </td>
            <td style="width: 87%; vertical-align: top; font-size: 10pt;">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">Authorized Disclosure</div>
            </td>
            <td style="width: 5%; vertical-align: top; font-size: 10pt; text-align: right;">65</td>
          </tr>
          <tr>
            <td style="width: 8%; vertical-align: top; font-size: 10pt; background-color: rgb(204, 238, 255);">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">13.4</div>
            </td>
            <td style="width: 87%; vertical-align: top; font-size: 10pt; background-color: rgb(204, 238, 255);">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">Press Release; Disclosure of Agreement</div>
            </td>
            <td style="width: 5%; vertical-align: top; font-size: 10pt; text-align: right; background-color: rgb(204, 238, 255);">65</td>
          </tr>
          <tr>
            <td style="width: 8%; vertical-align: top; font-size: 10pt;">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">13.5</div>
            </td>
            <td style="width: 87%; vertical-align: top; font-size: 10pt;">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">Publications</div>
            </td>
            <td style="width: 5%; vertical-align: top; font-size: 10pt; text-align: right;">66</td>
          </tr>

      </table>
      <div style="font-size: 10pt;"><br>
      </div>
      <div id="DSPFPageBreakArea" style="clear: both; margin-top: 9pt; margin-bottom: 9pt;">
        <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">iii</font></div>
        <div id="DSPFPageBreak" style="page-break-after:always;">
          <hr noshade="noshade" style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;"></div>
      </div>
      <table cellspacing="0" cellpadding="0" id="zb811aa7c92b1444ab4917db939d83644" style="font-family: 'Times New Roman'; font-size: 9pt; width: 100%; border-collapse: collapse; text-align: left; color: rgb(0, 0, 0);">

          <tr>
            <td style="width: 8%; vertical-align: top; font-size: 10pt; background-color: rgb(204, 238, 255);">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">13.6</div>
            </td>
            <td style="width: 87%; vertical-align: top; font-size: 10pt; background-color: rgb(204, 238, 255);">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">Remedies</div>
            </td>
            <td style="width: 5%; vertical-align: top; font-size: 10pt; text-align: right; background-color: rgb(204, 238, 255);">67</td>
          </tr>
          <tr>
            <td style="width: 8%; vertical-align: top; font-size: 10pt;">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">13.7</div>
            </td>
            <td style="width: 87%; vertical-align: top; font-size: 10pt;">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">Ongoing Obligation for Confidentiality</div>
            </td>
            <td style="width: 5%; vertical-align: top; font-size: 10pt; text-align: right;">67</td>
          </tr>
          <tr>
            <td style="width: 8%; vertical-align: top; font-size: 10pt; background-color: rgb(204, 238, 255);">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">13.8</div>
            </td>
            <td style="width: 87%; vertical-align: top; font-size: 10pt; background-color: rgb(204, 238, 255);">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">Use of Name; Acknowledgment</div>
            </td>
            <td style="width: 5%; vertical-align: top; font-size: 10pt; text-align: right; background-color: rgb(204, 238, 255);">64</td>
          </tr>
          <tr>
            <td style="vertical-align: top; font-size: 10pt;" colspan="2">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">ARTICLE 14 REPRESENTATIONS AND WARRANTIES</div>
            </td>
            <td style="width: 5%; vertical-align: top; font-size: 10pt; text-align: right;">67<br>
            </td>
          </tr>
          <tr>
            <td style="width: 8%; vertical-align: top; font-size: 10pt; background-color: rgb(204, 238, 255);">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">14.1</div>
            </td>
            <td style="width: 87%; vertical-align: top; font-size: 10pt; background-color: rgb(204, 238, 255);">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">Representations and Warranties of the Parties</div>
            </td>
            <td style="width: 5%; vertical-align: top; font-size: 10pt; text-align: right; background-color: rgb(204, 238, 255);">67</td>
          </tr>
          <tr>
            <td style="width: 8%; vertical-align: top; font-size: 10pt;">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">14.2</div>
            </td>
            <td style="width: 87%; vertical-align: top; font-size: 10pt;">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">Representations and Warranties of Akcea</div>
            </td>
            <td style="width: 5%; vertical-align: top; font-size: 10pt; text-align: right;">68</td>
          </tr>
          <tr>
            <td style="width: 8%; vertical-align: top; font-size: 10pt; background-color: rgb(204, 238, 255);">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">14.3</div>
            </td>
            <td style="width: 87%; vertical-align: top; font-size: 10pt; background-color: rgb(204, 238, 255);">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">Covenants of the Parties</div>
            </td>
            <td style="width: 5%; vertical-align: top; font-size: 10pt; text-align: right; background-color: rgb(204, 238, 255);">72</td>
          </tr>
          <tr>
            <td style="width: 8%; vertical-align: top; font-size: 10pt;">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">14.4</div>
            </td>
            <td style="width: 87%; vertical-align: top; font-size: 10pt;">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">Covenants of Akcea</div>
            </td>
            <td style="width: 5%; vertical-align: top; font-size: 10pt; text-align: right;">72</td>
          </tr>
          <tr>
            <td style="width: 8%; vertical-align: top; font-size: 10pt; background-color: rgb(204, 238, 255);">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">14.5</div>
            </td>
            <td style="width: 87%; vertical-align: top; font-size: 10pt; background-color: rgb(204, 238, 255);">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">Disclaimer</div>
            </td>
            <td style="width: 5%; vertical-align: top; font-size: 10pt; text-align: right; background-color: rgb(204, 238, 255);">73</td>
          </tr>
          <tr>
            <td style="vertical-align: top; font-size: 10pt;" colspan="2">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">ARTICLE 15 INDEMNIFICATION; INSURANCE</div>
            </td>
            <td style="width: 5%; vertical-align: top; font-size: 10pt; text-align: right;">74</td>
          </tr>
          <tr>
            <td style="width: 8%; vertical-align: top; font-size: 10pt; background-color: rgb(204, 238, 255);">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">15.1</div>
            </td>
            <td style="width: 87%; vertical-align: top; font-size: 10pt; background-color: rgb(204, 238, 255);">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">Indemnification by AstraZeneca</div>
            </td>
            <td style="width: 5%; vertical-align: top; font-size: 10pt; text-align: right; background-color: rgb(204, 238, 255);">74</td>
          </tr>
          <tr>
            <td style="width: 8%; vertical-align: top; font-size: 10pt;">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">15.2</div>
            </td>
            <td style="width: 87%; vertical-align: top; font-size: 10pt;">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">Indemnification by Akcea</div>
            </td>
            <td style="width: 5%; vertical-align: top; font-size: 10pt; text-align: right;">74</td>
          </tr>
          <tr>
            <td style="width: 8%; vertical-align: top; font-size: 10pt; background-color: rgb(204, 238, 255);">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">15.3</div>
            </td>
            <td style="width: 87%; vertical-align: top; font-size: 10pt; background-color: rgb(204, 238, 255);">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">Losses in the U.S</div>
            </td>
            <td style="width: 5%; vertical-align: top; font-size: 10pt; text-align: right; background-color: rgb(204, 238, 255);">75</td>
          </tr>
          <tr>
            <td style="width: 8%; vertical-align: top; font-size: 10pt;">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">15.4</div>
            </td>
            <td style="width: 87%; vertical-align: top; font-size: 10pt;">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">Procedure</div>
            </td>
            <td style="width: 5%; vertical-align: top; font-size: 10pt; text-align: right;">75</td>
          </tr>
          <tr>
            <td style="width: 8%; vertical-align: top; font-size: 10pt; background-color: rgb(204, 238, 255);">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">15.5</div>
            </td>
            <td style="width: 87%; vertical-align: top; font-size: 10pt; background-color: rgb(204, 238, 255);">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">Insurance</div>
            </td>
            <td style="width: 5%; vertical-align: top; font-size: 10pt; text-align: right; background-color: rgb(204, 238, 255);">77</td>
          </tr>
          <tr>
            <td style="width: 8%; vertical-align: top; font-size: 10pt;">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">15.6</div>
            </td>
            <td style="width: 87%; vertical-align: top; font-size: 10pt;">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">Damages Waiver</div>
            </td>
            <td style="width: 5%; vertical-align: top; font-size: 10pt; text-align: right;">77</td>
          </tr>
          <tr>
            <td style="vertical-align: top; font-size: 10pt; background-color: rgb(204, 238, 255);" colspan="2">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">ARTICLE 16 TERM AND TERMINATION</div>
            </td>
            <td style="width: 5%; vertical-align: top; font-size: 10pt; text-align: right; background-color: rgb(204, 238, 255);">78</td>
          </tr>
          <tr>
            <td style="width: 8%; vertical-align: top; font-size: 10pt;">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">16.1</div>
            </td>
            <td style="width: 87%; vertical-align: top; font-size: 10pt;">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">Term</div>
            </td>
            <td style="width: 5%; vertical-align: top; font-size: 10pt; text-align: right;">78</td>
          </tr>
          <tr>
            <td style="width: 8%; vertical-align: top; font-size: 10pt; background-color: rgb(204, 238, 255);">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">16.2</div>
            </td>
            <td style="width: 87%; vertical-align: top; font-size: 10pt; background-color: rgb(204, 238, 255);">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">Termination</div>
            </td>
            <td style="width: 5%; vertical-align: top; font-size: 10pt; text-align: right; background-color: rgb(204, 238, 255);">78</td>
          </tr>
          <tr>
            <td style="width: 8%; vertical-align: top; font-size: 10pt;">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">16.3</div>
            </td>
            <td style="width: 87%; vertical-align: top; font-size: 10pt;">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">Effects of Termination</div>
            </td>
            <td style="width: 5%; vertical-align: top; font-size: 10pt; text-align: right;">81</td>
          </tr>
          <tr>
            <td style="width: 8%; vertical-align: top; font-size: 10pt; background-color: rgb(204, 238, 255);">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">16.4</div>
            </td>
            <td style="width: 87%; vertical-align: top; font-size: 10pt; background-color: rgb(204, 238, 255);">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">Accrued Rights; Surviving Provisions of the Agreement</div>
            </td>
            <td style="width: 5%; vertical-align: top; font-size: 10pt; text-align: right; background-color: rgb(204, 238, 255);">87</td>
          </tr>
          <tr>
            <td style="vertical-align: top; font-size: 10pt;" colspan="2">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">ARTICLE 17 MISCELLANEOUS</div>
            </td>
            <td style="width: 5%; vertical-align: top; font-size: 10pt; text-align: right;">87</td>
          </tr>
          <tr>
            <td style="width: 8%; vertical-align: top; font-size: 10pt; background-color: rgb(204, 238, 255);">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">17.1</div>
            </td>
            <td style="width: 87%; vertical-align: top; font-size: 10pt; background-color: rgb(204, 238, 255);">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">Dispute Resolution</div>
            </td>
            <td style="width: 5%; vertical-align: top; font-size: 10pt; text-align: right; background-color: rgb(204, 238, 255);">87</td>
          </tr>
          <tr>
            <td style="width: 8%; vertical-align: top; font-size: 10pt;">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">17.2</div>
            </td>
            <td style="width: 87%; vertical-align: top; font-size: 10pt;">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">Governing Law; Jurisdiction; Equitable Relief; Losses; Remedies</div>
            </td>
            <td style="width: 5%; vertical-align: top; font-size: 10pt; text-align: right;">88</td>
          </tr>
          <tr>
            <td style="width: 8%; vertical-align: top; font-size: 10pt; background-color: rgb(204, 238, 255);">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">17.3</div>
            </td>
            <td style="width: 87%; vertical-align: top; font-size: 10pt; background-color: rgb(204, 238, 255);">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">Assignment and Successors</div>
            </td>
            <td style="width: 5%; vertical-align: top; font-size: 10pt; text-align: right; background-color: rgb(204, 238, 255);">89</td>
          </tr>
          <tr>
            <td style="width: 8%; vertical-align: top; font-size: 10pt;">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">17.4</div>
            </td>
            <td style="width: 87%; vertical-align: top; font-size: 10pt;">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">Performance by Affiliates</div>
            </td>
            <td style="width: 5%; vertical-align: top; font-size: 10pt; text-align: right;">90<br>
            </td>
          </tr>
          <tr>
            <td style="width: 8%; vertical-align: top; font-size: 10pt; background-color: rgb(204, 238, 255);">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">17.5</div>
            </td>
            <td style="width: 87%; vertical-align: top; font-size: 10pt; background-color: rgb(204, 238, 255);">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">Force Majeure</div>
            </td>
            <td style="width: 5%; vertical-align: top; font-size: 10pt; text-align: right; background-color: rgb(204, 238, 255);">90<br>
            </td>
          </tr>
          <tr>
            <td style="width: 8%; vertical-align: top; font-size: 10pt;">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">17.6</div>
            </td>
            <td style="width: 87%; vertical-align: top; font-size: 10pt;">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">Notices</div>
            </td>
            <td style="width: 5%; vertical-align: top; font-size: 10pt; text-align: right;">90<br>
            </td>
          </tr>
          <tr>
            <td style="width: 8%; vertical-align: top; font-size: 10pt; background-color: rgb(204, 238, 255);">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">17.7</div>
            </td>
            <td style="width: 87%; vertical-align: top; font-size: 10pt; background-color: rgb(204, 238, 255);">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">Export Clause</div>
            </td>
            <td style="width: 5%; vertical-align: top; font-size: 10pt; text-align: right; background-color: rgb(204, 238, 255);">92<br>
            </td>
          </tr>
          <tr>
            <td style="width: 8%; vertical-align: top; font-size: 10pt;">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">17.8</div>
            </td>
            <td style="width: 87%; vertical-align: top; font-size: 10pt;">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">Waiver</div>
            </td>
            <td style="width: 5%; vertical-align: top; font-size: 10pt; text-align: right;">92<br>
            </td>
          </tr>
          <tr>
            <td style="width: 8%; vertical-align: top; font-size: 10pt; background-color: rgb(204, 238, 255);">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">17.9</div>
            </td>
            <td style="width: 87%; vertical-align: top; font-size: 10pt; background-color: rgb(204, 238, 255);">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">Severability</div>
            </td>
            <td style="width: 5%; vertical-align: top; font-size: 10pt; text-align: right; background-color: rgb(204, 238, 255);">92<br>
            </td>
          </tr>
          <tr>
            <td style="width: 8%; vertical-align: top; font-size: 10pt;">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">17.10</div>
            </td>
            <td style="width: 87%; vertical-align: top; font-size: 10pt;">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">Parent Guaranty.</div>
            </td>
            <td style="width: 5%; vertical-align: top; font-size: 10pt; text-align: right;">92<br>
            </td>
          </tr>
          <tr>
            <td style="width: 8%; vertical-align: top; font-size: 10pt; background-color: rgb(204, 238, 255);">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">17.11</div>
            </td>
            <td style="width: 87%; vertical-align: top; font-size: 10pt; background-color: rgb(204, 238, 255);">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">Change of Control</div>
            </td>
            <td style="width: 5%; vertical-align: top; font-size: 10pt; text-align: right; background-color: rgb(204, 238, 255);">93<br>
            </td>
          </tr>
          <tr>
            <td style="width: 8%; vertical-align: top; font-size: 10pt;">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">17.12</div>
            </td>
            <td style="width: 87%; vertical-align: top; font-size: 10pt;">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">Entire Agreement; Amendments</div>
            </td>
            <td style="width: 5%; vertical-align: top; font-size: 10pt; text-align: right;"> 93<br>
            </td>
          </tr>

      </table>
      <div style="font-size: 10pt;"><br>
      </div>
      <div id="DSPFPageBreakArea" style="clear: both; margin-top: 9pt; margin-bottom: 9pt;">
        <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">iv</font></div>
        <div id="DSPFPageBreak" style="page-break-after:always;">
          <hr noshade="noshade" style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;"></div>
      </div>
      <table cellspacing="0" cellpadding="0" id="ze986ee5e2bb64e3d865e11b79a44a672" style="font-family: 'Times New Roman'; font-size: 9pt; width: 100%; border-collapse: collapse; text-align: left; color: rgb(0, 0, 0);">

          <tr>
            <td style="width: 8%; vertical-align: top; font-size: 10pt; background-color: rgb(204, 238, 255);">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">17.13</div>
            </td>
            <td style="width: 87%; vertical-align: top; font-size: 10pt; background-color: rgb(204, 238, 255);">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">Independent Contractors</div>
            </td>
            <td style="width: 5%; vertical-align: top; font-size: 10pt; background-color: rgb(204, 238, 255); text-align: right;"> 93<br>
            </td>
          </tr>
          <tr>
            <td style="width: 8%; vertical-align: top; font-size: 10pt;">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">17.14</div>
            </td>
            <td style="width: 87%; vertical-align: top; font-size: 10pt;">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">Headings; Construction; Interpretation</div>
            </td>
            <td style="width: 5%; vertical-align: top; font-size: 10pt; text-align: right;">94<br>
            </td>
          </tr>
          <tr>
            <td style="width: 8%; vertical-align: top; font-size: 10pt; background-color: rgb(204, 238, 255);">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">17.15</div>
            </td>
            <td style="width: 87%; vertical-align: top; font-size: 10pt; background-color: rgb(204, 238, 255);">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">Further Actions</div>
            </td>
            <td style="width: 5%; vertical-align: top; font-size: 10pt; text-align: right; background-color: rgb(204, 238, 255);">94</td>
          </tr>
          <tr>
            <td style="width: 8%; vertical-align: top; font-size: 10pt;">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">17.16</div>
            </td>
            <td style="width: 87%; vertical-align: top; font-size: 10pt;">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">Parties in Interest</div>
            </td>
            <td style="width: 5%; vertical-align: top; font-size: 10pt; text-align: right;">94</td>
          </tr>
          <tr>
            <td style="width: 8%; vertical-align: top; font-size: 10pt; background-color: rgb(204, 238, 255);">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">17.17</div>
            </td>
            <td style="width: 87%; vertical-align: top; font-size: 10pt; background-color: rgb(204, 238, 255);">
              <div style="margin-right: 21.6pt; color: rgb(0, 0, 0);">Counterparts</div>
            </td>
            <td style="width: 5%; vertical-align: top; font-size: 10pt; text-align: right; background-color: rgb(204, 238, 255);">94</td>
          </tr>

      </table>
      <div style="font-size: 10pt; font-weight: bold;"><br>
        SCHEDULES</div>
      <div style="font-size: 10pt;"><br>
      </div>
      <table cellspacing="0" cellpadding="0" border="0" id="zd3e7b415d6df4d03bbf31664c3a82612" style="font-family: 'Times New Roman'; font-size: 9pt; width: 100%; border-collapse: collapse; text-align: left; color: rgb(0, 0, 0);">

          <tr>
            <td style="width: 15%; vertical-align: top; font-size: 10pt; background-color: rgb(204, 238, 255);">
              <div>Schedule 1.11</div>
            </td>
            <td style="width: 85%; vertical-align: top; font-size: 10pt; background-color: rgb(204, 238, 255);">
              <div>Akcea Core Technology Patent Rights</div>
            </td>
          </tr>
          <tr>
            <td style="width: 15%; vertical-align: top; font-size: 10pt;">
              <div>Schedule 1.18</div>
            </td>
            <td style="width: 85%; vertical-align: top; font-size: 10pt;">
              <div>Akcea Manufacturing Patent Rights</div>
            </td>
          </tr>
          <tr>
            <td style="width: 15%; vertical-align: top; font-size: 10pt; background-color: rgb(204, 238, 255);">
              <div>Schedule 1.23</div>
            </td>
            <td style="width: 85%; vertical-align: top; font-size: 10pt; background-color: rgb(204, 238, 255);">
              <div>Akcea Product-Specific Patent Rights</div>
            </td>
          </tr>
          <tr>
            <td style="width: 15%; vertical-align: top; font-size: 10pt;">
              <div>Schedule 1.94</div>
            </td>
            <td style="width: 85%; vertical-align: top; font-size: 10pt;">
              <div>Existing In-License Agreements</div>
            </td>
          </tr>
          <tr>
            <td style="width: 15%; vertical-align: top; font-size: 10pt; background-color: rgb(204, 238, 255);">
              <div>Schedule 1.185</div>
            </td>
            <td style="width: 85%; vertical-align: top; font-size: 10pt; background-color: rgb(204, 238, 255);">
              <div>Prior Agreements</div>
            </td>
          </tr>
          <tr>
            <td style="width: 15%; vertical-align: top; font-size: 10pt;">
              <div>Schedule 2.2.1</div>
            </td>
            <td style="width: 85%; vertical-align: top; font-size: 10pt;">
              <div>Development Plan and Budget</div>
            </td>
          </tr>
          <tr>
            <td style="width: 15%; vertical-align: top; font-size: 10pt; background-color: rgb(204, 238, 255);">
              <div>Schedule 3.2.1</div>
            </td>
            <td style="width: 85%; vertical-align: top; font-size: 10pt; background-color: rgb(204, 238, 255);">
              <div>Allocation of Co-Commercialization and Medical Affairs Activities</div>
            </td>
          </tr>
          <tr>
            <td style="width: 15%; vertical-align: top; font-size: 10pt;">
              <div>Schedule 3.2.3(b)</div>
            </td>
            <td style="width: 85%; vertical-align: top; font-size: 10pt;">
              <div>Cost Share Scenarios</div>
            </td>
          </tr>
          <tr>
            <td style="width: 15%; vertical-align: top; font-size: 10pt; background-color: rgb(204, 238, 255);">
              <div>Schedule 6.8</div>
            </td>
            <td style="width: 85%; vertical-align: top; font-size: 10pt; background-color: rgb(204, 238, 255);">
              <div>Alliance Manager Activities</div>
            </td>
          </tr>
          <tr>
            <td style="width: 15%; vertical-align: top; font-size: 10pt;">
              <div>Schedule 7.2.2</div>
            </td>
            <td style="width: 85%; vertical-align: top; font-size: 10pt;">
              <div>Existing Third Party Subcontractors</div>
            </td>
          </tr>
          <tr>
            <td style="width: 15%; vertical-align: top; font-size: 10pt; background-color: rgb(204, 238, 255);">
              <div>Schedule 8.3.2</div>
            </td>
            <td style="width: 85%; vertical-align: top; font-size: 10pt; background-color: rgb(204, 238, 255);">
              <div>Authorized CMOs as of the Execution Date</div>
            </td>
          </tr>
          <tr>
            <td style="width: 15%; vertical-align: top; font-size: 10pt;">
              <div>Schedule 16.3.3(a)(ii)</div>
            </td>
            <td style="width: 85%; vertical-align: top; font-size: 10pt;">
              <div>Transition Plan Dispute Resolution</div>
            </td>
          </tr>

      </table>
      <div style="font-size: 10pt;"><br>
      </div>
      <div id="DSPFPageBreakArea" style="clear: both; margin-top: 9pt; margin-bottom: 9pt;">
        <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">v</font></div>
        <div id="DSPFPageBreak" style="page-break-after:always;">
          <hr noshade="noshade" style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;"></div>
      </div>
      <!--PROfilePageNumberReset%Num%1%%%-->
      <div style="font-size: 10pt;">
        <div>
          <div>
            <div style="text-align: justify; text-indent: 36pt;">This COLLABORATION AND LICENSE AGREEMENT (the &#8220;<font style="font-weight: bold; font-style: italic;">Agreement</font>&#8221;) is executed as of December 6, 2021 (the &#8220;<font style="font-weight: bold; font-style: italic;">Execution Date</font>&#8221;), by and between <font style="font-weight: bold; font-variant: small-caps;">AstraZeneca AB</font>, a company incorporated in Sweden under no. 556011-7482 with its registered office at SE-151 85
              S&#246;dert&#228;lje, Sweden and with offices at SE-431 83 M&#246;lndal, Sweden (&#8220;<font style="font-weight: bold; font-style: italic;">AstraZeneca</font>&#8221;), <font style="font-weight: bold; font-variant: small-caps;">Akcea Therapeutics, Inc.</font>, a
              Delaware corporation, having its principal place of business at 22 Boston Wharf Road, Boston, MA 02210 (&#8220;<font style="font-weight: bold; font-style: italic;">Akcea</font>&#8221;) and with respect to&#160;<u>Article 14</u>&#160;and <u>Section 17.10</u> only,
              Ionis Pharmaceuticals, Inc., a Delaware corporation, having its principal place of business at 2855 Gazelle Court, Carlsbad, CA 92010 (&#8220;<font style="font-weight: bold; font-style: italic;">Ionis</font>&#8221;). AstraZeneca and Akcea will be
              referred to herein individually as a &#8220;<font style="font-weight: bold; font-style: italic;">Party</font>&#8221; and collectively as the &#8220;<font style="font-weight: bold; font-style: italic;">Parties</font>&#8221;.</div>
            <div style="text-align: justify; text-indent: 36pt;"> <br>
            </div>
            <div style="text-align: center; font-weight: bold;">RECITALS<br>
              <br>
            </div>
            <div style="text-align: justify; text-indent: 36pt;">WHEREAS, AstraZeneca and Akcea are biopharmaceutical companies focused on developing, manufacturing and commercializing therapeutics on a global basis;</div>
            <div style="text-align: justify; text-indent: 36pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 36pt;">WHEREAS, pursuant to that certain Development, Commercialization and License Agreement between Akcea Therapeutics, Inc. and Ionis Pharmaceuticals, Inc. dated March 14, 2018 (the &#8220;<font style="font-weight: bold; font-style: italic;">Ionis/Akcea Agreement</font>&#8221;), Akcea has an exclusive license from its Affiliate, Ionis, to develop, manufacture and commercialize the Licensed Compound (as defined below) to treat all types
              of TTR amyloidosis (ATTR), a systemic, progressive and fatal disease;</div>
            <div style="text-align: justify; text-indent: 36pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 36pt;">WHEREAS, the Licensed Compound is currently being investigated in Phase 3 Clinical Trials, and the Parties desire to further Develop and Commercialize the Licensed Compound;<br>
              <br>
            </div>
            <div style="text-align: justify; text-indent: 36pt;">WHEREAS, AstraZeneca is granted certain rights under this Agreement, including an exclusive license to Develop and Commercialize Licensed Products (as defined below) in the Territory.</div>
            <div style="text-align: justify; text-indent: 36pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 36pt;">NOW, THEREFORE, in consideration of the premises and mutual covenants herein contained, and for other good and valuable consideration, the receipt and sufficiency of which are hereby
              acknowledged, the Parties agree as follows:</div>
            <div style="text-align: justify; text-indent: 36pt;"> <br>
            </div>
            <div style="text-align: center; font-weight: bold;">ARTICLE 1</div>
            <div style="text-align: center; font-weight: bold;">OVERVIEW</div>
            <div style="text-align: center; font-weight: bold;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold;">1.1</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160; <font style="font-weight: bold;"><u>Development and Commercialization</u></font>. The Parties intend that under this Agreement: (a) the
              Parties will jointly Develop the Licensed Product pursuant to a Development Plan and Budget and the Parties will share the costs of such Development activities according to certain cost-sharing ratios (and as further described in <u>Section
                2.4</u>); (b) the Parties will jointly Commercialize, and perform Medical Affairs activities with respect to, the Licensed Product in the United States pursuant to a U.S. Commercialization Plan and Budget and U.S. Medical Affairs Plan and
              Budget, as applicable, unless and until Akcea opts out of such activities in accordance with <u>Section 3.6</u>, and the Parties will share the costs of such activities according to certain cost-sharing ratios (as further described in <u>Section

                3.4</u>); and (c) AstraZeneca will have the sole right to Commercialize the Licensed Product in all other countries of the Territory pursuant to a corresponding ROW Commercialization Plan.</div>
            <div style="text-align: justify;"> <br>
            </div>
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            </div>
            <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold;">1.2</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160; <font style="font-weight: bold;"><u>Governance</u></font>. The Parties have agreed to form (a) a joint steering committee to oversee and
              coordinate the Development, Manufacturing, Commercialization and other Exploitation activities with respect to the Licensed Product under this Agreement, (b) a joint development committee reporting to the JSC to oversee the Development of the
              Licensed Product under this Agreement, (c) a joint commercialization and medical committee reporting to the JSC to oversee the Parties&#8217; Commercialization and Medical Affairs activities for the Licensed Product under this Agreement, and (d) a
              regulatory working group reporting to the JDC<font style="font-weight: bold; font-style: italic;">&#160;</font>to develop a Regulatory Strategy and coordinate the preparation and submission of Regulatory Filings in the Territory. The JSC, JDC,
              JCMC and RWG&#8217;s core focus will be the Exploitation of Licensed Products for the U.S. and will serve as information-sharing bodies with respect to Exploitation of the Licensed Products for the ROW Territory.</div>
            <div style="text-align: justify; text-indent: 36pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold;">1.3</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160; <font style="font-weight: bold;"><u>Purpose</u></font>. The purpose of this <u>Article 1</u> is to provide a high-level overview of the
              roles, responsibilities, rights and obligations of each Party under this Agreement, and therefore, this <u>Article 1</u> is qualified in its entirety by the more detailed provisions of this Agreement set forth below.</div>
            <div style="text-align: justify; text-indent: 36pt;"> <br>
            </div>
            <div style="text-align: center; font-weight: bold;">ARTICLE 2</div>
            <div style="text-align: center; font-weight: bold;">DEVELOPMENT</div>
            <div style="text-align: center; font-weight: bold;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold;">2.1</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160; <font style="font-weight: bold;"><u>Development Diligence</u></font>. From the Closing Date, subject to and in accordance with the terms
              and conditions of this Agreement, (a) Akcea will use Commercially Reasonable Efforts to perform its activities under the Development Plan and Budget and (b) AstraZeneca will use Commercially Reasonable Efforts to (i) obtain Regulatory
              Approval for a Licensed Product in [***] and (ii) on a [***] basis, to obtain Regulatory Approval for a Licensed Product in such [***], in each case ((i) and (ii)), in accordance with the Development Plan and Budget.</div>
            <div style="text-align: justify; text-indent: 36pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold;">2.2</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160; <font style="font-weight: bold;"><u>Development Plan and Budget and Updates</u></font>.</div>
            <div style="text-align: justify; text-indent: 36pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;">2.2.1</font>&#160;&#160;&#160;&#160; <font style="font-weight: bold;"><u>Development Plan and Budget</u></font>. Prior to the Execution Date, the Parties have agreed upon an
              initial development plan and corresponding budget for the Licensed Product, which initial development plan and budget is attached hereto as <u>Schedule 2.2.1</u> (such development plan and budget, as it may be modified in accordance with the
              terms and conditions of this Agreement, the &#8220;<font style="font-weight: bold; font-style: italic;">Development Plan and Budget</font>&#8221;). The initial Development Plan and Budget includes (and, subject to <u>Section</u><u> 3.6.2(a)(i)</u>, will
              at all times include): (a) prior to [***] in each of the Initial Indications, the Regulatory Strategy, (b) the high<font style="font-style: italic;">-</font>level Development activities that are to be undertaken by the Parties to obtain
              Regulatory Approval for the Licensed Product in each Major Market for each Initial Indication, including the Development activities that are to be undertaken by the Parties for the Clinical Trials that are ongoing as of the Execution Date,
              (c) the allocation of responsibilities between the Parties (which allocation will be consistent with <u>Section 2.2.2</u>) for all activities under the Development Plan and Budget, (d) the estimated timelines for all activities under the
              Development Plan and Budget and (e) a detailed written budget for the performance of the U.S. Development Activities and Global Development Activities under the Development Plan and Budget for the [***] subsequent Calendar Years, the [***] of
              which will be (on a rolling [***] basis) a reasonably detailed budget with costs categorized based on whether the activities are U.S. Development Activities, Global Development Activities or ROW Development Activities, and the next [***] of
              which will be a high-level estimated budget. The terms of, and activities set forth in, the Development Plan and Budget will at all times be designed to be in compliance with all applicable Laws and to be conducted in accordance with
              professional and ethical standards customary in the pharmaceutical industry, and, where applicable, each Party&#8217;s respective health care compliance policies and applicable standard operating procedures.</div>
            <div style="text-align: justify; text-indent: 72pt;"> <br>
            </div>
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            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;">2.2.2</font>&#160;&#160;&#160;&#160; <font style="font-weight: bold;"><u>Allocation of Development Activities</u></font>. The Development Plan and Budget will include the
              allocation of responsibilities for all Development activities for the Licensed Product. On an activity-by-activity basis, the Party with primary responsibility for a particular Development activity will be the &#8220;<font style="font-weight: bold; font-style: italic;">Lead Development Party</font>&#8221; for such Development activity. Subject to <u>Section 4.2.1(a)</u> and <u>Section 4.2.1(b)</u>, unless otherwise mutually agreed by the Parties and set forth in the Development Plan and
              Budget, the Development Plan and Budget will provide that: (a) Akcea will be the Lead Development Party for all Clinical Trials ongoing as of the Execution Date and (b) AstraZeneca will be the Lead Development Party for (i) all Clinical
              Trials initiated after the Closing Date and (ii) all Development activities that are [***] to support obtaining and maintaining Regulatory Approval or label expansion of a Licensed Product in the ROW Territory (such clause (b)(ii) Development
              activities, &#8220;<font style="font-weight: bold; font-style: italic;">ROW Development Activities</font>&#8221;).</div>
            <div style="text-align: justify; text-indent: 72pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;">2.2.3</font>&#160;&#160;&#160;&#160;&#160; <font style="font-weight: bold;"><u>Changes to the Development Plan and Budget</u></font>. If a Party wishes to make a change to the
              Development Plan and Budget, then such Party will submit its proposed change to the JDC for the JDC to review and discuss. Except for any change proposed by [***] and, subject to <u>Section</u><u> 3.6.2(a)(i)</u>, the JDC will revise (if and
              as appropriate) and make a recommendation to the JSC regarding whether to approve such proposed change. The JSC shall review and determine whether to approve any such proposed change to the Development Plan and Budget. <font style="color: #000000;">Each such update to the Development Plan and Budget will become effective and will supersede the previous Development Plan and Budget upon approval thereof by the JSC (which approval will be memorialized in the minutes of such JSC
                meeting). For clarity, any update or amendment to the Development Plan and Budget proposed by AstraZeneca with respect to [</font>***<font style="color: #000000;">].</font></div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="color: #000000;"> <br>
              </font></div>
            <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold;">2.3</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160; <font style="font-weight: bold;"><u>Development Activities Prior to Closing Date</u></font>. After the Execution Date and prior to the
              Closing Date, Akcea will continue performing Development activities for the Licensed Product in a manner, and with the level of resources, consistent with Akcea&#8217;s Development activities prior to the Execution Date. Akcea will promptly notify
              AstraZeneca if Akcea is required to make any material changes to such performance (a) to comply with any changes in applicable Law, (b) to comply with specific requirements imposed by Regulatory Authorities, or (c) as Akcea reasonably
              determines in good faith are [***], and, following such notice, Akcea will be permitted to make such changes to such performance.</div>
            <div style="text-align: justify; text-indent: 36pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold;">2.4</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160; <font style="font-weight: bold;"><u>Development Costs</u></font>.</div>
            <div style="text-align: justify; text-indent: 36pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;">2.4.1</font>&#160;&#160;&#160;&#160;&#160; <font style="font-weight: bold;"><u>Shared Development Costs</u></font>. The Parties will share, in accordance with <u>Section 2.4.1(a)</u>
              and subject to the reconciliations set forth in <u>Section </u><u>2.4.1(b)</u>, the Eligible Development Expenses that are reasonably allocable to Development of the Licensed Product prior to the Opt-Out Date, if any, that (x) are [***] to
              support obtaining and maintaining Regulatory Approval or label expansion for the Licensed Product in the U.S. (such Development activities, &#8220;<font style="font-weight: bold; font-style: italic;">U.S. Development Activities</font>&#8221;) or (y) are
              not ROW Development Activities or U.S. Development Activities (such Development activities, &#8220;<font style="font-weight: bold; font-style: italic;">Global Development Activities</font>&#8221;).</div>
            <div style="text-align: justify; text-indent: 72pt;"> <br>
            </div>
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            </div>
            <div style="text-align: justify; text-indent: 108pt;">(a)&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;<font style="font-weight: bold;">Share Ratios</font>.</div>
            <div style="text-align: justify; text-indent: 108pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 144pt;">(i)&#160; &#160; &#160;&#160;&#160;&#160; Subject to <u>Section 2.4.1(b)(ii)</u>, Akcea will bear [***]% and AstraZeneca will bear [***]% of all Eligible Development Expenses incurred in conducting the U.S. Development
              Activities or Global Development Activities from and after the Closing Date through December 31, 2025.</div>
            <div style="text-align: justify; text-indent: 144pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 144pt;">(ii)&#160;&#160;&#160;&#160;&#160;&#160;&#160; Subject to <u>Section</u><u> 2.4.1(b)(ii)</u>&#160;and <u>Section </u><u>2.4.1(b)(iii)</u>, Akcea will bear [***]% and AstraZeneca will bear [***]% of all Eligible Development
              Expenses incurred in conducting the U.S. Development Activities from and after January 1, 2026, and Akcea will bear [***]% and AstraZeneca will bear [***]% of all Eligible Development Expenses incurred in conducting the Global Development
              Activities from and after January 1, 2026.</div>
            <div style="text-align: justify; text-indent: 144pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 108pt;">(b)&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;<font style="font-weight: bold;">Shared Development Cost Payment Reconciliation</font>. Unless and until the Opt-Out Date occurs (and for the Calendar Quarter in which the
              Opt-Out Date occurs), the following provisions shall apply:</div>
            <div style="text-align: justify; text-indent: 108pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 144pt;">(i)&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;No later than [***] after the end of each Calendar Quarter, each Party will deliver to the other Party a non-binding estimate that sets forth the Eligible Development Expenses
              incurred by or on behalf of such Party in connection with the performance of the U.S. Development Activities and Global Development Activities during such Calendar Quarter. No later than [***] after the end of each Calendar Quarter, each
              Party will deliver to the other Party a written report that sets forth in detail the actual Eligible Development Expenses incurred by or on behalf of such Party in connection with the performance of U.S. Development Activities and Global
              Development Activities during such Calendar Quarter, including a comparison of its Eligible Development Expenses for a Development activity to the amount budgeted in the Development Plan and Budget for such activity (such report of actual
              expenses, the &#8220;<font style="font-weight: bold; font-style: italic;">Development Cost Share Notice</font>&#8221;). Each Party will provide the other Party with supporting documentation of such Eligible Development Expenses if reasonably requested by
              the other Party. For each Calendar Quarter, no later than [***] after receipt of the Development Cost Share Notice for such Calendar Quarter from each Party, the Party that incurred less than its allocation of Eligible Development Expenses
              during such Calendar Quarter will make a balancing payment to the other Party to effect the cost-sharing ratios set forth in <u>Section 2.4.1(a)</u>, to the extent the amounts set forth in the Development Cost Share Notices are undisputed.
              Any dispute regarding amounts set forth in a Development Cost Share Notice will be promptly referred to the JSC for resolution, and if the JSC determines that any disputed amount should be included in the applicable Development Cost Share
              Notice, then the Party that incurred less than its allocation of Eligible Development Expenses during such Calendar Quarter (taking into account any balancing payments previously made for such Calendar Quarter pursuant to the immediately
              preceding sentence) will make a balancing payment to the other Party to effect the cost-sharing ratios set forth in <u>Section </u><u>2.4.1(a)</u>&#160;within [***] of the JSC determination.</div>
            <div style="text-align: justify;"> <br>
            </div>
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            <div style="text-align: justify; text-indent: 144pt;">(ii)&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;If any ROW Development Activities conducted from and after the Closing Date relate to a Clinical Trial that [***] and (1) AstraZeneca will deliver to Akcea [***], and (2)
              AstraZeneca will [***] in <u>Section 2.4.1(a)</u> for Global Development Activities, to the extent the [***] <u>Section 11.5.1</u> or <u>Section 11.6.1</u>; <font style="font-style: italic;">provided</font> that in no event will [***]; <font style="font-style: italic;">provided, further, </font>that any dispute regarding [***] will be promptly referred to the JSC for resolution, and if the JSC determines that [***], AstraZeneca will [***] <u>Section</u><u> 11.5.1</u>&#160;or <u>Section</u><u>
                11.6.1</u>. Any [***]. As soon as reasonably practicable, AstraZeneca will promptly notify Akcea if it [***] and provide [***].</div>
            <div style="text-align: justify; text-indent: 144pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 144pt;">(iii)&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;If any U.S. Development Activities conducted from and after [***] relate to a Clinical Trial that [***], then such activities will be [***] and (1) Akcea will have the right
              to [***] and (2) Akcea will [***];<font style="font-style: italic;"> provided</font> that in no event will [***]. Any [***]; <font style="font-style: italic;">provided</font> that [***], then AstraZeneca [***].</div>
            <div style="text-align: justify; text-indent: 144pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 144pt;">(iv)&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;Notwithstanding the foregoing, the [***] from a Clinical Trial (A) in any annual or periodic safety reports to any Regulatory Authority with respect to the Licensed Product or
              (B) in the safety information portion of the Licensed Product labeling without the Licensed Product being approved for the applicable indication that was the subject of such Clinical Trial, in either case ((A) or (B)), shall not alone result
              in [***] under <u>Section</u><u> 2.4.1(b)(ii)</u>&#160;or <u>Section</u><u> 2.4.1(b)(iii)</u>.</div>
            <div style="text-align: justify; text-indent: 144pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;">2.4.2</font>&#160;&#160;&#160;&#160;&#160; <font style="font-weight: bold;"><u>ROW Eligible Development Expenses</u></font>. Except as set forth in <u>Section 2.4.1(b)(ii)</u>,
              [***] will be responsible for [***] costs and expenses incurred in connection with the ROW Development Activities for the Licensed Product.</div>
            <div style="text-align: justify; text-indent: 72pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold;">2.5</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;<font style="font-weight: bold;"><u>Additional Development</u></font>.</div>
            <div style="text-align: justify; text-indent: 36pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;">2.5.1</font>&#160;&#160;&#160;&#160; <font style="font-weight: bold;"><u>Additional </u><u>Development</u></font>. If AstraZeneca proposes to conduct any Development activity
              that would constitute U.S. Development Activities or Global Development Activities that is not set forth in the then-current Development Plan and Budget (&#8220;<font style="font-weight: bold; font-style: italic;">Additional Development</font>&#8221;),
              then AstraZeneca will present to the JDC, to review, discuss and make a recommendation to the JSC as to whether to approve, a proposal to add such Additional Development to the Development Plan and Budget, including the countries in which
              such activities would be conducted, the allocation of performance of such activities between the Parties, and, if applicable, a summary of the Regulatory Approval or expanded or modified label that AstraZeneca is seeking to obtain based on
              the data from such Additional Development (which summary will be consistent with any proposals prepared by AstraZeneca as part of its internal approval process for such Development) (an &#8220;<font style="font-weight: bold; font-style: italic;">Additional

                Development Proposal</font>&#8221;). The JSC shall review and determine whether to approve any such Additional Development Proposal. Each Additional Development Proposal will describe in reasonable detail the Development activities that
              AstraZeneca desires to conduct, including a proposed timeline and budget and an analysis of the business opportunity and revenue potential for such Additional Development and, with respect to any Clinical Trial, an outline of the Clinical
              Trial, the proposed enrollment criteria, the number of patients to be included, the endpoints to be measured, and the statistical design and powering.</div>
            <div style="text-align: justify; text-indent: 72pt;"> <br>
            </div>
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            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;">2.5.2</font>&#160;&#160;&#160;&#160;&#160;&#160; <font style="font-weight: bold;"><u>JSC Decision Regarding Additional </u><u>Development</u></font>.</div>
            <div style="text-align: justify; text-indent: 72pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 108pt;">(a)&#160;&#160;&#160; &#160; &#160;&#160; <font style="font-weight: bold;"><u>JSC Approval</u></font>. If the JSC approves an Additional Development Proposal, then, upon such an approval: (i) the Additional Development
              set forth in such Additional Development Proposal will be deemed &#8220;U.S. Development Activities&#8221; or &#8220;Global Development Activities&#8221; (as applicable) for purposes of this Agreement and (ii) the JDC will update the Development Plan and Budget to
              include such activities.</div>
            <div style="text-align: justify; text-indent: 108pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 108pt;">(b)&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;<font style="font-weight: bold;"><u>No </u><u>JSC Approval</u></font>. If the JSC fails to approve an Additional Development Proposal, then, upon such a failure, except as
              otherwise set forth in <u>Section 2.5.3</u>, the Additional Development proposed in the Additional Development Proposal will not be included in the Development Plan and Budget and AstraZeneca will have the right to conduct such Additional
              Development solely in accordance with <u>Section 2.5.3</u>.</div>
            <div style="text-align: justify; text-indent: 108pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;">2.5.3</font>&#160;&#160;&#160;&#160;&#160; <font style="font-weight: bold;"><u>Independent Performance of Additional </u><u>Development</u></font>. If the JSC fails to approve for
              inclusion in the Development Plan and Budget the Additional Development Proposal (or any modified version thereof), then AstraZeneca will have the right, upon written notice to Akcea, to conduct such Additional Development set forth in the
              Additional Development Proposal [***], subject to <u>Section </u><u>2.5.4</u>. AstraZeneca will conduct such Additional Development in accordance with the applicable Additional Development Proposal (including the budget therein) previously
              provided to the JSC that the JSC declined to approve; <font style="font-style: italic;">provided</font> that, upon written notice to Akcea, AstraZeneca may update or amend such Additional Development Proposal (and budget therein) so long as
              AstraZeneca does not materially change the scope of Additional Development to be conducted without repeating the Additional Development Proposal process set forth in <u>Section</u><u> 2.5.1</u>&#160;and <u>Section </u><u>2.5.2</u>. No
              Development activities included in an Additional Development Proposal may be included in or contemplated by the Development Plan and Budget if not approved by the JSC; <font style="font-style: italic;">provided </font>that any Additional
              Development Proposal that is not approved by the JSC may be described in the Development Plan and Budget for informational purposes only and will be marked as not approved by the JSC and not subject to the Parties&#8217; respective rights and
              obligations related to the Development Plan and Budget under this Agreement. AstraZeneca will keep the JSC reasonably informed of any progress and results of activities for such Additional Development undertaken by it or on its behalf at each
              regularly scheduled meeting thereof.</div>
            <div style="text-align: justify; text-indent: 72pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;">2.5.4</font>&#160;&#160;&#160;&#160;&#160; <font style="font-weight: bold;"><u>Successful Additional </u><u>Development</u></font>. With respect to any Additional Development
              conducted pursuant to <u>Section 2.5.3</u>, if the Additional Development [***], then AstraZeneca will have the right to deduct an amount equal to (a) [***] of Akcea&#8217;s applicable share of the costs of such Additional Development with respect
              to such Additional Development activities conducted prior to [***] and (b) [***] of Akcea&#8217;s applicable share of the costs of such Additional Development with respect to such Additional Development activities conducted on or after [***] (in
              each case which share will be based on whether such Additional Development was deemed to be U.S. Development Activities or Global Development Activities and the share ratios in <u>Section 2.4.1(a)</u>) from amounts payable to Akcea pursuant
              to <u>Section 11.5.1</u> or <u>Section 11.6.1</u>; <font style="font-style: italic;">provided</font> that in no event will the reductions under <u>Section 2.4.1(b)(ii)</u> and this <u>Section 2.5.4</u> collectively reduce the amounts
              payable to Akcea pursuant to <u>Section 11.5.1</u> or <u>Section 11.6.1</u>&#160;(as adjusted by <u>Section</u><u> 11.6.2</u>) by more than [***] in a given Calendar Quarter. Any excess amounts that would have otherwise been deducted in a
              Calendar Quarter shall be deducted from amounts payable to Akcea pursuant to <u>Section 11.5.1</u> or <u>Section 11.6.1</u> in successive Calendar Quarters until [***]; <font style="font-style: italic;">provided</font> that if any such
              excess amounts remain undeducted after [***] successive Calendar Quarters (or, if earlier, the end of the Term), then [***]. Notwithstanding the foregoing, the [***] from an Additional Development activity (a) in any annual or periodic safety
              reports to any Regulatory Authority with respect to the Licensed Product or (b) in the safety information portion of the Licensed Product labeling without the Licensed Product being approved for the applicable indication that was the subject
              of such Additional Development, in either case ((a) or (b)), shall not alone result in any right for AstraZeneca to deduct costs pursuant to this <u>Section</u><u> 2.5.4</u>.</div>
            <div style="text-align: justify; text-indent: 72pt;"> <br>
            </div>
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            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;">2.5.5</font>&#160;&#160;&#160;&#160;&#160; <font style="font-weight: bold;"><u>Other Development</u></font>. For the avoidance of doubt, neither Party will have the right to conduct
              any Development activities with respect to the Licensed Product that are not set forth in the Development Plan and Budget, except as expressly set forth in this <u>Section 2.5</u>.&#160; Notwithstanding anything to the contrary in this Agreement
              but without limiting each Party&#8217;s rights and obligations under <u>Article 8</u> and <u>Article 9</u>, the Parties agree that this Agreement may not be fit for the Development and Commercialization of [***], and neither Party shall
              clinically Develop or Commercialize [***] under this Agreement unless and until the Parties agree to appropriate amendments to this Agreement with respect thereto.</div>
            <div style="text-align: justify; text-indent: 72pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold;">2.6</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160; <font style="font-weight: bold;"><u>Records</u></font>. Each Party will, and will cause its Affiliates and subcontractors<font style="font-weight: bold; font-style: italic;">&#160;</font>to, maintain materially complete, current and accurate copies of records of all Development activities conducted by such Party pursuant to the Development Plan and Budget, and all
              results, data, developments and other Know-How made in conducting such activities. Such records will accurately reflect all such work done and results achieved in sufficient detail and in good scientific manner appropriate for applicable
              patent and regulatory purposes.</div>
            <div style="text-align: justify; text-indent: 36pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold;">2.7</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;<font style="font-weight: bold;"><u>Disclosure of Results</u></font>. Each Party will disclose to the other Party the results of all
              Development activities conducted by such Party under the Development Plan and Budget (other than [***]) in a reasonable manner as such results are obtained. Unless and until Akcea exercises the Opt-Out Right in accordance with <u>Section </u><u>3.6</u>,
              such disclosure will occur as soon as reasonably practicable. If Akcea exercises the Opt-Out Right in accordance with <u>Section 3.6</u>, then such disclosure will occur at each meeting of the JDC; <font style="font-style: italic;">provided</font>
              that for any material results, such disclosure will occur as soon as reasonably practicable. The Parties will provide reports and analyses at each meeting of the JDC as contemplated under <u>Section 6.3.3</u> (or as soon as practicable after
              the Completion of a Clinical Trial) detailing the current status of the Licensed Product under the Development Plan and Budget together with a summary of the data generated by such Party under the Development Plan and Budget.</div>
            <div style="text-align: justify; text-indent: 36pt;"> <br>
            </div>
            <div style="text-align: center; font-weight: bold;">ARTICLE 3</div>
            <div style="text-align: center; font-weight: bold;">COMMERCIALIZATION AND MEDICAL AFFAIRS</div>
            <div style="text-align: center; font-weight: bold;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold;">3.1</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;<font style="font-weight: bold;"><u>Commercialization Generally</u></font>.</div>
            <div style="text-align: justify; text-indent: 36pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;">3.1.1</font>&#160;&#160;&#160;&#160;&#160; <font style="font-weight: bold;"><u>Diligence</u></font>. From the Closing Date, subject to and in accordance with the terms and conditions
              of this Agreement, (a) each Party will use Commercially Reasonable Efforts to perform its respective activities under the U.S. Commercialization Plan and Budget and the U.S. Medical Affairs Plan and Budget and (b) AstraZeneca will use
              Commercially Reasonable Efforts to (i) following receipt of Regulatory Approval for a Licensed Product [***], Commercialize such Licensed Product for the treatment of [***] and (ii) on a [***] basis, following receipt of Regulatory Approval
              for a Licensed Product in [***], Commercialize such Licensed Product [***] in such [***].</div>
            <div style="text-align: justify; text-indent: 72pt;"> <br>
            </div>
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              <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">7</font></div>
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            </div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;">3.1.2</font>&#160;&#160;&#160;&#160;&#160; <font style="font-weight: bold;"><u>Responsibility</u></font>. Except for the Co-Commercialization and Medical Affairs Activities to be
              performed by Akcea in the U.S. consistent with the U.S. Commercialization Plan and Budget and U.S. Medical Affairs Plan and Budget, AstraZeneca will have the sole right to Commercialize the Licensed Products in the Territory. As between the
              Parties, AstraZeneca and its Affiliates and its and their Sublicensees will have the sole right and will be solely responsible for (a) determining and establishing the pricing of Licensed Products and the terms of sale (including any rebates
              or discounts) in the Territory, (b) invoicing, booking and recording sales of Licensed Products in the Territory, (c) warehousing and distribution of Licensed Products in the Territory, and (d) handling all governmental rebates and similar
              payments that are due and owing with respect to Licensed Products in the Territory, including the submission of any required reports, including price reports, to any Governmental Authority. Moreover, as between the Parties, AstraZeneca and
              its Affiliates and its and their Sublicensees will have the sole right and will be solely responsible for handling all returns of commercialized Licensed Product, as well as all aspects of Licensed Product order processing, invoicing and
              collection, distribution, inventory and receivables, in the Territory. The Parties will perform Co-Commercialization and Medical Affairs Activities in accordance with [***] operating policies and processes to the extent (i) such policies and
              processes (and any updates or changes thereto) are [***] and (ii) [***].</div>
            <div style="text-align: justify; text-indent: 72pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold;">3.2</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;<font style="font-weight: bold;"><u>U.S. Commercialization Plan and Budget, U.S. Medical Affairs Plan and Budget and Updates</u></font>.</div>
            <div style="text-align: justify; text-indent: 36pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;">3.2.1</font>&#160;&#160;&#160;&#160;&#160; <font style="font-weight: bold;"><u>U.S. Commercialization Plan and Budget</u></font>. Unless and until Akcea exercises the Opt-Out Right
              in accordance with <u>Section 3.6</u>, the Commercialization of the Licensed Product in the United States will be governed by a written plan that will include a corresponding budget (such Commercialization plan, as it may be modified in
              accordance with the terms and conditions of this Agreement, the &#8220;<font style="font-weight: bold; font-style: italic;">U.S. Commercialization Plan and Budget</font>&#8221;). Only activities that are solely or primarily intended for the U.S.
              (including post approval commitments required by the FDA) will be classified as &#8220;U.S. Commercial&#8221; activities in the U.S. Commercialization Plan and Budget, and [***] will not exercise its final decision-making right in <u>Section 6.6.5(e)</u>
              to approve a U.S. Commercialization Plan and Budget that is inconsistent with the foregoing.</div>
            <div style="text-align: justify; text-indent: 72pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 108pt;">(a)&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160; <font style="font-weight: bold;">Interim U.S. Commercialization Plan and Budget</font>. Within [***] after the Closing Date (or longer time period as may be agreed by the
              Parties), AstraZeneca will prepare, in consultation and with input from Akcea, an interim U.S. Commercialization Plan and Budget to govern the Commercialization of the Licensed Product in the U.S. from the Closing Date through [***] (the &#8220;<font style="font-weight: bold; font-style: italic;">Interim U.S. Commercialization Plan and Budget</font>&#8221;), which plan will contain (i) all Commercialization activities to be conducted by each Party for the Licensed Product in the United States
              from the Closing Date through [***], (ii) the allocation of responsibilities between the Parties (which allocation will be consistent with <u>Schedule 3.2.1</u>), (iii) the estimated timelines for all activities under the Interim U.S.
              Commercialization Plan and Budget, and (iv) a reasonably detailed written budget for the performance of all activities set forth in the Interim U.S. Commercialization Plan and Budget. AstraZeneca will present the Interim U.S.
              Commercialization Plan and Budget to the JCMC for the JCMC to review, discuss, revise (if and as appropriate) and make a recommendation to the JSC regarding whether to approve. The JSC shall review and determine whether to approve such
              Interim U.S. Commercialization Plan and Budget. The Interim U.S. Commercialization Plan and Budget will be considered the &#8220;U.S. Commercialization Plan and Budget&#8221; (including for purposes of cost-sharing) until a comprehensive U.S.
              Commercialization Plan and Budget is approved by the JSC pursuant to <u>Section 3.2.1(b)</u><font style="color: #000000;"> (which approval will be memorialized in the minutes of such JSC meeting). The Interim U.S. Commercialization Plan and
                Budget will focus primarily on Commercialization of the Licensed Products for [</font>***<font style="color: #000000;">], and any Commercialization activities with respect to [</font>***<font style="color: #000000;">] will be included at a
                high level.</font></div>
            <div style="text-align: justify; text-indent: 108pt;"><font style="color: #000000;"> <br>
              </font></div>
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              <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">8</font></div>
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            </div>
            <div style="text-align: justify; text-indent: 108pt;">(b)&#160;&#160;&#160;&#160;&#160;&#160;&#160; <font style="font-weight: bold;">Comprehensive U.S. Commercialization Plan and Budget</font>. At such time as the JCMC may determine, AstraZeneca will prepare, in consultation
              and with input from Akcea, and present to the JCMC, for the JCMC to review, discuss, revise (if and as appropriate) and make a recommendation to the JSC regarding whether to approve, an updated U.S. Commercialization Plan and Budget to
              replace the Interim U.S. Commercialization Plan and Budget. The JSC shall review and determine whether to approve such updated U.S. Commercialization Plan and Budget. The updated U.S. Commercialization Plan and Budget will at all times
              include: (i) all Commercialization activities to be conducted by each Party for the Licensed Product in the United States, including any post-approval commitments required by the FDA, (ii) a detailed [***] promotional plan for each Licensed
              Product (which will be consistent with the guidelines in <u>Schedule 3.2.1</u>), (iii) the allocation of responsibilities between the Parties (which allocation will be consistent with <u>Schedule 3.2.1</u>) and the estimated timelines for
              all activities under the U.S. Commercialization Plan and Budget, and (iv) a written budget for the performance of all activities set forth in the U.S. Commercialization Plan and Budget, in all cases (except for clause (ii)), for [***]; <font style="font-style: italic;">provided </font>that [***]. The Parties will use diligent efforts to enable the JSC to approve the comprehensive U.S. Commercialization Plan and Budget described in this <u>Section 3.2.1(b)</u> within [***]
              after the Closing Date; <font style="font-style: italic;">provided</font> that the first comprehensive U.S. Commercialization Plan and Budget<font style="color: #000000;"> will focus primarily on Commercialization of the Licensed Products
                for [</font>***<font style="color: #000000;">], and any Commercialization activities with respect to [</font>***<font style="color: #000000;">] will be included at a high level, with the understanding that AstraZeneca will update the</font>
              comprehensive U.S. Commercialization Plan and Budget to include additional detail regarding<font style="color: #000000;"> Commercialization of the Licensed Products for [</font>***<font style="color: #000000;">]</font>. The Interim U.S.
              Commercialization Plan and Budget will be superseded upon approval of the comprehensive U.S. Commercialization Plan and Budget described in this <u>Section 3.2.1(b)</u>.</div>
            <div style="text-align: justify; text-indent: 108pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;">3.2.2</font>&#160;&#160;&#160;&#160;&#160; <font style="font-weight: bold;"><u>U.S. Medical Affairs Plan and Budget</u></font>. Unless and until Akcea exercises the Opt-Out Right in
              accordance with <u>Section 3.6</u>, the Medical Affairs activities for the Licensed Product in the United States will be governed by a written plan that will include a corresponding budget (such Medical Affairs plan, as it may be modified in
              accordance with the terms and conditions of this Agreement, the &#8220;<font style="font-weight: bold; font-style: italic;">U.S. Medical Affairs Plan and Budget</font>&#8221; and the activities set forth in the U.S. Medical Affairs Plan and Budget,
              together with the activities set forth in the U.S. Commercialization Plan and Budget, the &#8220;<font style="font-weight: bold; font-style: italic;">Co-Commercialization and Medical Affairs Activities</font>&#8221;). Only activities that are solely or
              primarily intended for the U.S. will be classified as &#8220;U.S. Medical Affairs&#8221; activities in the U.S. Medical Affairs Plan and Budget, and [***] will not exercise its final decision-making right in <u>Section 6.6.5(f)</u> to approve a U.S.
              Medical Affairs Plan and Budget that is inconsistent with the foregoing.</div>
            <div style="text-align: justify; text-indent: 72pt;"> <br>
            </div>
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              <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">9</font></div>
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            </div>
            <div style="text-align: justify; text-indent: 108pt;">(a)&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160; <font style="font-weight: bold;">Interim U.S. Medical Affairs Plan and Budget</font>. Within [***] after the Closing Date (or longer time period as may be agreed by the
              Parties), AstraZeneca will prepare, in consultation and with input from Akcea, an interim U.S. Medical Affairs Plan and Budget to govern the Medical Affairs activities for the Licensed Product in the U.S. from the Closing Date through [***]
              (the &#8220;<font style="font-weight: bold; font-style: italic;">Interim U.S. Medical Affairs Plan and Budget</font>&#8221;), which plan will contain (i) all Medical Affairs activities to be conducted by each Party for the Licensed Product in the United
              States from the Closing Date through [***], (ii) the allocation of responsibilities between the Parties (which allocation will be consistent with <u>Schedule 3.2.1</u>), (iii) the estimated timelines for all activities under the Interim U.S.
              Medical Affairs Plan and Budget, and (iv) a reasonably detailed written budget for the performance of all activities set forth in the Interim U.S. Medical Affairs Plan and Budget. AstraZeneca will present the Interim U.S. Medical Affairs Plan
              and Budget to the JCMC for the JCMC to review, discuss, revise (if and as appropriate) and make a recommendation to the JSC regarding whether to approve the Interim U.S. Medical Affairs Plan and Budget. The JSC shall review and determine
              whether to approve such Interim U.S. Medical Affairs Plan and Budget. The Interim U.S. Medical Affairs Plan and Budget will be considered the &#8220;U.S. Medical Affairs Plan and Budget&#8221; (including for purposes of cost-sharing) until a
              comprehensive U.S. Medical Affairs Plan and Budget is approved by the JSC pursuant to <u>Section 3.2.2(b)</u><font style="color: #000000;"> (which approval will be memorialized in the minutes of such JSC meeting). The Interim U.S. </font>Medical

              Affairs <font style="color: #000000;">Plan and Budget will focus primarily on </font>Medical Affairs activities with respect to<font style="color: #000000;"> the Licensed Products [</font>***<font style="color: #000000;">], and any </font>Medical

              Affairs <font style="color: #000000;">activities with respect to [</font>***<font style="color: #000000;">] will be included at a high level. Notwithstanding any provision to the contrary in this Agreement, Akcea will have the right to
                continue conducting any Medical Affairs activities for the Licensed Product in the United States that were ongoing prior to the Closing Date until the JSC approves the Interim U.S. Medical Affairs Plan and Budget; </font><font style="font-style: italic; color: #000000;">provided</font><font style="color: #000000;"> that (x) upon the reasonable request of AstraZeneca, the Parties will meet to discuss such Medical Affairs activities and Akcea&#8217;s performance thereof,
                and (y) Akcea will use reasonable efforts to comply with AstraZeneca&#8217;s</font> operating policies and processes in the performance of such Medical Affairs activities to the extent (1) such policies and processes (and any updates or changes
              thereto) are provided reasonably in advance in writing to Akcea and (2) compliance with such policies and processes by Akcea or its Affiliates is reasonably practicable<font style="color: #000000;">.</font></div>
            <div style="text-align: justify; text-indent: 108pt;"><font style="color: #000000;"> <br>
              </font></div>
            <div style="text-align: justify; text-indent: 108pt;">(b)&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160; <font style="font-weight: bold;">Comprehensive U.S. Medical Affairs Plan and Budget</font>. At such time as the JCMC may determine, AstraZeneca will prepare, in consultation and
              with input from Akcea, and present to the JCMC, for the JCMC to review, discuss, revise (if and as appropriate) and make a recommendation to the JSC regarding whether to approve, an updated U.S. Medical Affairs Plan and Budget to replace the
              Interim U.S. Medical Affairs Plan and Budget. The JSC shall review and determine whether to approve such updated U.S. Medical Affairs Plan and Budget. The updated U.S. Medical Affairs Plan and Budget will at all times include: (i) all Medical
              Affairs activities to be conducted by each Party for the Licensed Product in the United States, (ii) the allocation of responsibilities between the Parties (which allocation will be consistent with <u>Schedule 3.2.1</u>) and the estimated
              timelines for all activities under the U.S. Medical Affairs Plan and Budget, (iii) the strategy for publications and medical congresses related to the Licensed Product, and (iv) a written budget for the performance of all activities set forth
              in the U.S. Medical Affairs Plan and Budget, in all cases, for [***]; <font style="font-style: italic;">provided</font> that [***]. The first comprehensive U.S. Medical Affairs Plan and Budget<font style="color: #000000;"> will focus
                primarily on </font>Medical Affairs<font style="color: #000000;"> activities with respect to the Licensed Products [</font>***<font style="color: #000000;">], and any </font>Medical Affairs<font style="color: #000000;"> activities with
                respect to [</font>***<font style="color: #000000;">] will be included at a high level, with the understanding that AstraZeneca will update the</font> comprehensive U.S. Medical Affairs Plan and Budget to include additional detail regarding<font style="color: #000000;">&#160;</font>Medical Affairs<font style="color: #000000;"> activities with respect to the Licensed Products [</font>***<font style="color: #000000;">].</font> The Interim U.S. Medical Affairs Plan and Budget will be
              superseded upon approval of the comprehensive U.S. Medical Affairs Plan and Budget described in this <u>Section 3.2.2(b)</u>.</div>
            <div style="text-align: justify; text-indent: 108pt;"> <br>
            </div>
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              <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">10</font></div>
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            </div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;">3.2.3</font>&#160;&#160;&#160;&#160;&#160;&#160; <font style="font-weight: bold;"><u>Changes to the U.S. Commercialization Plan and Budget or the U.S. Medical Affairs Plan and Budget</u></font>.</div>
            <div style="text-align: justify; text-indent: 72pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 108pt;">(a)&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;If a Party wishes to make a change to the U.S. Commercialization Plan and Budget or the U.S. Medical Affairs Plan and Budget, then such Party will submit its proposed change to
              the JCMC for the JCMC to review, discuss, revise (if and as appropriate) and make a recommendation to the JSC regarding whether to approve such change. The JSC shall review and determine whether to approve such change to the U.S.
              Commercialization Plan and Budget or the U.S. Medical Affairs Plan and Budget, as applicable. <font style="color: #000000;">Each such update to the U.S. Commercialization Plan and Budget or the U.S. Medical Affairs Plan and Budget will
                become effective and will supersede the previous U.S. Commercialization Plan and Budget or U.S. Medical Affairs Plan and Budget, as applicable, upon approval thereof by the JSC (which approval will be memorialized in the minutes of such JSC
                meeting).</font></div>
            <div style="text-align: justify; text-indent: 108pt;"><font style="color: #000000;"> <br>
              </font></div>
            <div style="text-align: justify; text-indent: 108pt;">(b)&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;For any Calendar Year in a U.S. Commercialization Plan and Budget and U.S. Medical Affairs Plan and Budget (such Calendar Year, the &#8220;<font style="font-weight: bold; font-style: italic;">Reference Calendar Year</font>&#8221;), if the Senior Officers are unable to agree to, and [***] exercises its final decision-making right in <u>Section</u><u> 6.6.5(e)</u> or <u>Section 6.6.5(f)</u>, as applicable, to approve, an
              update to the budget for the Reference Calendar Year set forth in any U.S. Commercialization Plan and Budget or U.S. Medical Affairs Plan and Budget, then the Parties&#8217; cost-sharing obligations under <u>Section 3.4.1</u> for such Reference
              Calendar Year under the U.S. Commercialization Plan and Budget and U.S. Medical Affairs Plan and Budget combined will be [***] (such amount, the &#8220;<font style="font-weight: bold; font-style: italic;">Cost Sharing Cap</font>&#8221;).&#160; Any FTE Costs
              and Out-of-Pocket Costs incurred for Commercialization or Medical Affairs activities for the Licensed Product in the U.S. in excess of the Cost Sharing Cap for a given Calendar Year will not constitute Eligible Expenses and AstraZeneca will
              be responsible for all such FTE Costs and Out-of-Pocket Costs. <u>Schedule 3.2.3(b)</u> contains examples of the budgeting and cap mechanism contemplated by this <u>Section 3.2.3(b)</u>, which examples are for illustrative purposes only.
              Notwithstanding the foregoing, if the Parties <font style="color: #000000;">approve by unanimous Party Vote or by the Senior Officers the budget </font>for the Reference Calendar Year set forth in the U.S. Commercialization Plan and Budget
              and the U.S. Medical Affairs Plan and Budget when the Reference Calendar Year is the immediately following Calendar Year (e.g., the Parties approve a budget for Calendar Year 2024 in the fourth quarter of 2023), then<font style="color: #000000;"> the provisions of this <u>Section 3.2.3(b)</u> and the Cost Sharing Cap shall not apply.</font></div>
            <div style="text-align: justify; text-indent: 108pt;"><font style="color: #000000;"> <br>
              </font></div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;">3.2.4</font>&#160;&#160;&#160;&#160;&#160; <font style="font-weight: bold;"><u>Co-Commercialization Agreement</u></font>. Without limiting <u>Section</u><u> 3.2.1</u>&#160;or<u> Section</u><u>
                3.2.2</u>, prior to [***] performing any marketing or promotional activities for the Licensed Product for the U.S., the Parties shall negotiate in good faith and enter into a co-commercialization agreement to govern the Parties&#8217; performance
              of co-commercialization, which agreement shall contain reasonable and customary terms for similar co-commercialization agreements that are consistent with the terms and conditions of this Agreement, including the U.S. Commercialization Plan
              and Budget, U.S. Medical Affairs Plan and Budget and <u>Schedule 3.2.1</u>.</div>
            <div style="text-align: justify; text-indent: 72pt;"> <br>
            </div>
            <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
              <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">11</font></div>
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            </div>
            <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold;">3.3</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;<font style="font-weight: bold;"><u>ROW Commercialization Plan and Updates</u></font>. AstraZeneca will have the sole right to
              Commercialize the Licensed Product in the ROW Territory and will conduct such Commercialization in accordance with a high-level written plan or a comparable document consistent with AstraZeneca&#8217;s then current internal practices for
              AstraZeneca&#8217;s internal programs outlining key aspects of Commercialization activities for such Licensed Product in the ROW Territory (the &#8220;<font style="font-weight: bold; font-style: italic;">ROW Commercialization Plan</font>&#8221;). The ROW
              Commercialization Plan will contain high-level information consistent with AstraZeneca&#8217;s commercialization plans for its similar products at similar stages of commercialization in the same AstraZeneca franchise, including a status update,
              timelines, goals, and success criteria, but excluding any confidential information of a Third Party that AstraZeneca is prohibited from sharing with Akcea under restrictions imposed by such Third Party (<font style="font-style: italic;">provided</font>
              that AstraZeneca will use Commercially Reasonable Efforts to ensure any agreement specific to the Licensed Compound or Licensed Product entered into after the Closing Date will allow for such sharing with Akcea). No later than [***] prior to
              the anticipated First Commercial Sale of the Licensed Product in [***], AstraZeneca will prepare the ROW Commercialization Plan and provide the JCMC with copies of such ROW Commercialization Plan to review and discuss; <font style="font-style: italic;">provided</font> that the first ROW Commercialization Plan<font style="color: #000000;"> will focus primarily on Commercialization of the Licensed Products in the ROW Territory [</font>***<font style="color: #000000;">], and any Commercialization activities in the ROW Territory with respect to [</font>***<font style="color: #000000;">] will be included at a high level, with the understanding that AstraZeneca will update the</font> ROW
              Commercialization Plan to include additional detail regarding<font style="color: #000000;"> Commercialization of the Licensed Products in the ROW Territory [</font>***<font style="color: #000000;">]</font>. At least once every [***] during
              the Term (or more frequently as may be consistent with AstraZeneca&#8217;s standard practice), AstraZeneca will review and update the ROW Commercialization Plan based on the currently available information and data for the Licensed Product and
              provide updated copies of such ROW Commercialization Plan to the JCMC for the JCMC to review and discuss. AstraZeneca will [***] any comments provided by Akcea on the ROW Commercialization Plan.</div>
            <div style="text-align: justify; text-indent: 36pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold;">3.4</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;<font style="font-weight: bold;"><u>Commercialization and Medical Affairs Costs</u></font>.</div>
            <div style="text-align: justify; text-indent: 36pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;">3.4.1</font>&#160;&#160;&#160;&#160;&#160; <font style="font-weight: bold;"><u>Shared Commercialization and Medical Affairs Costs</u></font>.</div>
            <div style="text-align: justify; text-indent: 72pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 108pt;">(a)&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;<font style="font-weight: bold;">Share Ratios</font>. The Parties will share the Eligible Commercialization Expenses and the Eligible Medical Affairs Expenses that are
              reasonably allocable to Commercialization and Medical Affairs activities for Licensed Products for the U.S. prior to the Opt-Out Date, if any, as follows, but subject to the Cost Sharing Cap (if applicable): Akcea will bear [***] and
              AstraZeneca will bear [***] of all Eligible Commercialization Expenses and Eligible Medical Affairs Expenses for Commercialization and Medical Affairs activities that are expressly classified as &#8220;U.S. Commercial&#8221; or &#8220;U.S. Medical Affairs&#8221;
              activities in the U.S. Commercialization Plan and Budget or the U.S. Medical Affairs Plan and Budget, as applicable; <font style="font-style: italic;">provided</font> that Akcea will bear [***] and AstraZeneca will bear [***] of (i) all
              Eligible Commercialization Expenses incurred in [***] and (ii) Eligible Commercialization Expenses and Eligible Medical Affairs Expenses for Commercialization and Medical Affairs activities that are [***], in the case of clause (ii) that are
              expressly classified in the U.S. Commercialization Plan and Budget or the U.S. Medical Affairs Plan and Budget, as applicable, as activities that are [***].</div>
            <div style="text-align: justify; text-indent: 108pt;"> <br>
            </div>
            <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
              <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">12</font></div>
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            </div>
            <div style="text-align: justify; text-indent: 108pt;">(b)&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;<font style="font-weight: bold;">Shared Commercialization and Medical Affairs Costs Payment Reconciliation</font>. Unless and until the Opt-Out Date occurs (and for the Calendar
              Quarter in which the Opt-Out Date occurs), the following shall apply:</div>
            <div style="text-align: justify; text-indent: 108pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 144pt;">(i)&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;No later than [***] after the end of each Calendar Quarter, each Party will deliver to the other Party a non-binding estimate that sets forth the Eligible Commercialization
              Expenses and Eligible Medical Affairs Expenses incurred by or on behalf of such Party during such Calendar Quarter. No later than [***]<font style="font-weight: bold; font-style: italic;">&#160;</font>after the end of each Calendar Quarter, each
              Party will deliver to the other Party a written report that sets forth in detail the actual Eligible Commercialization Expenses and Eligible Medical Affairs Expenses incurred by or on behalf of such Party during such Calendar Quarter,
              including a comparison of such Eligible Commercialization Expenses and Eligible Medical Affairs Expenses for a Commercialization or Medical Affairs activity, as applicable, to the amount budgeted for such activity in the U.S.
              Commercialization Plan and Budget or U.S. Medical Affairs Plan and Budget (the &#8220;<font style="font-weight: bold; font-style: italic;">Commercialization and Medical Affairs Cost Share Notice</font>&#8221;). Each Party will provide the other Party
              with supporting documentation of such Eligible Commercialization Expenses and Eligible Medical Affairs Expenses if reasonably requested by the other Party. For each Calendar Quarter, no later than [***] after receipt of the Commercialization
              and Medical Affairs Cost Share Notice for such Calendar Quarter from each Party, the Party that incurred less than its allocation of Eligible Commercialization Expenses and Eligible Medical Affairs Expenses during such Calendar Quarter will
              make a balancing payment to the other Party to effect the cost-sharing ratios set forth in <u>Section 3.4.1(a)</u>, to the extent the amounts set forth in the Commercialization and Medical Affairs Cost Share Notices are undisputed. Any
              dispute regarding amounts set forth in a Commercialization and Medical Affairs Cost Share Notice will be promptly referred to the JSC for resolution, and if the JSC determines that any disputed amount should be included in the applicable
              Commercialization and Medical Affairs Cost Share Notice, the Party that incurred less than its allocation of Eligible Commercialization Expenses and Eligible Medical Affairs Expenses during such Calendar Quarter (taking into account any
              balancing payments previously made for such Calendar Quarter pursuant to the immediately preceding sentence) will make a balancing payment to the other Party to effect the cost-sharing ratios set forth in <u>Section </u><u>3.4.1(a)</u>&#160;within

              [***] of the JSC determination.</div>
            <div style="text-align: justify; text-indent: 144pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;">3.4.2</font>&#160;&#160;&#160;&#160; <font style="font-weight: bold;"><u>ROW Commercialization Costs</u></font>. Except as set forth in <u>Section </u><u>3.4.1(a)</u>, [***]
              will be solely responsible for [***] of its costs and expenses incurred in connection with the Commercialization and Medical Affairs activities for the Licensed Product in the ROW Territory.</div>
            <div style="text-align: justify; text-indent: 72pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold;">3.5</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160; <font style="font-weight: bold;"><u>Commercialization and Medical Affairs Reporting</u></font>. On a quarterly basis, if a Party is
              conducting any Commercialization or Medical Affairs activities for the Licensed Product in the Territory, then such Party will, within [***] after the end of each Calendar Quarter, provide to the JCMC for its review and discussion, a
              high-level report summarizing such Party&#8217;s and its Affiliates&#8217; and Sublicensees&#8217; material Commercialization and Medical Affairs activities with respect to the Licensed Product over the prior Calendar Quarter.</div>
            <div style="text-align: justify; text-indent: 36pt;"> <br>
            </div>
            <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
              <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">13</font></div>
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            </div>
            <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold;">3.6</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;<font style="font-weight: bold;"><u>Akcea Opt-Out Right</u></font>.</div>
            <div style="text-align: justify; text-indent: 36pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;">3.6.1</font>&#160;&#160;&#160;&#160;&#160; <font style="font-weight: bold;"><u>Opt-Out Right and Exercise</u></font>. If Akcea no longer wants to participate in Co-Commercialization
              and Medical Affairs Activities, it will also have the right to opt-out of its rights and obligations to perform the Co-Commercialization and Medical Affairs Activities and to pay any portion of Eligible Expenses set forth under this Agreement
              (such right the &#8220;<font style="font-weight: bold; font-style: italic;">Opt-Out Right</font>&#8221;). Akcea may exercise the Opt-Out Right by providing written notice to AstraZeneca of such election anytime from the Closing Date until (a) [***] (such
              time period, including any extension as set forth in this <u>Section 3.6.1</u>, the &#8220;<font style="font-weight: bold; font-style: italic;">First Opt-Out Period</font>&#8221;) and (b) [***] (such time period, including any extension as set forth in
              this <u>Section 3.6.1</u>, the &#8220;<font style="font-weight: bold; font-style: italic;">Second Opt-Out Period</font>&#8221;). On an Initial Indication-by-Initial Indication basis, promptly after [***], unless Akcea has already exercised its Opt-Out
              Right, AstraZeneca will prepare and present to the JCMC, for the JCMC to review, discuss, revise (if and as appropriate) and make a recommendation to the JSC regarding whether to approve, an updated U.S. Commercialization Plan and Budget and
              U.S. Medical Affairs Plan and Budget that reflect the Co-Commercialization and Medical Affairs Activities for the Licensed Product in such Initial Indication, which will include AstraZeneca&#8217;s then most recent forecasted profit and loss model
              for each Licensed Product for the [***] Calendar Years; <font style="font-style: italic;">provided</font> that, for clarity, such profit and loss model shall be for information purposes only and shall not affect the U.S. Commercialization
              Plan and Budget or the U.S. Medical Affairs Plan and Budget or the financial allocations hereunder. If AstraZeneca fails to provide such updated U.S. Commercialization Plan and Budget and U.S. Medical Affairs Plan and Budget to the JCMC
              within [***] after [***], then the First Opt-Out Period or Second Opt-Out Period (as applicable) will be extended until [***] after AstraZeneca presents such updated U.S. Commercialization Plan and Budget and such updated U.S. Medical Affairs
              Plan and Budget to the JCMC.</div>
            <div style="text-align: justify; text-indent: 72pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;">3.6.2</font>&#160;&#160;&#160;&#160;&#160;&#160; <font style="font-weight: bold;"><u>Effects of Opt-Out</u></font>.</div>
            <div style="text-align: justify; text-indent: 72pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 108pt;">(a)&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;<font style="font-weight: bold;">In General</font>. If Akcea exercises the Opt-Out Right during either the First Opt-Out Period or the Second Opt-Out Period pursuant to this <u>Section

                3.6</u>, then as of (x) if Akcea provides written notice to AstraZeneca of such election prior to [***] and (y) if Akcea provides written notice to AstraZeneca of such election on or after [***] (the date described in clause (x) or clause
              (y), as applicable, &#8220;<font style="font-weight: bold; font-style: italic;">Opt-Out Date</font>&#8221;) (<font style="font-style: italic;">provided </font>that if Akcea is deemed to exercise the Opt-Out Right pursuant to <u>Section 16.3.4</u> or <u>Section

                17.11.3</u>, the Opt-Out Date shall be the date that AstraZeneca provides written notice thereof to Akcea pursuant to <u>Section 16.3.4</u> or <u>Section 17.11.3</u>, as applicable), without limiting any other effects of exercise of the
              Opt-Out Right set forth in this Agreement, the following effects will apply:</div>
            <div style="text-align: justify; text-indent: 108pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 144pt;">(i)&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;Unless otherwise agreed by the Parties, Akcea will no longer have any rights or obligations with respect to, and AstraZeneca will have the sole right to conduct, at its sole
              cost and expense, all further Development activities for the Licensed Product for the Territory, except that Akcea will continue to conduct any Clinical Trial allocated to Akcea under the Development Plan and Budget that is ongoing as of the
              Opt-Out Date at AstraZeneca&#8217;s sole cost and expense for Eligible Development Expenses, until the earlier of Completion of such Clinical Trial or AstraZeneca&#8217;s request for such Clinical Trial to be transferred to AstraZeneca (which transfer
              will be at AstraZeneca&#8217;s sole cost and expense and effectuated on a mutually agreed timeline). The JDC shall review and discuss (but not approve) any further updates or amendments to the Development Plan and Budget, and, notwithstanding <u>Section

              </u><u>2.2.1</u>, any future iterations of the Development Plan and Budget will be consistent with AstraZeneca&#8217;s then current internal practices for AstraZeneca&#8217;s internal programs outlining key aspects of the Development of the Licensed
              Product through all Regulatory Approval and will not need to include a budget;</div>
            <div style="text-align: justify; text-indent: 144pt;"> <br>
            </div>
            <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
              <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">14</font></div>
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            </div>
            <div style="text-align: justify; text-indent: 144pt;">(ii)&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160; the provisions of <u>Section</u><u> 2.5</u>&#160;(Additional Development) will no longer apply;</div>
            <div style="text-align: justify; text-indent: 144pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 144pt;">(iii)&#160;&#160;&#160;&#160;&#160;&#160;&#160; Akcea will no longer have any rights or obligations with respect to, and AstraZeneca will have the sole right to conduct, at its sole cost and expense, all further Medical
              Affairs activities for the Licensed Product in the Territory;</div>
            <div style="text-align: justify; text-indent: 144pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 144pt;">(iv)&#160;&#160;&#160;&#160;&#160;&#160;&#160; Akcea will no longer have any rights or obligations with respect to, and AstraZeneca will have the sole right to conduct, at its sole cost and expense, all further
              Commercialization activities for the Licensed Product in the Territory;</div>
            <div style="text-align: justify; text-indent: 144pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 144pt;">(v)&#160;&#160;&#160;&#160;&#160;&#160;&#160; the provisions of <u>Section</u><u> 3.2</u>&#160;(U.S. Commercialization Plan and Budget, U.S. Medical Affairs Plan and Budget and Updates) will no longer apply, and the provisions of
              <u>Section</u><u> 3.3</u>&#160;(ROW Commercialization Plan and Updates) will apply to the U.S. and the ROW Territory;</div>
            <div style="text-align: justify; text-indent: 144pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 144pt;">(vi)&#160;&#160;&#160;&#160;&#160;&#160;&#160; AstraZeneca&#8217;s reporting obligations under <u>Section</u><u> 3.5</u>&#160;(Commercialization and Medical Affairs Reporting) will apply to both the U.S. and the ROW Territory on [***]
              basis (rather than a quarterly basis);</div>
            <div style="text-align: justify; text-indent: 144pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 144pt;">(vii)&#160;&#160;&#160;&#160;&#160;&#160; AstraZeneca will buy, at [***], any API and drug product for the Licensed Product that is required by AstraZeneca to complete such ongoing Clinical Trials for the Licensed
              Product, if applicable; <font style="font-style: italic;">provided</font> that the foregoing shall not affect Akcea&#8217;s obligations under <u>Section</u><u> 5.1.1</u>&#160;to Manufacture and supply clinical supply of the Licensed Compound and the
              Licensed Product through the later of (A) [***] and (B) [***], and at [***] request, Akcea and AstraZeneca shall negotiate in good faith and enter into a supply agreement and quality agreement to govern such supply, which agreements shall
              contain reasonable and customary terms for similar supply and quality agreements that are not inconsistent with the terms and conditions of this Agreement;</div>
            <div style="text-align: justify; text-indent: 144pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 144pt;">(viii)&#160;&#160;&#160;&#160;&#160; the licenses granted to Akcea under <u>Section 8.2</u> will automatically and immediately terminate, except to the extent (and for so long as is) required to perform Development
              activities pursuant to <u>Section 3.6.2(a)(i)</u>&#160;and to Manufacture and supply clinical supply of the Licensed Compound and the Licensed Product in accordance with <u>Section </u><u>5.1.1</u>;</div>
            <div style="text-align: justify; text-indent: 144pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 144pt;">(ix)&#160;&#160;&#160;&#160;&#160;&#160;&#160; the provisions of <u>Section 5.4</u> (Capital Expenditures) will no longer apply;</div>
            <div style="text-align: justify; text-indent: 144pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 144pt;">(x)&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160; Akcea will not be responsible for any Eligible Expenses to the extent reasonably allocable to Exploitation of the Licensed Product from and after the Opt-Out Date; and</div>
            <div style="text-align: justify; text-indent: 144pt;"> <br>
            </div>
            <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
              <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">15</font></div>
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            </div>
            <div style="text-align: justify; text-indent: 144pt;">(xi)&#160;&#160;&#160;&#160;&#160;&#160;&#160; AstraZeneca will no longer be responsible for [***] achieved after the Opt-Out Date.</div>
            <div style="text-align: justify; text-indent: 144pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 108pt;">(b)&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;<font style="font-weight: bold;">Opt-Out Economics</font>.</div>
            <div style="text-align: justify; text-indent: 108pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 144pt;">(i)&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;<font style="font-weight: bold;">Scenario One</font>. Subject to the remainder of this <u>Section 3.6.2(b)</u>, if Akcea exercises the Opt-Out Right (including if Akcea is
              deemed to exercise the Opt-Out Right pursuant to <u>Section 16.3.4</u> or <u>Section 17.11.3</u>), then, in addition to the effects set forth in <u>Section 3.6.2(a)</u>, subject to <u>Section 3.6.2(b)(ii)</u>, AstraZeneca will pay Akcea
              royalties at royalty rates that are agreed to by the Parties within [***] of such exercise (such royalty rates, &#8220;<font style="font-weight: bold; font-style: italic;">Opt-Out Scenario One Royalty Rates</font>&#8221;) on Net Sales in the U.S. from
              and after the Opt-Out Date (&#8220;<font style="font-weight: bold; font-style: italic;">Opt-Out Scenario One Royalties</font>&#8221;). Subject to <u>Section 17.11.3</u>, such Opt-Out Scenario One Royalty Rates will be determined by the Parties to equate
              to [***] of the estimated average per unit U.S. operating profit with respect to the Licensed Product(s) from the First Commercial Sale of the Licensed Product through the anticipated expiration of the Royalty Term (taking into account the
              effects of any Patent Term Extensions) in the U.S. The &#8220;U.S. operating profit&#8221; will be determined consistently with AstraZeneca&#8217;s Accounting Standards (as such Accounting Standards are applied consistently across AstraZeneca&#8217;s products) and
              will not take into account any payments owed to Akcea under this Agreement. To facilitate the negotiation of such Opt-Out Scenario One Royalty Rates, AstraZeneca will provide, within [***] after the date that Akcea exercises the Opt-Out
              Right, Akcea with its [***]. For clarity, the Opt-Out Scenario One Royalty Rates will be determined one time (within [***] of Akcea&#8217;s exercise of the Opt-Out Right, subject to any extension pursuant to <u>Section 3.6.2(b)(ii)</u>) and shall
              not be adjusted or renegotiated after such Opt-Out Scenario One Royalty Rates are agreed. If the Parties agree on the Opt-Out Scenario One Royalty Rates, then (A) except in the case of a deemed exercise of the Opt-Out Right under <u>Section
                16.3.4</u> or <u>Section 17.11.3</u>, AstraZeneca will reimburse Akcea for [***] of Akcea&#8217;s share of the Eligible Expenses incurred and previously reconciled pursuant to <u>Section 2.4.1</u>, <u>Section 3.4.1</u> and <u>Section 11.10</u>,
              as applicable through the Opt-Out Date, which reimbursement shall be made within [***] after the Parties agree on the Opt-Out Scenario One Royalty Rates, (B) AstraZeneca will pay Akcea the Opt-Out Scenario One Royalties on Net Sales of each
              Licensed Product from and after the Opt-Out Date until the expiration of the Royalty Term for such Licensed Product in the U.S., and (C) AstraZeneca will provide reports and payments to Akcea consistent with <u>Section 11.7</u>.</div>
            <div style="text-align: justify; text-indent: 144pt;">(ii)&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;<font style="font-weight: bold;">Scenario Two</font>. If the Parties, acting reasonably and in good faith, fail to agree on the Opt-Out Scenario One Royalty Rates within [***]
              after the date that Akcea exercises the Opt-Out Right (<font style="font-style: italic;">provided</font> that if the Parties are still negotiating in good faith at the conclusion of such [***] period, then such negotiation period for the
              Opt-Out Scenario One Royalty Rates will be extended by an additional [***]), then, in addition to the effects set forth in <u>Section 3.6.2(a)</u>, AstraZeneca will instead pay Akcea royalties on the aggregate Net Sales resulting from the
              sale of each Licensed Product in the U.S. during each Calendar Year from and after the Opt-Out Date during the Royalty Term at [***] pursuant to <u>Section [***]</u>.</div>
            <div style="text-align: justify; text-indent: 144pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;">3.6.3</font>&#160;&#160;&#160;&#160;&#160;&#160; <font style="font-weight: bold;"><u>Effect of Not Opting-Out</u></font>. If Akcea does not exercise its Opt-Out Right prior to expiration
              of the Second Opt-Out Period, then Akcea will no longer have the Opt-Out Right except as set forth in <u>Section 16.3.4</u> and <u>Section 17.11.3</u>.</div>
            <div style="text-align: justify; text-indent: 72pt;"> <br>
            </div>
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            </div>
            <div style="text-align: center; font-weight: bold;">ARTICLE 4</div>
            <div style="text-align: center; font-weight: bold;">REGULATORY</div>
            <div style="text-align: center; font-weight: bold;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold;">4.1</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160; <font style="font-weight: bold;"><u>Regulatory Strategy</u></font>. The RWG will develop the overall regulatory strategy through [***] in
              each of the Initial Indications (the &#8220;<font style="font-weight: bold; font-style: italic;">Regulatory Strategy</font>&#8221;), which Regulatory Strategy shall be submitted to the JDC for review and approval as part of the Development Plan and
              Budget. The Regulatory Strategy shall include, for each Licensed Product, guidance and strategies for high-level documents, statistical analysis plans, clinical study reports, quality strategy pre- and post-Regulatory Approval and other
              materials to allow for the preparation and compilation of Regulatory Filings in both of the Initial Indications in the Territory. All Regulatory Filings (including Regulatory Approval Applications) for the treatment of the Initial Indications
              will be consistent with the Regulatory Strategy.</div>
            <div style="text-align: justify; text-indent: 36pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold;">4.2</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;<font style="font-weight: bold;"><u>Responsibility for Regulatory Filings and </u><u>Ownership of Regulatory Materials</u></font>.</div>
            <div style="text-align: justify; text-indent: 36pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;">4.2.1</font>&#160;&#160;&#160;&#160;&#160; <font style="font-weight: bold;"><u>In the U.S</u><u>. and Canada</u></font>.</div>
            <div style="text-align: justify; text-indent: 72pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 108pt;">(a)&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;<font style="font-weight: bold;">PN</font>.<font style="font-weight: bold;">&#160;</font>Unless and until responsibility is transferred to AstraZeneca in accordance with this <u>Section

                4.2.1(a)</u>, Akcea will be responsible for (i) the Regulatory Filings to support the Clinical Trials that are ongoing as of the Execution Date for the Licensed Product for the treatment of PN and (ii) the Regulatory Filings and Regulatory
              Approval Applications for the Licensed Product for the treatment of PN in the U.S. and Canada until receipt of Regulatory Approval of the Licensed Product for the treatment of PN. During the period in which Akcea is responsible for such
              Regulatory Filings to support such Clinical Trials and such other Regulatory Filings and Regulatory Approval Applications for the Licensed Product for the treatment of PN, Akcea will closely collaborate with AstraZeneca and provide
              AstraZeneca, through its representatives on the RWG, the right to review and approve (1) [***] and (2) [***].&#160; Any disagreement in the RWG will be escalated to the JDC for review and decision making. As soon as reasonably practicable after
              Regulatory Approval in each of the U.S. and Canada for the Licensed Product for the treatment of PN, Akcea and its Affiliates will transfer and assign to AstraZeneca, at [***] cost, the Regulatory Filings (including the IND, NDA (or its
              Canadian equivalent)), other Regulatory Approvals and all related documentation (including IND/CTA sequences, briefing documents, correspondence from/to FDA and Health Canada) for the U.S. or Canada, as applicable, related to the Licensed
              Product, <font style="font-style: italic;">except, </font>with respect to Regulatory Filings for Clinical Trials that are ongoing as of the Execution Date for the Licensed Product for the treatment of CM, such Regulatory Filings and all
              related documentation will be retained by Akcea to the extent required to perform Akcea&#8217;s obligations in <u>Section 4.2.1(b)</u>.&#160;&#160; Notwithstanding the foregoing, AstraZeneca will have the right, upon written notice to Akcea, to assume
              responsibility for (x) the Regulatory Filings (including, for clarity, the IND) to support the Clinical Trials that are ongoing as of the Execution Date for the Licensed Product for the treatment of PN and (y) the Regulatory Filings and
              Regulatory Approval Applications for the Licensed Product for the treatment of PN in the U.S. and Canada, at any time after the Closing Date but no later than receipt of Regulatory Approval in each of the U.S. and Canada for the Licensed
              Product for the treatment of PN.&#160; If AstraZeneca exercises such right, then as soon as practicable following such exercise, Akcea will transfer to AstraZeneca (and AstraZeneca will assume) such Regulatory Filings (including, for clarity, the
              IND) and Regulatory Approval Applications and, as soon as practicable, notwithstanding <u>Section 2.2.2</u>, AstraZeneca will assume sponsorship and responsibility for conducting any Clinical Trials that are governed by a Regulatory Filing
              transferred to AstraZeneca under this <u>Section 4.2.1(a)</u>.</div>
            <div style="text-align: justify; text-indent: 108pt;"> <br>
            </div>
            <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
              <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">17</font></div>
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            </div>
            <div style="text-align: justify; text-indent: 108pt;">(b)&#160; &#160; &#160;&#160;&#160;&#160; <font style="font-weight: bold;">CM</font>.<font style="font-weight: bold;">&#160;</font>Unless and until responsibility is transferred to AstraZeneca in accordance with this <u>Section

                4.2.1(b)</u>, Akcea will retain regulatory responsibility for Regulatory Filings to support the Clinical Trials that are ongoing as of the Execution Date for the Licensed Product for the treatment of CM, and, promptly following the
              Completion of all such Clinical Trials, Akcea will assign the Regulatory Filings, Regulatory Approvals and all related documentation (including IND/CTA sequences, briefing documents, correspondence from/to FDA and any other Regulatory
              Authority) related to the Licensed Product for the treatment of CM to AstraZeneca. During the period in which Akcea is responsible for Regulatory Filings to support such Clinical Trials, Akcea will closely collaborate with AstraZeneca and
              provide AstraZeneca, through its representatives on the RWG, the right to review and approve (i) [***] and (ii) [***]. Any disagreement at the RWG will be escalated to the JDC for review and decision making.&#160; Notwithstanding the foregoing,
              AstraZeneca will have the right to assume responsibility for such Regulatory Filings (including, for clarity, the IND) to support such Clinical Trials that are ongoing as of the Execution Date for the Licensed Product for the treatment of CM,
              at any time after the Closing Date but no later than Completion of all such Clinical Trials. If AstraZeneca exercises such right, then as soon as practicable following such exercise Akcea will transfer to AstraZeneca (and AstraZeneca will
              assume) such Regulatory Filings (including, for clarity, the IND) and Regulatory Approval Applications and, as soon as practicable, notwithstanding <u>Section 2.2.2</u>, AstraZeneca will assume sponsorship and responsibility for conducting
              any Clinical Trials that are governed by a Regulatory Filing transferred to AstraZeneca under this <u>Section 4.2.1(b)</u>.</div>
            <div style="text-align: justify; text-indent: 108pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;">4.2.2</font>&#160;&#160;&#160;&#160;&#160; <font style="font-weight: bold;"><u>In the EU</u></font>. Akcea will be responsible for initial discussions with the EMA and MHRA regarding
              the path for Regulatory Approval for the Licensed Product for the treatment of [***], and will provide AstraZeneca, through its representatives on the RWG, the right to review and approve (a) [***] and (b) [***]. Any disagreement in the RWG
              will be escalated to the JDC for review and decision making.&#160; Prior to submission of the Regulatory Approval Application to the EMA or MHRA for the Licensed Product for the treatment of [***], Akcea will assign all Regulatory Filings,
              Regulatory Approvals and all related documentation (including the applicable IND and MAA (or their equivalent), IND/CTA sequences, briefing documents, correspondence from/to FDA and any other Regulatory Authority) for the EU to AstraZeneca.
              As between the Parties, AstraZeneca will be responsible, in accordance with the Development Plan and Budget and to the extent consistent with its obligations in <u>Section 2.1</u>, for filing and holding the Regulatory Filings and Regulatory
              Approvals for the Licensed Product for the treatment of the Initial Indications and any other Indications in the EU.</div>
            <div style="text-align: justify; text-indent: 72pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;">4.2.3</font>&#160;&#160;&#160;&#160;&#160; <font style="font-weight: bold;"><u>Other</u></font>. Except as otherwise provided in <u>Section 4.1</u>, <u>Section 4.2.1</u> and <u>Section

                4.2.2</u>, as between the Parties, AstraZeneca will have the sole right and will bear all expense for (a) determining the regulatory plans and strategies for the Licensed Product, (b) making all Regulatory Filings with respect to the
              Licensed Product, and (c) obtaining and maintaining Regulatory Approvals, in each case consistent with the Regulatory Strategy.</div>
            <div style="text-align: justify; text-indent: 72pt;"> <br>
            </div>
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              <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">18</font></div>
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            <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold;">4.3</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;<font style="font-weight: bold;"><u>Regulatory Cooperation</u></font>.</div>
            <div style="text-align: justify; text-indent: 36pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;">4.3.1</font>&#160;&#160;&#160;&#160; <font style="font-weight: bold;"><u>Regulatory Owner Responsibilities</u></font>. Subject to applicable Law and this <u>Section 4.3</u>,
              the Party responsible for filing and holding Regulatory Filings and Regulatory Approvals in a particular territory for a particular Licensed Product (if applicable, in a particular Indication) in accordance with <u>Section 4.2</u> (the &#8220;<font style="font-weight: bold; font-style: italic;">Regulatory Owner</font>&#8221;) will oversee, monitor and manage all regulatory interactions, communications and filings with, and submissions to, Regulatory Authorities in connection with such
              Regulatory Filings. During the period in which Akcea is the Regulatory Owner in any country, each Party will assign a Global Regulatory Affairs lead to the Licensed Product, and the Akcea Global Regulatory Affairs Lead for the Licensed
              Product will work in regular contact with the AstraZeneca Global Regulatory Affairs Lead and provide AstraZeneca, through its representatives on the RWG, the right to review and [***] major documents that are submitted by Akcea to Regulatory
              Authorities in connection with such Regulatory Filings.&#160; Any disagreement in the RWG will be escalated to the JDC for review and decision making.</div>
            <div style="text-align: justify; text-indent: 72pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;">4.3.2</font>&#160;&#160;&#160;&#160; <font style="font-weight: bold;"><u>Regulatory Submissions and Correspondence</u></font>. Subject to applicable Law, the Party that is not
              the Regulatory Owner will have the right to attend, as a participant, all material meetings, conferences and discussions by the Regulatory Owner or its Affiliate with Regulatory Authorities pertaining to the Development or Regulatory Approval
              of the Licensed Product in [***]. The Regulatory Owner will provide the other Party with reasonable advance notice of all such interactions and will provide advance copies of all related documents and other relevant information relating to
              such interactions in [***]. In addition, Akcea will provide the RWG with advance drafts<font style="font-weight: bold; font-style: italic;">&#160;</font>of any Regulatory Filings and any material documents or other material correspondence
              pertaining to Regulatory Approvals for the Licensed Products that Akcea plans to submit to any Regulatory Authority in accordance with <u>Section</u><u> 4.2</u> for the RWG to review, discuss, and [***]. With respect to each Party&#8217;s
              obligation to provide advance copies of Regulatory Filings and correspondences in the preceding sentences, (a) for Regulatory Approval Applications, the Parties will agree on a timeline for review of advance drafts and each Party will use
              commercially reasonable efforts to comply with such timeline and (b) for all other material regulatory submissions and correspondences, each Party will provide advance copies at least [***] prior to submission (unless a shorter time frame is
              necessary to comply with the requests or requirements of any applicable Regulatory Authority or under any applicable Law). Each Party will provide the other Party with copies of all material submissions it makes to, and all material
              correspondence it receives from, a Regulatory Authority pertaining to Regulatory Approvals for the Licensed Product in [***].</div>
            <div style="text-align: justify; text-indent: 72pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;">4.3.3</font>&#160;&#160;&#160;&#160;&#160; <font style="font-weight: bold;"><u>Assistance</u></font>. The Parties will cooperate with each other to achieve the regulatory objectives
              contemplated herein in a timely, accurate, and responsive manner. The non-Regulatory Owner will use reasonable efforts to assist the Regulatory Owner, including by meeting with the Regulatory Owner to prepare Regulatory Filings and other
              documents to be filed, providing access to relevant data and information (including relevant safety data) and addressing requests from Regulatory Authorities, in each case, in order for such Regulatory Owner to obtain and maintain each
              applicable Regulatory Approval for the Licensed Product in the Territory. Without limiting the foregoing, Akcea will provide AstraZeneca with the support necessary or reasonably requested by AstraZeneca to obtain and maintain Regulatory
              Approvals for the Licensed Product in [***], including by drafting provisions of any Regulatory Filing, answering questions from Regulatory Authorities with respect to the Licensed Product and attending any meetings with Regulatory
              Authorities, in each case, at AstraZeneca&#8217;s request and, with respect to support requested by AstraZeneca, at [***].</div>
            <div style="text-align: justify; text-indent: 72pt;"> <br>
            </div>
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              <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">19</font></div>
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            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;">4.3.4</font>&#160;&#160;&#160;&#160;&#160; <font style="font-weight: bold;"><u>Global Regulatory Coordination</u></font>. The Parties will cooperate to harmonize Regulatory Filings
              and regulatory activities in the U.S. with Regulatory Filings and regulatory activities outside of the U.S. for the Licensed Product with respect to [***], consistent with the Regulatory Strategy. To the extent practicable, the data and
              information and presentation of information will be consistent across Regulatory Filings made in the U.S. and Regulatory Filings made outside of the U.S.</div>
            <div style="text-align: justify; text-indent: 72pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold;">4.4</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160; <font style="font-weight: bold;"><u>Class Generic Claims for the Licensed Product</u></font>. To the extent AstraZeneca intends to make any
              claims in a Licensed Product label or Regulatory Filing that are class generic to ASOs or any of Akcea&#8217;s technology incorporated into a Licensed Product, AstraZeneca will provide such claims and Regulatory Filings to Akcea in advance and will
              [***] any proposals and comments made by Akcea.</div>
            <div style="text-align: justify; text-indent: 36pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold;">4.5</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160; <font style="font-weight: bold;"><u>Recalls</u></font>. The applicable Regulatory Owner will determine whether to initiate any recall,
              withdrawal, or stock recovery of any Licensed Product in any country or jurisdiction in the Territory; <font style="font-style: italic;">provided </font>that the Regulatory Owner will implement any recall, withdrawal, or stock recovery that
              is required by applicable Law or a Regulatory Authority, and in each case, consistent with the requirements of applicable Law or such Regulatory Authority.<font style="font-weight: bold; font-style: italic;">&#160;</font>Each Party will notify the
              other Party promptly upon its determination that any event, incident or circumstance has occurred that may result in the need for a recall, market withdrawal or stock recovery of a Licensed Product (but in no event later than 48 hours and in
              all cases prior to the execution of such recall, market withdrawal or stock recovery) and will consider the comments of the other Party in good faith. For all recalls, market withdrawals and stock recoveries that are taken, the Regulatory
              Owner will be responsible for execution, and the other Party will reasonably cooperate in all such efforts.</div>
            <div style="text-align: justify; text-indent: 36pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold;">4.6</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;<font style="font-weight: bold;"><u>Adverse Event Reporting; Global Safety Database</u></font>.</div>
            <div style="text-align: justify; text-indent: 36pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;">4.6.1</font>&#160;&#160;&#160;&#160;&#160; The then-current holder of the IND with respect to a given Clinical Trial will have Territory-wide responsibility for pharmacovigilance with
              respect to such Clinical Trial consistent with the Regulatory Strategy, including for all reportable events associated with such Clinical Trial to the applicable Regulatory Authorities. Each Party will use reasonable efforts to complete the
              transfer to AstraZeneca of the global safety database and datasets for the Licensed Product in the Territory promptly following the first Regulatory Approval for the Licensed Product (or, if earlier, the date on which AstraZeneca becomes the
              Regulatory Owner for the Licensed Product in any Major Market) and, following such transfer, AstraZeneca will have the sole right and responsibility for holding and maintaining such global safety database.</div>
            <div style="text-align: justify; text-indent: 72pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;">4.6.2</font>&#160;&#160;&#160;&#160;&#160; Promptly after the Closing Date, the Parties will negotiate in good faith and enter into a mutually-agreed safety data exchange agreement
              (the &#8220;<font style="font-weight: bold; font-style: italic;">SDEA</font>&#8221;)&#160;(which must be executed prior to the transfer of any IND or Regulatory Approval or the global safety database and datasets), which agreement will provide for the
              responsibilities of the Parties related to the management of safety information related to the Licensed Product, including any such information received by either Party or its Affiliates from any Third Party (including reports from Clinical
              Trials, health care personnel (HCP) and customers). It is understood that each Party and its Affiliates and licensees or sublicensees will disclose such information necessary to comply with applicable Laws as well as requirements of any
              applicable Regulatory Authority. The SDEA will remain in effect for so long as the exchange of safety information is required by Law.</div>
            <div style="text-align: justify; text-indent: 72pt;"> <br>
            </div>
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              <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">20</font></div>
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            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;">4.6.3</font>&#160;&#160;&#160;&#160;&#160; <font style="font-weight: bold;"><u>Akcea&#8217;s Internal Antisense Safety Database</u></font>.</div>
            <div style="text-align: justify; text-indent: 72pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 108pt;">(a)&#160;&#160;&#160;&#160;&#160;&#160;&#160; Akcea maintains an internal database that includes information regarding the tolerability of its drug compounds, individually and as a class, including information discovered
              during pre-clinical and clinical development (the &#8220;<font style="font-weight: bold; font-style: italic;">Akcea Internal ASO Safety Database</font>&#8221;). In an effort to maximize understanding of the safety profile and pharmacokinetics of Akcea
              compounds, AstraZeneca will cooperate in connection with populating the Akcea Internal ASO Safety Database, <font style="font-style: italic;">provided</font> that AstraZeneca&#8217;s obligations pursuant to this <u>Section 4.6.3</u> are subject
              to applicable Law and in particular AstraZeneca will not be required to disclose any information in contravention of applicable Law relating to data privacy. To the extent collected by AstraZeneca and, in the form in which AstraZeneca
              uses/stores such information for its own purposes, AstraZeneca will provide Akcea with material information concerning toxicology, pharmacokinetics, safety pharmacology study(ies), serious adverse events and other safety information related
              to the Licensed Product as soon as practicable following the date such information is available to AstraZeneca (but not later than [***] after AstraZeneca&#8217;s receipt of such information). In connection with any reported serious adverse event,
              AstraZeneca will provide Akcea with all serious adverse event reports, including initial, interim, follow-up, amended, and final reports. In addition, with respect to the Licensed Product, AstraZeneca will provide Akcea with copies of annual
              safety updates filed with each IND and the safety sections of any final Clinical Trial reports. Furthermore, AstraZeneca will promptly provide Akcea with any supporting data and answer any follow-up questions reasonably requested by Akcea to
              conduct analyses to keep Akcea and its partners informed regarding class generic properties of ASOs, including with respect to safety. All such information disclosed by AstraZeneca to Akcea will be AstraZeneca Confidential Information; <font style="font-style: italic;">provided</font>, <font style="font-style: italic;">however</font>, that so long as Akcea does not disclose the identity of the Licensed Product (or the Licensed Compound) or AstraZeneca&#8217;s identity, Akcea may
              disclose any such AstraZeneca Confidential Information to Regulatory Authorities and Akcea&#8217;s other partners pursuant to <u>Section 4.6.3(b)</u> below if such information is regarding class generic properties of ASOs and, with respect to
              Akcea&#8217;s partners, such partners have agreed to a similar provision permitting the disclosure of their Confidential Information relating to ASOs to Akcea&#8217;s partners. AstraZeneca will deliver all such information to Akcea for the Akcea Internal
              ASO Safety Database to Akcea Therapeutics, Inc., 2855 Gazelle Court, Carlsbad, CA 92010, Attention: Chief Medical Officer (or to such other address/contact designated in writing by Akcea). AstraZeneca will also cause its Affiliates and its
              and their Sublicensees to comply with this <u>Section 4.6.3(a)</u>.</div>
            <div style="text-align: justify; text-indent: 108pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 108pt;">(b)&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;From time to time, Akcea utilizes the information in the Akcea Internal ASO Safety Database to conduct analyses to keep Akcea and its partners (including its Affiliates&#8217;
              partners) informed regarding class generic properties of ASOs, including with respect to safety. As such, if and when Akcea identifies safety or other related issues that may be relevant to the Licensed Product (including any potential
              class-related toxicity), Akcea will promptly inform AstraZeneca of such issues and provide the data supporting Akcea&#8217;s conclusions.</div>
            <div style="text-align: center; font-weight: bold;"> <br>
            </div>
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            <div style="text-align: center; font-weight: bold;">ARTICLE 5</div>
            <div style="text-align: center; font-weight: bold;">MANUFACTURING AND SUPPLY</div>
            <div style="text-align: center; font-weight: bold;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold;">5.1</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;<font style="font-weight: bold;"><u>Supply of the Licensed Products</u></font>.</div>
            <div style="text-align: justify; text-indent: 36pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;">5.1.1</font>&#160;&#160;&#160;&#160;&#160; <font style="font-weight: bold;"><u>Manufacturing Responsibility for Ongoing Clinical Trials</u></font>. Akcea will, itself or with or
              through an Affiliate or CMO, Manufacture and supply clinical supply of the Licensed Compound and the Licensed Product for the Parties&#8217; Development activities under this Agreement in accordance with the Development Plan and Budget through the
              later of (a) [***] and (b) [***]. Akcea will not make any material changes to the Manufacturing process for the Licensed Compound or the Licensed Product, nor any changes to the applicable CMOs conducting such Manufacturing activities,
              without the prior written consent of AstraZeneca.</div>
            <div style="text-align: justify; text-indent: 72pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;">5.1.2</font>&#160;&#160;&#160;&#160;&#160;&#160; <font style="font-weight: bold;"><u>Additional Clinical and Commercial Manufacturing Responsibility</u></font>. From and after completion
              of the activities set forth in the Manufacturing Transition Plan, except as otherwise expressly set forth in <u>Section 5.1.1</u>, this <u>Section 5.1.2</u> or as otherwise agreed by the Parties, AstraZeneca will be solely responsible for
              the Manufacture of the Licensed Compound and Licensed Product, including Manufacture of registration batches, stability batches and commercial batches, and management of the overall manufacturing strategy and tactics, formulation, CMO
              selection for API and finished Licensed Product and associated audits; <font style="font-style: italic;">provided</font>, that (a) [***], (b) [***] and (c) Akcea will be responsible for managing the process performance qualification batches
              for API and finished Licensed Product for such Authorized CMOs for the Initial Indications in the United States and Canada.</div>
            <div style="text-align: justify; text-indent: 72pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;">5.1.3</font>&#160;&#160;&#160;&#160;&#160; <font style="font-weight: bold;"><u>Existing Inventory</u></font>. If there is any clinical supply of the Licensed Product or Licensed
              Product Manufactured pursuant to process performance qualification batches to support Regulatory Approval, in each case, remaining after Regulatory Approval for the Licensed Product that is suitable for commercial sale (including appropriate
              shelf life), then AstraZeneca will use reasonable efforts to purchase such Licensed Product at: (a) [***] and (b) [***].</div>
            <div style="text-align: justify; text-indent: 72pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold;">5.2</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;<font style="font-weight: bold;"><u>Manufacturing </u><u>Transition Plan</u></font>.</div>
            <div style="text-align: justify; text-indent: 36pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;">5.2.1</font>&#160;&#160;&#160;&#160;&#160;&#160; As soon as reasonably practicable but in any event within [***] after the Closing Date, the Parties will establish a plan sufficient to
              enable AstraZeneca or its designee to manufacture the amount of Licensed Compound and Licensed Product necessary for the Parties to conduct the activities as contemplated by the Development Plan and Budget, the U.S. Commercialization Plan and
              Budget and the ROW Commercialization Plan (or drafts thereof if any such plan has yet to be finalized or approved) (the &#8220;<font style="font-weight: bold; font-style: italic;">Manufacturing Transition Plan</font>&#8221;), which Manufacturing
              Transition Plan will (a) contemplate that Akcea will continue to Manufacture and supply the clinical supply of the Licensed Compound and the Licensed Product through the completion of all Clinical Trials that are ongoing as of the Execution
              Date pursuant to <u>Section</u><u> 5.1.1</u> and will manage the process performance qualification batches for API and finished Licensed Product, and AstraZeneca will be responsible for the Manufacture and supply of all commercial supply of
              Licensed Compound and Licensed Product, and (b) provide for a smooth transition to AstraZeneca between the clinical and commercial supply phases, including any gaps therein. Pursuant to the process and timelines set forth in the Manufacturing
              Transition Plan (and in any event within the later of (i) [***] or (ii) [***], Akcea will assign to AstraZeneca any agreements with Akcea&#8217;s CMOs for the Licensed Product, unless [***], in which case [***].</div>
            <div style="text-align: justify; text-indent: 72pt;"> <br>
            </div>
            <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
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            </div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;">5.2.2</font>&#160;&#160;&#160;&#160;&#160; If, despite AstraZeneca&#8217;s Commercially Reasonable Efforts, the [***] does not occur or is not sufficient for AstraZeneca or its designee to
              manufacture the Licensed Compound and Licensed Product (either at the time of [***]), then, at a time and to the extent requested by AstraZeneca, the Parties will amend the Manufacturing Transition Plan to include, and Akcea shall conduct, a
              manufacturing technology transfer to AstraZeneca or its Affiliate or any designee approved by Akcea in accordance with <u>Section </u><u>7.2.1</u>&#160;(if applicable), including, to the extent not already transferred to AstraZeneca, the
              transfer of (a) the manufacturing processes for Licensed Compounds and all Know-How and materials with respect thereto (including all raw material specifications, quality and in process testing and data, release testing and data, and
              stability data), in each case, in Akcea&#8217;s or its Affiliates&#8217; possession or control, including any such Know-How and materials maintained by Akcea&#8217;s Third Party providers, that Akcea has the right to transfer, (b) all other Akcea Manufacturing
              and Analytical Know-How that [***] to Manufacture the Licensed Compounds, (c) all inventory of Licensed Compounds, drug substance and drug product in Akcea&#8217;s possession or control and (d) reasonable amounts of analytical reagents and raw
              materials that are reasonably requested by AstraZeneca, in Akcea&#8217;s possession or control and, in the case of analytical reagents and raw materials being used in connection with other Akcea programs, <font style="font-style: italic;">provided</font>
              that any amounts requested by AstraZeneca take into account Akcea&#8217;s continuing needs for its other programs. Notwithstanding any provision to the contrary in this Agreement, Akcea will only be required to conduct one manufacturing technology
              transfer pursuant to this <u>Section 5.2.2</u> (<font style="font-style: italic;">i.e.</font>, only one additional manufacturing technology transfer in addition to the initial manufacturing technology transfer set forth in <u>Section 5.2.1</u>),

              which manufacturing technology transfer must be to either AstraZeneca, its Affiliate or a single designee approved by Akcea in accordance with <u>Section 7.2.1</u> (if applicable).</div>
            <div style="text-align: justify; text-indent: 72pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold;">5.3</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;<font style="font-weight: bold;"><u>Manufacturing Improvements</u>.</font></div>
            <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold;"> <br>
              </font></div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;">5.3.1</font>&#160;&#160;&#160;&#160;&#160; <font style="font-weight: bold;"><u>Akcea Improvements</u></font>.</div>
            <div style="text-align: justify; text-indent: 72pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 108pt;">(a)&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;<font style="font-weight: bold;">Disclosure</font>. During the Term, Akcea shall promptly disclose to AstraZeneca (i) all modifications, enhancements and improvements to the
              processes for the Manufacture of the Licensed Compound and Licensed Product and (ii) [***], in each case ((i) and (ii)) conceived, discovered, invented or created or acquired (whether by license, option, acquisition or otherwise) or otherwise
              Controlled by or on behalf of Akcea or any of its Affiliates that [***] to Manufacture the Licensed Products ((i) and (ii) together with the Patent Rights Covering the foregoing, &#8220;<font style="font-weight: bold; font-style: italic;">Akcea
                Manufacturing Improvements</font>&#8221;). At AstraZeneca&#8217;s request, Akcea shall provide AstraZeneca with reasonable assistance to enable AstraZeneca (or its Affiliate or CMO, as applicable) to implement such modifications, enhancements and
              improvements with respect to the Licensed Compound and Licensed Product, and AstraZeneca shall reimburse Akcea for the [***] incurred by Akcea with respect to such assistance.</div>
            <div style="text-align: justify; text-indent: 108pt;"> <br>
            </div>
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            </div>
            <div style="text-align: justify; text-indent: 108pt;">(b)&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160; <font style="font-weight: bold;">Third Party Agreements</font>. To the extent that any Akcea Manufacturing Improvement is in-licensed or acquired by Akcea or any of its
              Affiliates (any such agreement, an &#8220;<font style="font-weight: bold; font-style: italic;">Akcea Manufacturing Improvement In-License</font>&#8221;), (i) Akcea shall provide a copy of such Akcea Manufacturing Improvement In-License to AstraZeneca
              (which copy may be redacted as necessary to comply with its obligations of confidentiality to the counterparty provided that such redactions do not undermine AstraZeneca&#8217;s ability to comply with such Akcea Manufacturing Improvement In-License
              or understand the [***] applicable to AstraZeneca), and any license to AstraZeneca under such Akcea Manufacturing Improvements pursuant to <u>Section 8.1</u> shall be subject to the terms and conditions of such Akcea Manufacturing
              Improvement In-License, (ii) AstraZeneca shall (A) provide the necessary reporting information to Akcea in sufficient time as reasonably requested by Akcea to enable Akcea to comply with its obligations under such Akcea Manufacturing
              Improvement In-License and Akcea&#8217;s obligation to [***] pursuant to clause (B), (B) [***] and (C) not, and shall cause its Affiliates and Sublicensees not to, take or fail to take any action if doing so (or not doing so) would cause Akcea to
              be in breach of any such Akcea Manufacturing Improvement In-License to the extent that any applicable obligations have been disclosed to AstraZeneca and (iii) [***]. Neither Akcea nor its Affiliates will amend, modify, terminate, or waive any
              rights under any Akcea Manufacturing Improvement In-License in a manner that would adversely affect AstraZeneca&#8217;s rights or obligations under this <u>Section 5.3.1</u> without AstraZeneca&#8217;s prior written consent. Neither Akcea nor its
              Affiliates will commit any acts or permit the occurrence of any omissions that would cause or result in the termination of any Akcea Manufacturing Improvement In-License which termination would adversely affect AstraZeneca&#8217;s rights or
              obligations under this <u>Section 5.3.1</u>, without AstraZeneca&#8217;s prior written consent.<br>
              <br>
            </div>
            <div style="text-align: justify; text-indent: 108pt;">(c)&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160; <font style="font-weight: bold;">Right to Terminate</font>. AstraZeneca may terminate its license under all or any portion of any Akcea Manufacturing Improvements at any time by
              providing written notice to Akcea and upon Akcea&#8217;s receipt of such notice the applicable Know-How or Patent Rights shall be excluded from Licensed Technology and from the licenses granted to AstraZeneca pursuant to <u>Section 8.1</u>.</div>
            <div style="text-align: justify; text-indent: 108pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;">5.3.2</font>&#160;&#160;&#160;&#160;&#160; <font style="font-weight: bold;"><u>AstraZeneca Improvements</u></font>.</div>
            <div style="text-align: justify; text-indent: 72pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 108pt;">(a)&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160; <font style="font-weight: bold;">Grant to Akcea</font>. Subject to <u>Section</u><u> 8.1</u>, <u>Section</u><u> 5.3.2(b)</u>&#160;and <u>Section</u><u> 5.3.2(c)</u>, AstraZeneca
              hereby grants to Akcea a non-exclusive, royalty-free, perpetual, irrevocable non-transferable, non-sublicensable (except in accordance with the following proviso) license under all modifications, enhancements and improvements to the processes
              for the Manufacture of the Licensed Compound and Licensed Product that were transferred to AstraZeneca pursuant to <u>Section</u><u> 5.2</u>&#160;and <u>Section</u><u> 5.3.1</u>&#160;made under this Agreement during the Term and any Patent Rights
              that claim any such modifications, enhancements or improvements to the extent such modifications, enhancements, improvements or Patent Rights, as applicable, are Controlled by AstraZeneca (collectively, &#8220;<font style="font-weight: bold; font-style: italic;">AstraZeneca Manufacturing Improvements</font>&#8221;) for all Manufacturing purposes other than in a manner that would violate the exclusivity obligations in <u>Section 9.2</u> or the exclusive licenses granted by Akcea to
              AstraZeneca under this Agreement; <font style="font-style: italic;">provided</font>, <font style="font-style: italic;">however</font>, that Akcea shall not practice or use any AstraZeneca Manufacturing Improvements for the benefit of any
              Affiliate or Third Party, or grant any Affiliate or Third Party a sublicense under any AstraZeneca Manufacturing Improvements, in either case, unless Akcea has the right to grant AstraZeneca a (sub)license (with the right to sublicense
              through multiple tiers) with respect to all modifications, enhancements and improvements to (i) Akcea&#8217;s or its Affiliates&#8217; Manufacturing processes or any portion therefor [***] in the Manufacture of the Licensed Product [***] and (ii)
              AstraZeneca Manufacturing Improvements, in each case, ((i) and (ii)), that are conceived, discovered, invented or created or acquired (whether by license, option, acquisition or otherwise) or otherwise controlled by such Affiliate or Third
              Party, as applicable. During the Term, AstraZeneca will promptly disclose to Akcea all AstraZeneca Manufacturing Improvements.</div>
            <div style="text-align: justify; text-indent: 108pt;"> <br>
            </div>
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              <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">24</font></div>
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            </div>
            <div style="text-align: justify; text-indent: 108pt;">(b)&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160; <font style="font-weight: bold;">Third Party Agreements</font>. To the extent that any AstraZeneca Manufacturing Improvement is in-licensed or acquired by AstraZeneca or any of
              its Affiliates (any such agreement, an &#8220;<font style="font-weight: bold; font-style: italic;">AstraZeneca Manufacturing Improvement In-License</font>&#8221;), (i) AstraZeneca shall provide a copy of such AstraZeneca Manufacturing Improvement
              In-License to Akcea (which copy may be redacted as necessary to comply with its obligations of confidentiality to the counterparty provided that such redactions do not undermine Akcea&#8217;s ability to comply with such AstraZeneca Manufacturing
              Improvement In-License or understand [***]), and any license to Akcea under such AstraZeneca Manufacturing Improvements pursuant to <u>Section</u><u> 5.3.2(a)</u>&#160;shall be subject to the terms and conditions of such AstraZeneca Manufacturing
              Improvement In-License, (ii) Akcea shall (A) provide the necessary reporting information to AstraZeneca in sufficient time as reasonably requested by AstraZeneca to enable AstraZeneca to comply with its obligations under such AstraZeneca
              Manufacturing Improvement In-License and AstraZeneca&#8217;s obligation to [***] pursuant to clause (B), (B) [***] and (C) not, and shall cause its Affiliates and (sub)licensees not to, take or fail to take any action if doing so (or not doing so)
              would cause AstraZeneca to be in breach of any such AstraZeneca Manufacturing Improvement In-License to the extent that any applicable obligations have been disclosed to Akcea and (iii) [***]. Neither AstraZeneca nor its Affiliates will
              amend, modify, terminate, or waive any rights under any AstraZeneca Manufacturing Improvement In-License in a manner that would adversely affect Akcea&#8217;s rights or obligations under this <u>Section 5.3.2</u> without Akcea&#8217;s prior written
              consent. Neither AstraZeneca nor its Affiliates will commit any acts or permit the occurrence of any omissions that would cause or result in the termination of any AstraZeneca Manufacturing Improvement In-License which termination would
              adversely affect Akcea&#8217;s rights or obligations under this <u>Section 5.3.2</u>, without Akcea&#8217;s prior written consent.</div>
            <div style="text-align: justify; text-indent: 108pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 108pt;">(c)&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;<font style="font-weight: bold;">Right to Terminate</font>. Akcea may terminate its license under all or any portion of any AstraZeneca Manufacturing Improvements at any time by
              providing written notice to AstraZeneca and upon AstraZeneca&#8217;s receipt of such notice the applicable Know-How or Patent Rights shall be excluded from AstraZeneca Manufacturing Improvements and from the licenses granted to Akcea pursuant to <u>Section</u><u>
                5.3.2(a)</u>. AstraZeneca shall have the right to terminate Akcea&#8217;s rights under <u>Section</u><u> 5.3.2(a)</u>, on written notice to Akcea, if Akcea breaches its obligations under the proviso set forth therein or under <u>Section</u><u>
                5.3.2(b)</u> and does not cure such breach within [***] after written notice from AstraZeneca of such breach.</div>
            <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold;"> <br>
              </font></div>
            <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold;">5.4</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;<font style="font-weight: bold;"><u>Capital Expenditures</u></font>. Unless and until the Opt-Out Date occurs, if AstraZeneca [***],
              AstraZeneca shall [***]. If, [***]. For clarity, the foregoing sharing shall not include [***].</div>
            <div style="text-align: center; font-weight: bold;"> <br>
            </div>
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              <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">25</font></div>
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            </div>
            <div style="text-align: center; font-weight: bold;">ARTICLE 6</div>
            <div style="text-align: center; font-weight: bold;">GOVERNANCE</div>
            <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold;"> <br>
              </font></div>
            <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold;">6.1</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;<font style="font-weight: bold;"><u>Joint Steering Committee</u></font>.</div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;"> <br>
              </font></div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;">6.1.1</font>&#160;&#160;&#160;&#160;&#160; <font style="font-weight: bold;"><u>Establishment of Joint Steering Committee</u></font>. Within [***] of the Closing Date, the Parties
              shall establish a Joint Steering Committee (the &#8220;<font style="font-weight: bold; font-style: italic;">Joint Steering Committee</font>&#8221; or &#8220;<font style="font-weight: bold; font-style: italic;">JSC</font>&#8221;) to oversee and coordinate the
              Development, Manufacturing, Commercialization and other Exploitation activities with respect to the Licensed Product for the United States under this Agreement and to share information between the Parties regarding the Development,
              Manufacturing, Commercialization and other Exploitation activities with respect to the Licensed Product for the ROW Territory under this Agreement. The JSC will consist of an appropriate number of representatives as may be agreed upon by the
              Parties, with an equal number of representatives<font style="font-weight: bold; font-style: italic;">&#160;</font>designated by each of the Parties. The initial members of the JSC will be nominated by the Parties promptly following the Closing
              Date. Such representatives shall be individuals suitable in seniority and experience and having sufficient authority to make decisions of the JSC with respect to matters within the scope of the JSC&#8217;s responsibilities. The JSC shall operate in
              accordance with the provisions of this <u>Article 6</u>, and shall have no authority to alter, amend or waive the terms and conditions of this Agreement. A Party may change one or more of its representatives serving on the JSC at any time
              upon written notice to the other Parties, <font style="font-style: italic;">provided</font> that such replacement satisfies the requirements set forth above in this <u>Section </u><u>6.1.1</u>.</div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;"> <br>
              </font></div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;">6.1.2</font>&#160;&#160;&#160;&#160;&#160;&#160; <font style="font-weight: bold;"><u>Responsibilities of JSC</u></font>. The JSC shall perform the following functions:</div>
            <div style="text-align: justify; text-indent: 108pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 108pt;">(a)&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;oversee the overall strategic relationship between the Parties as described in <u>Section </u><u>6.1.1</u>;</div>
            <div style="text-align: justify; text-indent: 108pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 108pt;">(b)&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;review and discuss any potential AstraZeneca Third Party Product-Specific License, as described in <u>Section 11.8.2(b)</u>;</div>
            <div style="text-align: justify; text-indent: 108pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 108pt;">(c)&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;review and discuss any results, information, analyses, reports and recommendations submitted by the JDC, JCMC or any other Subcommittees, including any drafts of, or updates or
              changes to, the Development Plan and Budget (including any Additional Development Proposals), the U.S. Commercialization Plan and Budget (including, for clarity, the Interim U.S. Commercialization Plan and Budget) and U.S. Medical Affairs
              Plan and Budget (including, for clarity, the Interim U.S. Medical Affairs Plan and Budget), and make decisions or provide approvals with respect thereto as provided in&#160;<u>Article 2</u>&#160;and&#160;<u>Article 3</u>;</div>
            <div style="text-align: justify; text-indent: 108pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 108pt;">(d)&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;review, discuss and approve any Allowable Overruns described in clause (b) of the definition thereof;</div>
            <div style="text-align: justify; text-indent: 108pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 108pt;">(e)&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;review, discuss and resolve any issues escalated to the JSC by any of the Subcommittees; and</div>
            <div style="text-align: justify; text-indent: 108pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 108pt;">(f)&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;perform such other functions as are specifically designated for the JSC in this Agreement or that the Parties mutually agree in writing to refer to the JSC.</div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;"> <br>
              </font></div>
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              <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">26</font></div>
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            </div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;">6.1.3</font>&#160;&#160;&#160;&#160;&#160;&#160; <font style="font-weight: bold;"><u>JSC Meetings; Minutes</u></font>.</div>
            <div style="text-align: justify; text-indent: 108pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 108pt;">(a)&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;The JSC will meet in person, by videoconference or by teleconference at least once each Calendar Quarter, unless otherwise agreed by the Parties,<font style="font-weight: bold; font-style: italic;">&#160;</font>on such dates and at such times and places as agreed to by the members of the JSC. Each Party will be responsible for its own expenses relating to attendance at, or participation in, JSC meetings. In addition to
              scheduled meetings, at any Party&#8217;s reasonable request, the JSC may meet (including by videoconference or teleconference) upon [***] prior written notice on an ad-hoc basis to address any urgent matters that arise with respect to the
              Development, Manufacturing, Commercialization or other Exploitation of the Licensed Product. Each Party will ensure that its representatives at such meetings are officers or employees of such Party having sufficient seniority within the
              applicable Party to make decisions within the purview of the JSC.</div>
            <div style="text-align: justify; text-indent: 108pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 108pt;">(b)&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;The Alliance Managers or their designees will provide the members of the JSC with draft written minutes for approval from each meeting within [***] after each such meeting. The
              JSC will approve the minutes from a meeting (with each Party&#8217;s representatives on the JSC collectively having one vote) within [***] after receiving such minutes. The results, reports, analyses and other information regarding the Licensed
              Product disclosed by one Party to the other Parties through the JSC constitute Confidential Information of both Parties<font style="font-weight: bold; font-style: italic;">&#160;</font>and may be used only in accordance with the rights granted and
              other terms and conditions under this Agreement. Any reports of the JSC may take the form of and be recorded in minutes of the meetings of the Parties as contemplated under this <u>Section 6.1.3(b)</u>, including copies of any slides
              relating to the results and presented at such meetings.</div>
            <div style="text-align: justify; text-indent: 108pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold;">6.2</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160; <font style="font-weight: bold;"><u>Subcommittees</u></font>. The JDC and the JCMC will be established as subcommittees to the JSC
              pursuant to <u>Section 6.3</u> and <u>Section 6.4</u>, respectively, and the JSC may establish such other subcommittees or working groups as may be necessary or desirable to facilitate the activities under this Agreement (each a &#8220;<font style="font-weight: bold; font-style: italic;">Subcommittee</font>&#8221;). The JSC will delegate such specifically-defined duties as the JSC deems appropriate to any such Subcommittee. Each Subcommittee and its activities will be subject to the
              oversight of, and will report to, the JSC. No Subcommittee will have authorities that exceed the authorities specified for the JSC, the JDC, or the JCMC in this <u>Article 6</u>. Any disagreement between the representatives of the Parties on
              a Subcommittee will be referred to the JSC for resolution in accordance with <u>Section 6.6</u>.</div>
            <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold;"> <br>
              </font></div>
            <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold;">6.3</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160; <font style="font-weight: bold;"><u>Joint Development Committee</u></font>.</div>
            <div style="text-align: justify; text-indent: 36pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;">6.3.1</font>&#160;&#160;&#160;&#160;&#160; <font style="font-weight: bold;"><u>Establishment of Joint Development Committee</u></font>. Within [***] of the Closing Date, the Parties
              shall establish a joint development committee (the &#8220;<font style="font-weight: bold; font-style: italic;">Joint Development Committee</font>&#8221; or &#8220;<font style="font-weight: bold; font-style: italic;">JDC</font>&#8221;) to oversee and coordinate the
              Clinical Trials ongoing as of the Execution Date and Development of the Licensed Products in the United States under this Agreement and to share information between the Parties regarding the Development of the Licensed Products in the ROW
              Territory under this Agreement. The JDC will consist of an appropriate number of representatives as may be agreed upon by the Parties, with an equal number of representatives designated by each of the Parties. The initial members of the JDC
              will be nominated by the Parties promptly following the Closing Date. Such representatives shall be individuals suitable in seniority and experience and having sufficient authority to make decisions of the JDC with respect to matters within
              the scope of the JDC&#8217;s responsibilities. The JDC shall operate in accordance with the provisions of this <u>Article 6</u>, and shall have no authority to alter, amend or waive the terms and conditions of this Agreement. A Party may change
              one or more of its representatives serving on the JDC at any time upon written notice to the other Parties, <font style="font-style: italic;">provided</font> that such replacement satisfies the requirements set forth above in this <u>Section

              </u><u>6.3.1</u>.</div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;"> <br>
              </font></div>
            <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
              <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">27</font></div>
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            </div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;">6.3.2</font>&#160;&#160;&#160;&#160;&#160;&#160; <font style="font-weight: bold;"><u>Responsibilities of JDC</u></font>. The JDC shall perform the following functions:</div>
            <div style="text-align: justify; text-indent: 108pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 108pt;">(a)&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;review, discuss and oversee the conduct and progress of the Parties&#8217; activities under the Development Plan and Budget, including all Clinical Trials conducted under the
              Development Plan and Budget;</div>
            <div style="text-align: justify; text-indent: 108pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 108pt;">(b)&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;review and discuss any critical issues, including regulatory, technical or scientific issues, arising out of the conduct of the activities in the Development Plan and Budget,
              and provide direction on how such issues are to be resolved;</div>
            <div style="text-align: justify; text-indent: 108pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 108pt;">(c)&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;review, discuss and, except for [***], revise (if and as appropriate) and make a recommendation to the JSC regarding whether to approve any proposed changes to the Development
              Plan and Budget, including any Additional Development Proposals and changes to the Regulatory Strategy;</div>
            <div style="text-align: justify; text-indent: 108pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 108pt;">(d)&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;review, discuss and make a recommendation to the JSC regarding whether to approve any Allowable Overruns described in clause (b) of the definition thereof with respect to the
              Development Plan and Budget;</div>
            <div style="text-align: justify; text-indent: 108pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 108pt;">(e)&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;facilitate the exchange of information regarding activities conducted under the Development Plan and Budget and the results of such activities;</div>
            <div style="text-align: justify; text-indent: 108pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 108pt;">(f)&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;review and discuss the status of Development activities and regulatory activities and material communications received from Regulatory Authorities in the U.S. and the ROW
              Territory with respect to the Licensed Product, including in relation to the Clinical Trials and Regulatory Approval Applications for the Licensed Product; and</div>
            <div style="text-align: justify; text-indent: 108pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 108pt;">(g)&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;perform such other functions as are specifically designated for the JDC in this Agreement or that the Parties mutually agree in writing to refer to the JDC.</div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;"> <br>
              </font></div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;">6.3.3</font>&#160;&#160;&#160;&#160;&#160;&#160; <font style="font-weight: bold;"><u>JDC Meetings; Minutes</u></font>.</div>
            <div style="text-align: justify; text-indent: 108pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 108pt;">(a)&#160;&#160;&#160;&#160;&#160;&#160;&#160; The JDC will meet in person, by videoconference or by teleconference at least once each Calendar Quarter, unless otherwise agreed by the Parties,<font style="font-weight: bold; font-style: italic;">&#160;</font>on such dates and at such times and places as agreed to by the members of the JDC. Each Party will be responsible for its own expenses relating to attendance at, or participation in, JDC meetings. In addition to
              scheduled meetings, at any Party&#8217;s reasonable request, the JDC may meet (including by videoconference or teleconference) upon [***] prior written notice on an ad-hoc basis to address any urgent matters that arise with respect to the
              Development of the Licensed Product. Each Party will ensure that its representatives at such meetings are officers or employees of such Party having sufficient seniority within the applicable Party to make decisions of the JDC with respect to
              matters within the scope of the JDC&#8217;s responsibilities.</div>
            <div style="text-align: justify; text-indent: 108pt;"> <br>
            </div>
            <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
              <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">28</font></div>
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            </div>
            <div style="text-align: justify; text-indent: 108pt;">(b)&#160;&#160;&#160;&#160;&#160;&#160;&#160; The Alliance Managers or their designees will provide the members of the JDC with draft written minutes for approval from each meeting within [***] after each such meeting. The
              JDC will approve the minutes from a meeting (with each Party&#8217;s representatives on the JDC collectively having one vote) within [***]<font style="font-weight: bold; font-style: italic;">&#160;</font>after receiving such minutes. The results,
              reports, analyses and other information regarding the Licensed Product disclosed by one Party to the other Party through the JDC constitute Confidential Information of both Parties<font style="font-weight: bold; font-style: italic;">&#160;</font>and

              may be used only in accordance with the rights granted and other terms and conditions under this Agreement. Any reports of the JDC may take the form of and be recorded in minutes of the meetings of the Parties as contemplated under this <u>Section

                6.3.3(b)</u>, including copies of any slides relating to the results and presented at such meetings.</div>
            <div style="text-align: justify; text-indent: 108pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold;">6.4</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;<font style="font-weight: bold;"><u>Joint Commercialization and Medical Committee</u></font>.</div>
            <div style="text-align: justify; text-indent: 36pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;">6.4.1</font>&#160;&#160;&#160;&#160; <font style="font-weight: bold;"><u>Establishment of Joint Commercialization and Medical Committee</u></font>. Within [***] of the Closing
              Date, the Parties shall establish a joint commercialization and medical committee (the &#8220;<font style="font-weight: bold; font-style: italic;">Joint Commercialization and Medical Committee</font>&#8221; or &#8220;<font style="font-weight: bold; font-style: italic;">JCMC</font>&#8221;) to share information between the Parties and to coordinate efforts regarding the Commercialization of, and Medical Affairs activities with respect to, the Licensed Product in the United States. The JCMC will consist
              of an appropriate number of representatives as may be agreed upon by the Parties, with an equal number of representatives designated by each of the Parties. The initial members of the JCMC will be nominated by the Parties promptly following
              the Closing Date. Such representatives shall be individuals suitable in seniority and experience and having sufficient authority to make decisions of the JCMC with respect to matters within the scope of the JCMC&#8217;s responsibilities. The JCMC
              shall operate in accordance with the provisions of this <u>Article 6</u>, and shall have no authority to alter, amend or waive the terms and conditions of this Agreement. A Party may change one or more of its representatives serving on the
              JCMC at any time upon written notice to the other Party, <font style="font-style: italic;">provided</font> that such replacement satisfies the requirements set forth above in this <u>Section</u><u> 6.4.1</u>.</div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;"> <br>
              </font></div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;">6.4.2</font>&#160;&#160;&#160;&#160;&#160;&#160; <font style="font-weight: bold;"><u>Responsibilities of JCMC</u></font>. The JCMC shall perform the following functions:</div>
            <div style="text-align: justify; text-indent: 72pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 108pt;">(a)&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;review, discuss, revise (if and as appropriate) and make a recommendation to the JSC regarding whether to approve the U.S. Commercialization Plan and Budget (including, for
              clarity, the Interim U.S. Commercialization Plan and Budget) and any proposed changes thereto;</div>
            <div style="text-align: justify; text-indent: 108pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 108pt;">(b)&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;review, discuss, revise (if and as appropriate) and make a recommendation to the JSC regarding whether to approve the U.S. Medical Affairs Plan and Budget (including, for
              clarity, the Interim U.S. Medical Affairs Plan and Budget) and any proposed changes thereto;</div>
            <div style="text-align: justify; text-indent: 108pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 108pt;">(c)&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;review, discuss and make a recommendation to the JSC regarding whether to approve any Allowable Overruns described in clause (b) of the definition thereof with respect to the
              U.S. Commercialization Plan and Budget and U.S. Medical Affairs Plan and Budget;</div>
            <div style="text-align: justify; text-indent: 108pt;"> <br>
            </div>
            <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
              <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">29</font></div>
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            </div>
            <div style="text-align: justify; text-indent: 108pt;">(d)&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;review and oversee the conduct and progress of the Parties&#8217; activities under the U.S. Commercialization Plan and Budget and the U.S. Medical Affairs Plan and Budget;</div>
            <div style="text-align: justify; text-indent: 108pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 108pt;">(e)&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;review any critical issues arising out of the conduct of the activities in the U.S. Commercialization Plan and Budget and the U.S. Medical Affairs Plan and Budget, and provide
              direction to the Parties on how such issue is to be resolved;</div>
            <div style="text-align: justify; text-indent: 108pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 108pt;">(f)&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;facilitate the exchange of information regarding activities conducted under the U.S. Commercialization Plan and Budget and the U.S. Medical Affairs Plan and Budget and the
              results of such activities;</div>
            <div style="text-align: justify; text-indent: 108pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 108pt;">(g)&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;discuss how to leverage the relationships each Party has with HCPs and patient communities in order to more effectively Commercialize the Licensed Products under the U.S.
              Commercialization Plan and Budget;</div>
            <div style="text-align: justify; text-indent: 108pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 108pt;">(h)&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;review and discuss the ROW Commercialization Plan; and</div>
            <div style="text-align: justify; text-indent: 108pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 108pt;">(i)&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;perform such other functions as are specifically designated for the JCMC in this Agreement or that the Parties mutually agree in writing to refer to the JCMC.</div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;"> <br>
              </font></div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;">6.4.3</font>&#160;&#160;&#160;&#160;&#160;&#160; <font style="font-weight: bold;"><u>JCMC Meetings; Minutes</u></font>.</div>
            <div style="text-align: justify; text-indent: 108pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 108pt;">(a)&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;The JCMC will meet in person, videoconference or by teleconference at least once each Calendar Quarter, unless otherwise agreed by the Parties,<font style="font-weight: bold; font-style: italic;">&#160;</font>on such dates and at such times and places as agreed to by the members of the JCMC. Each Party will be responsible for its own expenses relating to attendance at, or participation in, JCMC meetings.</div>
            <div style="text-align: justify; text-indent: 108pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 108pt;">(b)&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;The Alliance Managers or their designees will provide the members of the JCMC with draft written minutes for approval from each meeting within [***] after each such meeting. The
              JCMC will approve the minutes from a meeting (with each Party&#8217;s representatives on the JCMC collectively having one vote) within [***]<font style="font-weight: bold; font-style: italic;">&#160;</font>after receiving such minutes. The results,
              reports, analyses and other information regarding the Licensed Product disclosed by one Party to the other Party through the JCMC constitute Confidential Information of both Parties and may be used only in accordance with the rights granted
              and other terms and conditions under this Agreement. Any reports of the JCMC may take the form of and be recorded in minutes of the meetings of the Parties as contemplated under this <u>Section 6.4.3(b)</u>, including copies of any slides
              relating to the results and presented at such meetings.</div>
            <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold;"> <br>
              </font></div>
            <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold;">6.5</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;<font style="font-weight: bold;"><u>Regulatory Working Group</u></font>.</div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;"> <br>
              </font></div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;">6.5.1</font>&#160;&#160;&#160;&#160;&#160;&#160; <font style="font-weight: bold;"><u>Establishment of Regulatory Working Group</u></font>. Within [***] of the Closing Date, the Parties
              shall establish a regulatory working group (the &#8220;<font style="font-weight: bold; font-style: italic;">Regulatory Working Group</font>&#8221; or &#8220;<font style="font-weight: bold; font-style: italic;">RWG</font>&#8221;) as a working group of the JDC. The
              RWG will consist of an appropriate number of representatives as may be agreed upon by the Parties, with an equal number of representatives designated by each of the Parties. The initial members of the RWG will be nominated by the Parties
              promptly following the Closing Date. Such representatives shall be individuals suitable in seniority and experience and having sufficient authority to make decisions of the RWG with respect to matters within the scope of the RWG&#8217;s
              responsibilities. The RWG shall operate in accordance with policies and procedures that to be agreed by the RWG, and shall have no authority to alter, amend or waive the terms and conditions of this Agreement. A Party may change one or more
              of its representatives serving on the RWG at any time upon written notice to the other Party, <font style="font-style: italic;">provided</font> that such replacement satisfies the requirements set forth above in this <u>Section </u><u>6.5.1</u>.</div>
            <div style="text-align: justify; text-indent: 72pt;"> <br>
            </div>
            <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
              <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">30</font></div>
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            </div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;">6.5.2</font>&#160;&#160;&#160;&#160;&#160; <font style="font-weight: bold;"><u>Responsibilities of RWG</u></font>. The RWG shall perform the following functions:</div>
            <div style="text-align: justify; text-indent: 72pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 108pt;">(a)&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;develop a Regulatory Strategy and any updates thereto for the JDC to review, discuss, revise (if and as appropriate) and make a recommendation to the JSC regarding whether to
              approve;</div>
            <div style="text-align: justify; text-indent: 108pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 108pt;">(b)&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;further define (in a manner that is consistent with <u>Article 4</u>) the regulatory roles and responsibilities of each Party;</div>
            <div style="text-align: justify; text-indent: 108pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 108pt;">(c)&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;define the access and transfer methods (such as secure databases) through which the Parties would share draft communications and Regulatory Filings and other data and
              information required or reasonably requested to obtain and maintain Regulatory Approvals consistent with&#160;<u>Article 4</u>; and</div>
            <div style="text-align: justify; text-indent: 108pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 108pt;">(d)&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;review, discuss and determine [***] certain regulatory communications and Regulatory Filings made by Akcea in accordance with <u>Article 4</u>.</div>
            <div style="text-align: justify; text-indent: 108pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold;">6.6</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;<font style="font-weight: bold;"><u>Decision-Making</u></font>.</div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;"> <br>
              </font></div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;">6.6.1</font>&#160;&#160;&#160;&#160;&#160; <font style="font-weight: bold;"><u>General Decision-Making Process</u></font>. Each Party&#8217;s representatives on the JSC and each
              Subcommittee will, collectively, have one vote (the &#8220;<font style="font-weight: bold; font-style: italic;">Party Vote</font>&#8221;) on all matters brought before such committee for a decision by consensus. The JSC and each Subcommittee will make
              decisions as to matters within its jurisdiction by unanimous Party Vote, which will be reflected in the minutes of the committee meeting. Except as otherwise expressly set forth in this Agreement, the words &#8220;determine&#8221; or &#8220;approve&#8221; by the JSC
              or any Subcommittee and similar phrases used in this Agreement will mean approval in accordance with this <u>Section 6.6</u>. For the avoidance of doubt, matters that are specified in <u>Section 6.1.2</u>, <u>Section 6.3.2</u>, <u>Section
                6.4.2</u> or <u>Section 6.5.2</u>, to be reviewed and discussed (as opposed to approved) do not require any agreement by the JSC or any Subcommittee and are not subject to the voting and decision-making procedures set forth in this <u>Section

                6.6</u>.</div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;"> <br>
              </font></div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;">6.6.2</font>&#160;&#160;&#160;&#160;&#160; <font style="font-weight: bold;"><u>Decisions of the Subcommittees</u></font>. If any Subcommittee cannot reach unanimous agreement using
              good faith efforts on any matter within its respective scope of authority within [***], or such shorter time as may be determined by the Parties, after it begins discussing any such matter, then a Party, through its Alliance Manager, may
              refer such matter to the JSC for resolution in accordance with <u>Section 6.6.3</u>.</div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;"> <br>
              </font></div>
            <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
              <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">31</font></div>
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            </div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;">6.6.3</font>&#160;&#160;&#160;&#160;&#160; <font style="font-weight: bold;"><u>Decisions of the JSC</u></font>. The JSC will use good faith efforts, in compliance with this <u>Section

                6.6.3</u>, to promptly resolve any such matter for which it has authority. If, after the use of good faith efforts, the JSC is unable to resolve any such matter referred to it by any Subcommittee or any other matter within the scope of the
              JSC&#8217;s authority, in each case, within [***], or such shorter time as may be determined by the Parties, after the matter was escalated to or discussed at a meeting by the JSC, then a Party may refer such matter to the Parties&#8217; respective
              Senior Officers for resolution in accordance with <u>Section 6.6.4</u>.</div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;"> <br>
              </font></div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;">6.6.4</font>&#160;&#160;&#160;&#160;&#160; <font style="font-weight: bold;"><u>Referral to Senior Officers</u></font>. If a Party makes an election under <u>Section 6.6.3</u> to
              escalate for resolution by the Senior Officers a matter as to which the JSC cannot reach a consensus decision, then the Senior Officers will use good faith efforts to resolve any such matter so escalated to them as soon as practicable but in
              any event within [***] after such matter is escalated to them, and any final decision that the Senior Officers agree to in writing will be conclusive and binding on the Parties.</div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;"> <br>
              </font></div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;">6.6.5</font>&#160;&#160;&#160;&#160;&#160; <font style="font-weight: bold;"><u>Final Decision-Making Authority</u></font>. If the Senior Officers are unable to reach agreement on any
              such matter so referred within [***] after such matter is referred to them (or such longer period as the Senior Officers may agree upon), then:</div>
            <div style="text-align: justify; text-indent: 108pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 108pt;">(a)&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160; except as set forth in <u>Section 6.6.5(c)</u> and subject to <u>Section 3.6.2(a)(i)</u>, with respect to updates or changes to the Development Plan and Budget (other than
              updates or amendments for ROW Development Activities that would not be reasonably expected to impact the U.S. Development Activities), any updates or changes require mutual agreement of the Parties (and, absent such agreement, the <font style="font-style: italic;">status quo</font> remains except as set forth in <u>Section 2.5</u>);</div>
            <div style="text-align: justify; text-indent: 108pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 108pt;">(b)&#160;&#160;&#160;&#160;&#160;&#160;&#160; with respect to updates or changes to the ROW Development Activities that would not be reasonably expected to impact the U.S. Development Activities, AstraZeneca has final
              decision-making authority (and otherwise, such matter shall require mutual agreement of the Parties);</div>
            <div style="text-align: justify; text-indent: 108pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 108pt;">(c)&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;with respect to the Regulatory Strategy, [***] has final decision-making authority;</div>
            <div style="text-align: justify; text-indent: 108pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 108pt;">(d)&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;with respect to any Regulatory Filing or communication made by Akcea, [***] has final decision-making authority, except to the extent such Regulatory Filing or communication
              implicates [***], in which case [***] has final decision-making authority to the extent of such matters (<font style="font-style: italic;">provided</font> such Regulatory Filing or communication is consistent with the Regulatory Strategy); </div>
            <div style="text-align: justify; text-indent: 108pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 108pt;">(e)&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;with respect to the U.S. Commercialization Plan and Budget or any updates or amendments thereto, subject to <u>Section 3.2.1</u> and <u>Section 3.2.3(b)</u>, [***] has final
              decision-making authority (<font style="font-style: italic;">provided</font> that [***] cannot exercise its final decision making authority in a manner that requires [***] to perform any Co-Commercialization and Medical Affairs Activities
              without [***] consent);</div>
            <div style="text-align: justify; text-indent: 108pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 108pt;">(f)&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;with respect to the U.S. Medical Affairs Plan and Budget or any updates or amendments thereto, subject to <u>Section 3.2.2</u>, [***] has final decision-making authority (<font style="font-style: italic;">provided</font> that [***] cannot exercise its final decision making authority in a manner that causes [***] to perform any Co-Commercialization and Medical Affairs Activities without [***] consent);</div>
            <div style="text-align: justify; text-indent: 108pt;"> <br>
            </div>
            <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
              <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">32</font></div>
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            </div>
            <div style="text-align: justify; text-indent: 108pt;">(g)&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;with respect to any disputed amount included in a cost notice pursuant to <u>Section</u><u> 2.4.1(b)(i)</u>, <u>Section</u><u> 2.4.1(b)(ii)</u>, <u>Section</u><u> 3.4.1(b)(i)</u>&#160;or

              <u>Section</u><u> 11.10.2</u>, no Party shall have final decision-making authority and instead, such matter will be subject to resolution in accordance with <u>Section</u><u> 17.1.2</u>; and</div>
            <div style="text-align: justify; text-indent: 108pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 108pt;">(h)&#160;&#160;&#160;&#160;&#160;&#160;&#160; with respect to the approval of any amount, on an activity-by-activity basis, that is [***] or more than the most recent JSC-approved budgeted costs and expenses for the
              applicable activity for a Calendar Year on a year-to-date basis set forth in any Development Plan and Budget, U.S. Medical Affairs Plan and Budget, or U.S. Commercialization Plan and Budget, as applicable, as an Allowable Overrun, such
              decision will require mutual agreement of the Parties.</div>
            <div style="text-align: justify;">For purposes of this Agreement, decisions of the JSC in accordance with <u>Section</u><u> 6.6.3</u>, decisions of the Senior Officers in accordance with <u>Section</u><u> 6.6.4</u>, and exercise by a Party of
              its final decision making authority in accordance with <u>Section</u><u> 6.6.5</u>, in each case, will be considered a decision of the Subcommittee or JSC, as applicable, in which the matter was first subject to a decision.</div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;"> <br>
              </font></div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;">6.6.6</font>&#160;&#160;&#160;&#160;&#160; <font style="font-weight: bold;"><u>Limitation on Decision-Making</u></font>. Notwithstanding anything to the contrary set forth in this
              Agreement, without the other Party&#8217;s prior written consent, neither Party (in the exercise of a Party&#8217;s final decision-making authority), nor the JSC nor any Subcommittee thereof, may make a decision that could reasonably be expected to: (a)
              require a Party to take any action that such Party reasonably believes would (i) violate any applicable Law, the requirements of any Regulatory Authority, or any agreement with any Third Party entered into by such Party or (ii) require such
              Party to infringe or misappropriate any intellectual property rights of any Third Party; or (b) conflict with, amend, interpret, modify, or waive compliance by a Party under, this Agreement.</div>
            <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold;"> <br>
              </font></div>
            <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold;">6.7</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;<font style="font-weight: bold;"><u>Discontinuation</u></font>.</div>
            <div style="text-align: justify; text-indent: 36pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;">6.7.1</font>&#160;&#160;&#160;&#160;&#160; Subject to <u>Section 17.11</u>, the JSC shall continue to exist until the earliest of (a) the Parties mutually agreeing in writing to
              disband the JSC, (b) written notice from Akcea that it desires to disband the JSC, and (c) the end of the Royalty Term in the U.S.</div>
            <div style="text-align: justify; text-indent: 72pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;">6.7.2</font>&#160;&#160;&#160;&#160;&#160; The JDC shall continue to exist until the earliest of (a) the JSC disbanding, (b) completion of activities under the Development Plan and
              Budget, and (c) the Parties mutually agreeing in writing to disband the JDC.</div>
            <div style="text-align: justify; text-indent: 72pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;">6.7.3</font>&#160;&#160;&#160;&#160;&#160; The JCMC shall continue to exist until the earliest of (a) the JSC disbanding, (b) the date on which the Parties cease all
              Co-Commercialization and Medical Affairs Activities of the Licensed Product in the U.S., (c) the Opt-Out Date and (d) the Parties mutually agreeing in writing to disband the JCMC.</div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;"> <br>
              </font></div>
            <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
              <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">33</font></div>
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            </div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;">6.7.4</font>&#160;&#160;&#160;&#160;&#160;&#160; The RWG shall continue to exist until the earliest of (a) the JSC disbanding, (b) the JDC disbanding, and (c) the Parties mutually agreeing
              in writing to disband the RWG.</div>
            <div style="text-align: justify; text-indent: 72pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;">6.7.5</font>&#160;&#160;&#160;&#160;&#160; Notwithstanding anything herein to the contrary, once the JSC, JDC, JCMC or Regulatory Working Group disbands in accordance with this
              Agreement, such committee or working group shall be terminated and shall have no further rights or obligations under this Agreement, and thereafter any requirement of Akcea to provide information or other materials to such committee or
              working group shall be deemed a requirement to provide such information or other materials to AstraZeneca, AstraZeneca shall have the right to solely decide, without consultation with Akcea, all matters subject to the review or approval by
              such committee or working group hereunder that were previously subject to AstraZeneca&#8217;s final decision-making authority and all other matters subject to the review or approval by such committee or working group hereunder will be decided by
              mutual agreement of the Parties.</div>
            <div style="text-align: justify; text-indent: 72pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold;">6.8</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160; <font style="font-weight: bold;"><u>Alliance Managers</u></font>. Each Party will appoint a representative to act as its alliance manager
              (each, an &#8220;<font style="font-weight: bold; font-style: italic;">Alliance Manager</font>&#8221;) to progress the activities under this Agreement. The role of the Alliance Manager is to act as a single point of contact between the Parties to assure a
              successful collaboration. The Alliance Managers shall attend all meetings of the JSC, JDC, and JCMC (and each Alliance Manager may attend any other committee or working group meetings he or she desires to attend) as non-voting participants
              and support the committee or working group in the discharge their responsibilities. Alliance Managers may not serve as a member of any committee or working group but shall be non-voting participants in committee or working group meetings. An
              Alliance Manager may bring any matter to the attention of any committee or working group if such Alliance Manager reasonably believes that such matter warrants such attention. Each Alliance Manager will be responsible for performing the
              activities listed in <u>Schedule </u><u>6.8</u>. Each Party may change its Alliance Manager at any time upon written notice to the other Party.</div>
            <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold;"> <br>
              </font></div>
            <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold;">6.9</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160; <font style="font-weight: bold;"><u>Annual Review</u></font>. Without limiting the other provisions of this <u>Article 6</u>, on at least
              an annual basis during the Term, senior leaders of each Party will meet at a mutually agreed time and place, which may include by videoconference or teleconference, to discuss the progress of the Development, Manufacturing, Commercialization
              and other Exploitation of the Licensed Product under this Agreement and any issues arising with respect thereto or otherwise with respect to the relationship of the Parties.</div>
            <div style="text-align: justify; text-indent: 36pt;"> <br>
            </div>
            <div style="text-align: center; font-weight: bold;">ARTICLE 7</div>
            <div style="text-align: center; font-weight: bold;">GENERAL PROVISIONS RELATING TO THE PROGRAM</div>
            <div style="text-align: center; font-weight: bold;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold;">7.1</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160; <font style="font-weight: bold;"><u>Compliance</u></font>. Each Party and its Affiliates will perform its activities pursuant to this
              Agreement (and will use Commercially Reasonable Efforts to require any applicable Third Parties to perform any such activities) in compliance with all applicable Laws and regulations, including Good Laboratory Practices (cGLP), Good Clinical
              Practices (cGCP), and Good Manufacturing Practices (cGMP), in each case as applicable under the Laws and regulations of the country and the state and local government wherein such activities are conducted or which are otherwise affected.</div>
            <div style="text-align: justify; text-indent: 36pt;"> <br>
            </div>
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              <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">34</font></div>
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            </div>
            <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold;">7.2</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;<font style="font-weight: bold;"><u>Subcontracting Rights</u></font>.</div>
            <div style="text-align: justify; text-indent: 36pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;">7.2.1</font>&#160; &#160; &#160; <font style="font-weight: bold;"><u>AstraZeneca Subcontractors</u></font>. Subject to the terms and conditions of this Agreement, including
              <u>Section 7.2.3</u>, AstraZeneca will have the right to engage Affiliates or Third Party subcontractors to perform any of its obligations under this Agreement at its sole discretion; <font style="font-style: italic;">provided </font>that
              [***].</div>
            <div style="text-align: justify; text-indent: 72pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;">7.2.2</font>&#160;&#160;&#160;&#160;&#160; <font style="font-weight: bold;"><u>Akcea Subcontractors</u></font>. Subject to the terms and conditions of this Agreement, including <u>Section

                7.2.3</u>, Akcea will have the right to engage Affiliates or Third Party subcontractors to perform its obligations under the Development Plan and Budget, the Manufacturing Transition Plan, the U.S. Commercialization Plan and Budget and U.S.
              Medical Affairs Plan and Budget, at its sole discretion; <font style="font-style: italic;">provided</font> that [***] (Existing Third Party Subcontractors); <font style="font-style: italic;">provided, further, </font>that, [***], in which
              case [***] under the Development Plan and Budget, the Manufacturing Transition Plan, the U.S. Commercialization Plan and Budget or the U.S. Medical Affairs Plan and Budget [***].</div>
            <div style="text-align: justify; text-indent: 72pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;">7.2.3</font>&#160;&#160;&#160;&#160;&#160; <font style="font-weight: bold;"><u>Subcontract Requirements</u></font>. Any Affiliate or Third Party subcontractor to be engaged by a
              Party to perform a Party&#8217;s obligations set forth in this Agreement will meet the qualifications typically required by such Party for the performance of work similar in scope and complexity to the subcontracted activity; <font style="font-style: italic;">provided </font>that any Party engaging an Affiliate or Third Party subcontractor hereunder will remain principally responsible and obligated for such activities and for such Affiliate or Third Party&#8217;s
              compliance with all applicable terms and conditions of this Agreement. Notwithstanding anything to the contrary in this Agreement, the Parties may only engage a Third Party subcontractor to perform its activities under the Agreement if: <font style="color: #000000;">(a)</font> no rights of the other Party under this Agreement would be diminished or otherwise adversely affected as a result of such subcontracting, <font style="color: #000000;">(b)</font> the subcontractor
              undertakes the obligations of confidentiality and non-use regarding Confidential Information that are substantially the same as those undertaken by the Parties pursuant to <u>Article 13</u> hereof, and <font style="color: #000000;">(c)</font>
              the subcontractor agrees that any intellectual property developed in the course of the work hereunder, other than improvements to such subcontractor&#8217;s background intellectual property, shall be assigned or exclusively and perpetually licensed
              to such subcontracting Party to the extent required to permit licensing of such intellectual property to the other Party as required by the terms and conditions of this Agreement.</div>
            <div style="text-align: justify; text-indent: 72pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold;">7.3</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160; <font style="font-weight: bold;"><u>Materials Transfer</u></font>. In order to facilitate the activities under this Agreement, either
              Party may provide to the other Party certain materials for use by the other Party in furtherance of the activities to be performed under this Agreement pursuant to a Materials Transfer Agreement to be agreed and executed by the Parties.
              Unless agreed otherwise between the Parties, all such materials will be used by the receiving Party in accordance with the terms and conditions of this Agreement and the Materials Transfer Agreement solely for purposes of exercising its
              rights and performing its obligations under this Agreement, and the receiving Party will not transfer such materials to any Third Party unless expressly contemplated by this Agreement or the Materials Transfer Agreement or upon the written
              consent of the supplying Party. The receiving Party shall not use, or authorize use of, the provided materials on or in humans for any purpose under any circumstances, unless specifically provided in the Development Plan and Budget or the
              Materials Transfer Agreement. The receiving Party acknowledges that the provided materials are experimental in nature and may have unknown characteristics and therefore agrees to use prudence and reasonable care in the use, handling, storage,
              transportation and disposition and containment of such materials. ANY SUCH MATERIALS ARE SUPPLIED TO THE OTHER PARTY &#8220;AS IS&#8221;, WITH NO WARRANTIES, EXPRESS OR IMPLIED, AND THE PROVIDING PARTY EXPRESSLY DISCLAIMS ANY WARRANTY OF MERCHANTABILITY,
              FITNESS FOR A PARTICULAR PURPOSE, OR NON-INFRINGEMENT OF ANY INTELLECTUAL PROPERTY RIGHTS OF ANY THIRD PARTY. For clarity, this <u>Section </u><u>7.3</u>&#160;shall not apply to the supply of any Licensed Compound, analytical reagents, raw
              materials, drug substance or drug product supplied or transferred pursuant to&#160;<u>Article 5</u>.</div>
            <div style="text-align: justify;"> <br>
            </div>
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              <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">35</font></div>
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            </div>
            <div style="text-align: center; font-weight: bold;">ARTICLE 8</div>
            <div style="text-align: center; font-weight: bold;">LICENSE GRANTS</div>
            <div style="font-weight: bold;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold;">8.1</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;<font style="font-weight: bold;"><u>License Grant to AstraZeneca</u></font>.</div>
            <div style="text-align: justify; text-indent: 36pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;">8.1.1</font>&#160;&#160;&#160;&#160;&#160; Subject to the terms and conditions of this Agreement and effective as of the Closing Date, Akcea hereby grants to AstraZeneca, and
              AstraZeneca accepts, an exclusive (even as to Akcea and its Affiliates), royalty-bearing, non-transferable (except in accordance with <u>Section 17.3</u>), sublicensable (through multiple tiers, but subject to <u>Section 8.3</u>) license
              under the Licensed Technology to Exploit the Licensed Compounds and the Licensed Products in the Field in the Territory;<font style="font-style: italic;"> provided</font> that (a) [***] and (b) for clarity, the license grant under this <u>Section</u><u>
                8.1</u> shall not include the right to Exploit the Licensed Compounds and the Licensed Products in the PTC Territory unless and until the date that is the earlier of (i) such time as Akcea shall have the right to grant the foregoing
              exclusive license to AstraZeneca in the PTC Territory pursuant to Sections 7.1 and 7.2 of the PTC Agreement and (ii) such time as Akcea and its Affiliates are otherwise no longer subject to Sections 7.1 and 7.2 of the PTC Agreement (such
              date, the &#8220;<font style="font-weight: bold; font-style: italic;">PTC Territory License Date</font>&#8221;) (<font style="font-style: italic;">provided</font> that, if any antitrust approvals are required under applicable Law in any country in the
              PTC Territory prior to the inclusion of rights for AstraZeneca in such country under this Agreement, then the Parties will cooperate in good faith in accordance with <u>Section </u><u>10.2</u>&#160;(<font style="font-style: italic;">mutatis
                mutandis </font>with respect to such country) to promptly secure such approvals, and the PTC Territory License Date shall be the date that all such approvals are received). If Akcea or any of its Affiliates [***], then Akcea will (1)
              [***], (2) [***], and (3) [***].</div>
            <div style="text-align: justify; text-indent: 72pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;">8.1.2</font>&#160;&#160;&#160;&#160; Subject to the terms and conditions of this Agreement and effective as of the Closing Date, Akcea hereby grants to AstraZeneca, and
              AstraZeneca accepts, a non-exclusive, royalty-bearing, non-transferable (except in accordance with <u>Section</u><u> 17.3</u>), sublicensable (through multiple tiers, but subject to <u>Section</u><u> 8.3</u>) license under the Licensed
              Technology to Manufacture and Develop Licensed Compounds and Licensed Products in the [***] solely for the purpose of Developing and Commercializing Licensed Compounds and Licensed Products [***].</div>
            <div style="text-align: justify; text-indent: 72pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold;">8.2</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;<font style="font-weight: bold;"><u>License Grants to Akcea</u></font>.</div>
            <div style="text-align: justify; text-indent: 36pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;">8.2.1</font>&#160; &#160; &#160; Subject to the terms and conditions of this Agreement and effective as of the Closing Date, AstraZeneca hereby grants to Akcea, and Akcea
              accepts, a non-exclusive, royalty-free, non-transferable (except in accordance with <u>Section 17.3</u>), sublicensable (through multiple tiers, but solely to Akcea&#8217;s Affiliates and its and their subcontractors permitted under <u>Section </u><u>7.2.2</u>)
              (sub)license under the Licensed Technology and the AstraZeneca IP to (a) perform U.S. Development Activities and Global Development Activities in the Field in the Territory pursuant to the Development Plan and Budget (to the extent permitted
              under <u>Article 2</u>) and (b) Manufacture (to the extent permitted under <u>Article 5</u>) the Licensed Compound and the Licensed Product in the Field in the Territory through the later of (i) [***] and (ii) [***].</div>
            <div style="text-align: justify; text-indent: 72pt;"> <br>
            </div>
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              <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">36</font></div>
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            </div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;">8.2.2</font>&#160; &#160; &#160; Subject to the terms and conditions of this Agreement and effective as of the Closing Date, AstraZeneca hereby grants to Akcea, and Akcea
              accepts, a non-exclusive, royalty-free, non-transferable (except in accordance with <u>Section 17.3</u>), sublicensable (through multiple tiers, but solely to Akcea&#8217;s Affiliates and its and their subcontractors permitted under <u>Section </u><u>7.2.2</u>)
              (sub)license under the Licensed Technology and the AstraZeneca IP to perform Co-Commercialization and Medical Affairs Activities (to the extent permitted under <u>Article 3</u>) for the Licensed Compound and the Licensed Product in the Field
              in the United States.</div>
            <div style="text-align: justify; text-indent: 72pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold;">8.3</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;<font style="font-weight: bold;"><u>AstraZeneca&#8217;s Sublicensing Rights</u></font>. Subject to the terms and conditions of this Agreement,
              AstraZeneca will have the right to grant sublicenses under the licenses granted under <u>Section 8.1</u> above:</div>
            <div style="text-align: justify; text-indent: 36pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;">8.3.1</font>&#160;&#160;&#160;&#160;&#160; under the Licensed Technology other than Akcea Manufacturing IP to an Affiliate of AstraZeneca or a Third Party; <font style="font-style: italic;">provided </font>that Akcea&#8217;s prior written consent (not to be unreasonably withheld, conditioned, or delayed) will be required for any sublicense to a Third Party of Commercialization rights in the U.S. (except any sublicense to a
              CSO or other vendor or service provider); and</div>
            <div style="text-align: justify; text-indent: 72pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;">8.3.2</font>&#160;&#160;&#160;&#160;&#160;&#160; under the Akcea Manufacturing IP solely to (a) [***], (b) [***] (each, an &#8220;<font style="font-weight: bold; font-style: italic;">Authorized
                CMO</font>&#8221;), which such Authorized CMOs as of the Execution Date are set forth on <u>Schedule 8.3.2</u> attached hereto, or (c) [***].</div>
            <div style="text-align: justify; text-indent: 72pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold;"><font style="font-weight: bold;">8.4</font> &#160;&#160;&#160;&#160;&#160;&#160;&#160; <u>Sublicense Conditions</u></font>. For each such sublicense granted by AstraZeneca under its licenses
              set forth in <u>Section</u><u> 8.1</u>&#160;(other than a Settlement Sublicense) or Akcea under its licenses set forth in <u>Section</u><u> 8.2</u> (a &#8220;<font style="font-weight: bold; font-style: italic;">Sublicense</font>&#8221;), the sublicensing
              Party shall promptly notify the other Party of the granting of such Sublicense, and shall ensure that the terms of such Sublicense (a) are subject to the applicable terms and conditions of this Agreement and (b) without limiting the
              foregoing, contain provisions requiring that the Sublicensee (i) undertakes the obligations of confidentiality and non-use regarding Confidential Information that are substantially the same as those undertaken by the Parties pursuant to <u>Article

                13</u> hereof, (ii) agrees that any intellectual property developed in the course of the work hereunder shall be assigned or licensed to the sublicensing Party to the extent required to permit licensing of such intellectual property to the
              other Party as required by the terms and conditions of this Agreement, and (iii) submits applicable sales or other reports to the sublicensing Party to the extent necessary or relevant to the reports or records required to be maintained under
              this Agreement. The sublicensing Party will provide the other Party with a fully-executed copy of any agreement reflecting any such Sublicense (excluding any Sublicense with an Affiliate of the sublicensing Party), which may be reasonably
              redacted to exclude the sublicensing Party&#8217;s proprietary information, other competitively sensitive information, or any other information not necessary for the other Party to verify compliance with the preceding sentence, promptly (but no
              later than [***]) after the execution thereof, which copy shall be treated as the sublicensing Party&#8217;s Confidential Information. The sublicensing Party assumes full responsibility, and will remain primarily liable, for causing the performance
              of all obligations of each of its Sublicensees/(sub)licensees and their compliance with all applicable terms and conditions of this Agreement.</div>
            <div style="text-align: justify;"> <br>
            </div>
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            </div>
            <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold;">8.5</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160; <font style="font-weight: bold;"><u>Effect of Termination on Sublicenses</u></font>. If this Agreement terminates for any reason, any
              Sublicensee will, from the effective date of such termination, automatically become a direct licensee of Akcea with respect to the rights sublicensed to the Sublicensee by AstraZeneca; <font style="font-style: italic;">so long as</font> (a)
              such Sublicensee is not in breach of its Sublicense, (b) Akcea is not required to assume any obligations or liabilities (contingent or otherwise) not set forth in this Agreement, (c) such Sublicensee agrees in writing to comply with all of
              the terms and conditions of this Agreement to the extent applicable to the rights originally sublicensed to it by AstraZeneca, and (d) such Sublicensee agrees to pay directly to Akcea AstraZeneca&#8217;s payments under this Agreement to the extent
              applicable to the rights sublicensed to it by AstraZeneca.<br>
              <br>
            </div>
            <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold;">8.6</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160; <font style="font-weight: bold;"><u>Technology Transfer</u></font>. After the Closing Date, Akcea will promptly deliver copies of the
              Know-How licensed to AstraZeneca under <u>Section 8.1</u> (other than the Akcea Manufacturing and Analytical Know-How which will be transferred pursuant to <u>Section 5.2</u>) in Akcea&#8217;s possession or control that has not previously been
              provided hereunder, for use solely in accordance with the license granted under <u>Section 8.1</u>. To assist with the transfer of such Know-How and if reasonably requested by AstraZeneca, Akcea will make its personnel reasonably available
              to AstraZeneca during normal business hours to transfer such Know-How under this <u>Section </u><u>8.6</u>. Any Out-of-Pocket Costs incurred by either Party in connection with this transfer will be considered Other Operating Expenses and
              shared by the Parties in accordance with <u>Section 11.10</u>.<font style="font-weight: bold; font-style: italic;">&#160;</font>Without limiting the foregoing, upon Completion of each Clinical Trial ongoing as of the Execution Date, Akcea will,
              as soon as reasonably practicable, transfer to AstraZeneca the clinical and regulatory databases with respect to such Clinical Trial.</div>
            <div style="text-align: justify; text-indent: 36pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold;">8.7</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160; <font style="font-weight: bold;"><u>Consequence of Natural Expiration of this Agreement</u></font>. If this Agreement expires (<font style="font-style: italic;">i.e.</font>, is not terminated early) in a particular country in accordance with <u>Section 16.1</u> then the license granted to AstraZeneca under the Licensed Technology shall become perpetual, irrevocable and
              fully paid-up on a country-by-country basis.</div>
            <div style="text-align: justify; text-indent: 36pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold;">8.8</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160; <font style="font-weight: bold;"><u>No Other Rights and Retained Rights</u></font>. Except as otherwise expressly provided in this
              Agreement, under no circumstances will a Party, as a result of this Agreement, obtain any ownership interest, license right or other right in any Know-How, Patent Rights or other intellectual property rights of the other Party or any of its
              Affiliates, including items owned, controlled, developed or acquired by the other Party or any of its Affiliates, or provided by the other Party to the first Party at any time pursuant to this Agreement. AstraZeneca will not practice the
              Licensed Technology other than as expressly licensed and permitted under this Agreement, and Akcea will not practice the AstraZeneca IP other than as expressly licensed and permitted under this Agreement. Any rights not expressly granted to a
              Party by the other Party under this Agreement are hereby retained by such other Party.</div>
            <div style="text-align: justify; text-indent: 36pt;"> <br>
            </div>
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              <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">38</font></div>
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            </div>
            <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold;">8.9</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160; <font style="font-weight: bold;"><u>Section 365(n) of the Bankruptcy Code</u></font>. The Parties intend to take advantage of the
              protections of Section 365(n) (or any successor provision) of the U.S. Bankruptcy Code or any analogous provisions in any other country or jurisdiction to the maximum extent permitted by Law. All rights and licenses granted under or pursuant
              to this Agreement by a Party to the other Party, but only to the extent they constitute licenses of a right to &#8220;intellectual property&#8221; as defined in Section 101 of the U.S. Bankruptcy Code or foreign counterparty thereto, are and will
              otherwise be deemed to be, for purposes of Section 365(n) of the U.S. Bankruptcy Code or any foreign counterpart thereto, licenses of rights to &#8220;<font style="font-style: italic;">intellectual property.</font>&#8221;<font style="font-style: italic;">&#160;</font>The

              Parties agree that the Parties will retain and may fully exercise all of their rights and elections under the U.S. Bankruptcy Code and any foreign counterpart thereto, including the right to obtain the intellectual property from another
              entity. In the event of the commencement of a bankruptcy proceeding by or against either Party under the U.S. Bankruptcy Code or any foreign counterparty thereto, the Party that is not subject to such proceeding will further be entitled to a
              complete duplicate of, or complete access to, any such intellectual property, and all embodiments which, if not already in its possession, will be promptly delivered to the non-subject Party upon written request (a) upon commencement of a
              bankruptcy proceeding, unless the Party subject to such proceeding continues to perform all of its obligations under this Agreement, or (b) if not delivered pursuant to clause (a) above because the subject Party continues to perform, upon the
              rejection of this Agreement by or on behalf of the subject Party. Unless and until the subject Party rejects this Agreement, the subject Party shall perform this Agreement or provide the intellectual property (including all embodiments of
              such intellectual property) to the non-subject Party, and shall not interfere with the rights of the non-subject Party to such intellectual property, including the right to obtain the intellectual property from another entity. The upfront
              fee, milestone payments and Royalties to be paid by AstraZeneca under this Agreement will be considered &#8220;<font style="font-style: italic;">royalties</font>&#8221; for purposes of Section 365(n) of the U.S. Bankruptcy Code.</div>
            <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold;"> <br>
              </font></div>
            <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold;">8.10</font>&#160;&#160;&#160;&#160;&#160;&#160; <font style="font-weight: bold;"><u>License Conditions; Limitations</u></font>. The licenses granted under <u>Section 8.1</u> and the
              sublicense rights under <u>Section 8.3</u> are subject to and limited by (a) the Prior Agreements, (b) the Existing In-License Agreements (in each case of clauses (a) and (b), to the extent and in the form that such agreements are disclosed
              to AstraZeneca as of the Execution Date or as such agreements may be amended as permitted by this Agreement), (c) subject to Akcea&#8217;s compliance with <u>Section 11.8.4</u>, any Future In-License Agreements (in the case of this clause (c), to
              the extent and in the form that such agreements (and any amendments thereto) are disclosed to AstraZeneca pursuant to the terms of <u>Section 14.4.8</u> and as such agreements may be amended as permitted by this Agreement) and (d) the
              granting of, or performance of obligations under, Permitted Licenses.</div>
            <div style="text-align: justify; text-indent: 36pt;"> <br>
            </div>
            <div style="text-align: center; font-weight: bold;">ARTICLE 9</div>
            <div style="text-align: center; font-weight: bold;">ROFN AND EXCLUSIVITY PROVISIONS</div>
            <div style="text-align: center; font-weight: bold;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold;">9.1</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160; <font style="font-weight: bold;"><u>ROFN for [***]</u></font>. During the Exclusivity Period, if Akcea or any of its Affiliates discovers
              or otherwise obtains rights to a [***] and intends to [***] (itself or through a Third Party) (such Development program, &#8220;<font style="font-weight: bold; font-style: italic;">Potential </font>[***]&#8221;), then Akcea shall provide prompt notice
              to AstraZeneca in writing (each such written notice, a &#8220;<font style="font-weight: bold; font-style: italic;">Notice of Intent</font>&#8221;), which Notice of Intent will include a detailed description of such Potential [***]. Following a Notice of
              Intent, Akcea shall promptly provide AstraZeneca with other information and documentation reasonably related to such Potential [***] that is requested by AstraZeneca within [***] after AstraZeneca&#8217;s receipt of the Notice of Intent.
              AstraZeneca shall have [***]<font style="font-weight: bold; font-style: italic;">&#160;</font>from the later of receipt of the Notice of Intent or receipt of any information or documentation related to such Potential [***] that is reasonably
              requested by AstraZeneca within [***] of receipt of the Notice of Intent within which to inform Akcea in writing that AstraZeneca has an interest in obtaining exclusive Development and Commercialization rights from Akcea with respect to such
              [***] (each such written notice, a &#8220;<font style="font-weight: bold; font-style: italic;">Statement of Interest</font>&#8221;). Following receipt of a timely Statement of Interest, Akcea will negotiate in good faith exclusively with AstraZeneca for
              [***] (or such longer period mutually agreed to by the Parties, the &#8220;<font style="font-weight: bold; font-style: italic;">Negotiation Period</font>&#8221;) the financial and other material terms and conditions of this Agreement that the Parties
              would amend in consideration for including the Potential [***] as part of this Agreement (the &#8220;<font style="font-weight: bold; font-style: italic;">Right of First Negotiation</font>&#8221;). Subject to the foregoing, during the applicable
              Negotiation Period, [***]. If AstraZeneca does not provide a Statement of Interest within the [***] period, or if AstraZeneca does provide a Statement of Interest but the Parties do not reach agreement regarding the terms of such a
              transaction within the Negotiation Period, then such Right of First Negotiation with respect to such Potential [***] shall expire, and Akcea will have the right to progress the Development of such Potential [***], subject to the remainder of
              this <u>Article 9</u>; <font style="font-style: italic;">provided</font> that [***].<font style="font-weight: bold;">&#160;</font>Any agreement reached by the Parties with respect to the Potential [***] shall be memorialized in and governed by
              an amendment to this Agreement or a separate written agreement addressing the terms and conditions of such Potential [***].</div>
            <div style="text-align: justify; text-indent: 36pt;"> <br>
            </div>
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              <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">39</font></div>
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            </div>
            <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold;">9.2</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;<font style="font-weight: bold;"><u>Exclusivity Covenants</u></font>. Except in the performance of its obligations or exercise of its
              rights under this Agreement and except as otherwise set forth in <u>Section 9.3</u> and <u>Section 9.4</u>, for the period commencing on the Closing Date and expiring upon the earlier of (a) [***], and (b) [***] (the &#8220;<font style="font-weight: bold; font-style: italic;">Exclusivity Period</font>&#8221;), neither Party nor any of its respective Affiliates will, either alone or with or for any Third Party, work independently or for or with any Third Party (including
              the grant of any license or other rights to any Third Party) with respect to the Development or Commercialization of a Competitive Oligo. Notwithstanding anything to the contrary in this Agreement and solely for purposes of this <u>Section </u><u>9.2</u>&#160;and

              <u>Section</u><u> 9.4</u>, &#8220;<font style="font-style: italic;">Development</font>&#8221; will be deemed to exclude all pre-clinical research and pre-clinical development activities, such that pre-clinical research and pre-clinical development
              activities will not violate this <u>Section </u><u>9.2</u>.</div>
            <div style="text-align: justify; text-indent: 36pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold;">9.3</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;<font style="font-weight: bold;"><u>Limitations and Exceptions to Akcea&#8217;s Exclusivity Covenants</u></font>. Akcea&#8217;s or its Affiliates&#8217;
              practice of the following will not violate <u>Section </u><u>9.2</u>:</div>
            <div style="text-align: justify; text-indent: 36pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;">9.3.1</font>&#160;&#160;&#160;&#160;&#160;&#160; the licenses granted by Akcea or its Affiliates, or the performance by Akcea or its Affiliates of any obligations, under the Prior
              Agreements;</div>
            <div style="text-align: justify; text-indent: 72pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;">9.3.2</font>&#160;&#160;&#160;&#160;&#160;&#160; the granting of, or performance of obligations under, Permitted Licenses;</div>
            <div style="text-align: justify; text-indent: 72pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;">9.3.3</font>&#160;&#160;&#160;&#160;&#160;&#160; any activities permitted under <u>Section 9.4</u> below;</div>
            <div style="text-align: justify; text-indent: 72pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;">9.3.4</font>&#160;&#160;&#160;&#160;&#160;&#160; the Exploitation of any Inotersen Product; and</div>
            <div style="text-align: justify; text-indent: 72pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;">9.3.5</font>&#160;&#160;&#160;&#160;&#160; [***].<br>
              <br>
            </div>
            <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold;">9.4</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;<font style="font-weight: bold;"><u>Competitive Oligo Transactions</u></font>.</div>
            <div style="text-align: justify; text-indent: 36pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;">9.4.1</font>&#160;&#160;&#160;&#160;&#160; The Parties acknowledge that after the Execution Date a Party or its Affiliate may acquire a Third Party (including through merger,
              reorganization, consolidation or business combination). In the case of such a transaction after the Execution Date and prior to the end of the Exclusivity Period where such Third Party is Developing or Commercializing a Competitive Oligo that
              would violate <u>Section </u><u>9.2</u>, notwithstanding anything to the contrary in this Agreement, within [***] after such acquisition (or if at the time of such acquisition there are ongoing Clinical Trials, if later, within [***] after
              Completion of such Clinical Trials), such Party (or its Affiliate) and such Third Party must either (a) [***], (b) [***], (c) [***], or (d) [***]. If such acquiring Party (or its Affiliate) and such Third Party do not take one of the steps
              set forth in clause (a) through clause (d) above (as applicable) or do not comply with the immediately following sentence, then such Development or Commercialization of such Competitive Oligo will be a violation of <u>Section </u><u>9.2</u>.&#160;

              During the period between the closing of such acquisition and the date that the acquiring Party (or its Affiliate) completes one of the steps set forth in clause (a) through clause (d) above, the acquiring Party shall establish reasonable
              procedures, including firewalls between the teams responsible for such Competitive Oligo and the teams responsible for the Licensed Product (other than members of senior management of the acquiring Party responsible for overall product
              portfolio management), to prevent the use of any Confidential Information of the other Party or any Patent Rights or Know-How that are subject to a license grant under this Agreement from being used by the acquiring Party or its Affiliates in
              connection with the Development or Commercialization of such Competitive Oligo.</div>
            <div style="text-align: justify; text-indent: 72pt;"> <br>
            </div>
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              <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">40</font></div>
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            </div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;">9.4.2</font>&#160;&#160;&#160;&#160;&#160; The Parties acknowledge that after the Execution Date a Party may undergo a Change of Control (including through merger, reorganization,
              consolidation or business combination). In the case of a Change of Control after the Execution Date and prior to the end of the Exclusivity Period where the Acquirer or its pre-existing Affiliate (other than a Party Affiliate) is, at the time
              of such Change of Control, Developing or Commercializing a Competitive Oligo that would violate <u>Section </u><u>9.2</u> if conducted by a Party or its Affiliate, the continued Development or Commercialization of such Competitive Oligo
              will not be a violation of <u>Section </u><u>9.2</u>, <font style="font-style: italic;">provided</font> that the Acquirer establishes reasonable procedures, including firewalls between the teams responsible for such Competitive Oligo and
              the teams responsible for the Licensed Product (other than members of senior management of the Acquirer responsible for overall product portfolio management), to prevent the use of any Confidential Information of the other Party or any Patent
              Rights or Know-How that are subject to a license grant under this Agreement from being used by the Acquirer or its Affiliates in connection with the Development or Commercialization of such Competitive Oligo.</div>
            <div style="text-align: justify; text-indent: 72pt;"> <br>
            </div>
            <div style="text-align: center; font-weight: bold;">ARTICLE 10</div>
            <div style="text-align: center; font-weight: bold;">CLOSING</div>
            <div style="text-align: center; font-weight: bold;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold;">10.1</font>&#160;&#160;&#160;&#160;&#160;&#160; <font style="font-weight: bold;"><u>Closing</u></font>. Subject to the last sentence of <u>Section 16.1</u>, the closing of the
              transactions contemplated by this Agreement (the &#8220;<font style="font-weight: bold; font-style: italic;">Closing</font>&#8221;) shall be deemed to have taken place on the date that all necessary authorizations, consents, orders or approval of, or
              declarations or filings with, or expirations of waiting periods under the HSR Act, as applicable to the consummation of the transactions contemplated by this Agreement (&#8220;<font style="font-weight: bold; font-style: italic;">HSR Clearance</font>&#8221;)

              have been received, authorized, permitted or expired (the &#8220;<font style="font-weight: bold; font-style: italic;">Closing Date</font>&#8221;). AstraZeneca shall immediately provide written notice to Akcea of such Closing Date. Except for the Parties&#8217;
              rights and obligations under <u>Section 2.3</u> (Development Activities Prior to Closing Date), <u>Article 13</u> (Confidentiality), <u>Article 14</u> (Representations and Warranties), <u>Section</u><u> 17.1</u>&#160;(Dispute Resolution), <u>Section</u><u>
                17.2</u>&#160;(Governing Law; Jurisdiction; Equitable Relief; Losses; Remedies), <u>Section 17.11</u> (Change of Control) and this <u>Article 10</u> (Closing), which will be effective as of the Execution Date, this Agreement will not become
              effective until the Closing Date. Upon the occurrence of the Closing Date, all other provisions of this Agreement shall become effective automatically without the need for further action by the Parties.</div>
            <div style="text-align: justify; text-indent: 36pt;"> <br>
            </div>
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              <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">41</font></div>
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            </div>
            <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold;">10.2</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160; <font style="font-weight: bold;"><u>Antitrust Filings</u></font>.</div>
            <div style="text-align: justify; text-indent: 36pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;">10.2.1</font>&#160;&#160;&#160; Akcea and AstraZeneca shall, as promptly as practicable (but no later than 10 Business Days after the Execution Date), and before the
              expiration of any relevant legal deadline, prepare and file with the United States Federal Trade Commission and the Antitrust Division of the United States Department of Justice, the Notification and Report Form for Certain Mergers and
              Acquisitions (as that term is defined in the HSR Act) required for the transactions contemplated hereby, together with all required documentary attachments thereto any supplemental information requested in connection therewith pursuant to the
              HSR Act (the &#8220;<font style="font-weight: bold; font-style: italic;">Antitrust Filings</font>&#8221;). Notwithstanding the foregoing, the Parties may, upon mutual agreement, delay the filing of any of the Antitrust Filings if they reasonably believe
              that such delay would result in obtaining any clearance required under the HSR Act for the consummation of this Agreement and the transactions contemplated hereby more expeditiously. Each of Akcea and AstraZeneca shall cooperate in the
              antitrust clearance process, including by furnishing to each other&#8217;s counsel such necessary information and reasonable assistance as the other may request in connection with its preparation of any filing or submission that is necessary under
              the HSR Act and to furnish promptly with the Antitrust Authorities any information reasonably requested by them in connection with such filings. Each Party shall be responsible for its own fees, costs and expenses associated with any
              Antitrust Filings or in connection with its obligations pursuant to this <u>Section </u><u>10.2</u>.</div>
            <div style="text-align: justify; text-indent: 72pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;">10.2.2</font>&#160;&#160; Akcea and AstraZeneca shall use their commercially reasonable efforts to promptly obtain HSR Clearance and shall keep each other apprised of
              the status of any communications with, and any inquiries or requests for additional information from, any Antitrust Authority and shall comply promptly with any such inquiry or request. Commercially reasonable efforts as used in this <u>Section

              </u><u>10.2.2</u>&#160;will not include proposing, negotiating, committing to or effecting, by consent decree, hold separate order, or otherwise, (a) the sale, divestiture, disposition, licensing or sublicensing of any of a Party&#8217;s or its
              Affiliates&#8217; assets, properties or businesses, (b) behavioral limitations, conduct restrictions or commitments with respect to such assets, properties or business, or of any of the rights or obligations of a Party under this Agreement, or (c)
              defending through litigation any claim asserted in court by any Third Party that would restrain, prevent or delay the Closing Date.</div>
            <div style="text-align: justify; text-indent: 72pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;">10.2.3</font>&#160;&#160;&#160; Subject to <u>Section 10.2.2</u>, the Parties shall instruct their respective counsel to cooperate with each other and use commercially
              reasonable efforts to facilitate and expedite the identification and resolution of any issues arising under the HSR Act at the earliest practicable dates. Such commercially reasonable efforts and cooperation include counsel&#8217;s undertaking (a)
              to keep each other informed of communications, inquiries and requests from and to personnel of the reviewing Antitrust Authorities, including by providing copies thereof to the other Party (subject to reasonable redactions for privilege or
              confidentiality concerns), and (b) to confer with each other regarding appropriate contacts with and response to personnel of such Antitrust Authorities and the content of any such contacts or presentations. Each of Akcea and AstraZeneca
              shall consult with the other Party, to the extent practicable, in advance of participating in any substantive meeting or discussion with any Antitrust Authority with respect to any such filings, applications, investigation, or other inquiry
              and, to the extent permitted by the relevant Antitrust Authority, give the other Party the opportunity to attend and participate in such meeting or discussion (which, at the request of either AstraZeneca or Akcea, shall be limited to outside
              antitrust counsel only). Akcea and AstraZeneca shall each give the other Party the opportunity to review in advance, and shall consider in good faith the other Party&#8217;s reasonable comments in connection with, the content of any presentations,
              white papers or other written materials to be submitted to any Antitrust Authority. Neither Party shall withdraw its filing under the HSR Act or agree to delay the Closing Date without the prior written consent of the other Party. The
              Parties&#8217; rights and obligations hereunder apply only in so far as they relate to this Agreement and to the transactions contemplated under this Agreement.</div>
            <div style="text-align: justify; text-indent: 72pt;"> <br>
            </div>
            <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
              <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">42</font></div>
              <div style="page-break-after: always;" id="DSPFPageBreak">
                <hr noshade="noshade" style="border-width: 0px; clear: both; margin: 4px 0px; width: 100%; height: 2px; color: #000000; background-color: #000000;"></div>
            </div>
            <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold;">10.3</font>&#160;&#160;&#160;&#160;&#160;&#160; <font style="font-weight: bold;"><u>Covenants between Signing and Closing</u></font>. From the Execution Date and until the Closing Date or
              the earlier termination of this Agreement in accordance with <u>Article 16</u>, except as consented to in writing by AstraZeneca, (a) Akcea shall conduct its business with respect to the Licensed Product in the ordinary course of business
              consistent with past practice and in accordance with all applicable Law with respect to the performance of its obligations under this Agreement, including with respect to its activities under any Clinical Trials of the Licensed Product that
              are ongoing as of the Execution Date, and (b) Akcea shall not (i) license, transfer or otherwise dispose of any Licensed Technology; (ii) abandon, cancel or allow to lapse or fail to maintain or protect any Licensed Technology; or (iii) enter
              into, modify, extend, renew or amend any contract, in each case of (i), (ii) and (iii) that would materially limit or impair Akcea&#8217;s or its Affiliates&#8217; ability to carry out its obligations or AstraZeneca&#8217;s rights under this Agreement.</div>
            <div style="text-align: justify; text-indent: 36pt;"> <br>
            </div>
            <div style="text-align: center; font-weight: bold;">ARTICLE 11</div>
            <div style="text-align: center; font-weight: bold;">UPFRONT FEE; MILESTONES AND ROYALTIES; REIMBURSEMENTS; PAYMENTS</div>
            <div style="text-align: center; font-weight: bold;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold;">11.1</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160; <font style="font-weight: bold;"><u>Upfront Fees</u></font>.</div>
            <div style="text-align: justify; text-indent: 36pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;">11.1.1</font>&#160;&#160;&#160;&#160; <font style="font-weight: bold;"><u>U.S. Rights</u></font>. In partial consideration for the rights and licenses granted to AstraZeneca
              hereunder with respect to the U.S., and subject to the terms and conditions of this Agreement, within 30 days after receipt of an invoice from Akcea, which invoice may be issued on or after the Closing Date but not earlier than December 10,
              2021, AstraZeneca will pay Akcea a one-time upfront fee of $100,000,000.<br>
              <br>
            </div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;">11.1.2</font>&#160;&#160;&#160;&#160; <font style="font-weight: bold;"><u>ROW Rights</u></font>. In partial consideration for the rights and licenses granted to AstraZeneca
              hereunder with respect to the ROW Territory, and subject to the terms and conditions of this Agreement, within 30 days after receipt of an invoice from Akcea, which invoice may be issued on or after the Closing Date but not earlier than
              December 10, 2021, AstraZeneca will pay Akcea a one-time upfront fee of $100,000,000.</div>
            <div style="text-align: justify; text-indent: 72pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold;">11.2</font>&#160;&#160;&#160;&#160;&#160;&#160; <font style="font-weight: bold;"><u>Development and Regulatory Milestone Payments</u></font>. In further consideration for the rights and
              licenses granted to AstraZeneca hereunder, and subject to the terms and conditions of this Agreement (including <u>Section</u><u> 11.6.2(d)</u><u>)</u>, in accordance with <u>Section 11.4</u>, AstraZeneca will pay Akcea the one-time
              milestone payments set forth in <font style="font-variant: small-caps;"><u>Table 1</u></font> below when a Development or regulatory milestone event listed in <font style="font-variant: small-caps;"><u>Table 1</u></font> is first achieved
              by or on behalf of AstraZeneca or its Affiliates or its or their Sublicensees after the Closing Date during the Term for a Licensed Product:</div>
            <div style="text-align: justify;"> <br>
            </div>
            <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
              <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">43</font></div>
              <div style="page-break-after: always;" id="DSPFPageBreak">
                <hr noshade="noshade" style="border-width: 0px; clear: both; margin: 4px 0px; width: 100%; height: 2px; color: #000000; background-color: #000000;"></div>
            </div>
            <table cellspacing="0" cellpadding="0" border="0" align="center" id="z2c7548988a9d4c8c8850b92d582b378f" style="border-collapse: collapse; width: 90%; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; text-align: left;">

                <tr>
                  <td style="width: 1%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); border-top: 2px solid rgb(0, 0, 0);" colspan="5" rowspan="1">
                    <div style="color: rgb(0, 0, 0); font-variant: small-caps; font-weight: bold; text-align: center;"><u>Table 1</u></div>
                  </td>
                </tr>
                <tr>
                  <td style="width: 1%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);" colspan="1">&#160;</td>
                  <td style="width: 5%; vertical-align: top; border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
                    <div style="color: rgb(0, 0, 0); font-weight: bold;"><u>No.</u></div>
                  </td>
                  <td style="width: 1%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);" colspan="1">&#160;</td>
                  <td style="width: 68%; vertical-align: top; border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
                    <div style="text-align: center; color: rgb(0, 0, 0); font-weight: bold;"><u>Milestone Event</u></div>
                  </td>
                  <td style="width: 15%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
                    <div style="text-align: center; color: rgb(0, 0, 0); font-weight: bold;"><u>Milestone Payment</u></div>
                  </td>
                </tr>
                <tr>
                  <td style="width: 1%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);" colspan="1">&#160;</td>
                  <td style="width: 5%; vertical-align: top; border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
                    <div style="color: rgb(0, 0, 0);">1.</div>
                  </td>
                  <td style="width: 1%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);" colspan="1">&#160;</td>
                  <td style="width: 68%; vertical-align: top; border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
                    <div>[***]</div>
                  </td>
                  <td style="width: 15%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
                    <div style="text-align: center;"><font style="color: rgb(0, 0, 0);">$</font>[***]<font style="color: #000000;">*</font></div>
                  </td>
                </tr>
                <tr>
                  <td style="width: 1%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);" colspan="1">&#160;</td>
                  <td style="width: 5%; vertical-align: top; border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
                    <div style="color: rgb(0, 0, 0);">2.</div>
                  </td>
                  <td style="width: 1%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);" colspan="1">&#160;</td>
                  <td style="width: 68%; vertical-align: top; border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
                    <div>[***]</div>
                  </td>
                  <td style="width: 15%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
                    <div style="text-align: center;"><font style="color: rgb(0, 0, 0);">$</font>[***]<font style="color: #000000;">*</font></div>
                  </td>
                </tr>
                <tr>
                  <td style="width: 1%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);" colspan="1">&#160;</td>
                  <td style="width: 5%; vertical-align: top; border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
                    <div style="color: rgb(0, 0, 0);">3.</div>
                  </td>
                  <td style="width: 1%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);" colspan="1">&#160;</td>
                  <td style="width: 68%; vertical-align: top; border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
                    <div>[***]</div>
                  </td>
                  <td style="width: 15%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
                    <div style="text-align: center;"><font style="color: rgb(0, 0, 0);">$</font>[***]</div>
                  </td>
                </tr>
                <tr>
                  <td style="width: 1%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);" colspan="1">&#160;</td>
                  <td style="width: 5%; vertical-align: top; border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
                    <div>4.</div>
                  </td>
                  <td style="width: 1%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);" colspan="1">&#160;</td>
                  <td style="width: 68%; vertical-align: top; border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
                    <div>[***]</div>
                  </td>
                  <td style="width: 15%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
                    <div style="text-align: center;">$[***]</div>
                  </td>
                </tr>
                <tr>
                  <td style="width: 1%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);" colspan="1">&#160;</td>
                  <td style="width: 5%; vertical-align: top; border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
                    <div style="color: rgb(0, 0, 0);">5.</div>
                  </td>
                  <td style="width: 1%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);" colspan="1">&#160;</td>
                  <td style="width: 68%; vertical-align: top; border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
                    <div>[***]</div>
                  </td>
                  <td style="width: 15%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
                    <div style="text-align: center;"><font style="color: rgb(0, 0, 0);">$</font>[***]</div>
                  </td>
                </tr>
                <tr>
                  <td style="width: 1%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);" colspan="1">&#160;</td>
                  <td style="width: 5%; vertical-align: top; border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
                    <div style="color: rgb(0, 0, 0);">6.</div>
                  </td>
                  <td style="width: 1%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);" colspan="1">&#160;</td>
                  <td style="width: 68%; vertical-align: top; border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
                    <div>[***]</div>
                  </td>
                  <td style="width: 15%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
                    <div style="text-align: center;"><font style="color: rgb(0, 0, 0);">$</font>[***]</div>
                  </td>
                </tr>
                <tr>
                  <td style="width: 1%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);" colspan="1">&#160;</td>
                  <td style="width: 5%; vertical-align: top; border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
                    <div style="color: rgb(0, 0, 0);">7.</div>
                  </td>
                  <td style="width: 1%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);" colspan="1">&#160;</td>
                  <td style="width: 68%; vertical-align: top; border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
                    <div>[***]</div>
                  </td>
                  <td style="width: 15%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
                    <div style="text-align: center;"><font style="color: rgb(0, 0, 0);">$</font>[***]</div>
                  </td>
                </tr>

            </table>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="color: rgb(0, 0, 0);">*Notwithstanding the foregoing, Milestone Payment No. 1 will be </font>[***]<font style="color: #000000;"> and Milestone Payment No. 2 will be </font>[***]<font style="color: #000000;">; </font><font style="font-style: italic; color: #000000;">provided</font><font style="color: #000000;"> that for purposes of determining if Milestone Event No. 2 is &#8220;achieved&#8221; </font>[***]<font style="color: #000000;">. For example, if </font>[***]<font style="color: #000000;"> then AstraZeneca will provide Akcea with written notice of such milestone achievement within </font>[***]<font style="color: #000000;"> and AstraZeneca will pay Akcea
                $</font>[***]<font style="color: #000000;"> within </font>[***]<font style="color: #000000;"> after receipt of such invoice.</font></div>
            <div style="text-align: justify;"><font style="color: #000000;"> <br>
              </font></div>
            <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold;">11.3</font>&#160;&#160;&#160;&#160;&#160;&#160; <font style="font-weight: bold;"><u>Sales Milestone Payments</u></font>. In further consideration for the rights and licenses granted to
              AstraZeneca hereunder, and subject to the terms and conditions of this Agreement, AstraZeneca will pay Akcea the one-time sales milestone payments set forth in <font style="font-variant: small-caps;"><u>Table 2</u></font> below, in
              accordance with <u>Section 11.4</u>, when a sales milestone event listed in <font style="font-variant: small-caps;"><u>Table 2</u></font> is first achieved by or on behalf of AstraZeneca or its Affiliates or its or their Sublicensees after
              the Closing Date during the Term for the Licensed Products in a given Calendar Year:</div>
            <div style="text-align: justify; text-indent: 36pt;"> <br>
            </div>
            <table cellspacing="0" cellpadding="0" border="0" align="center" id="z2fcdd9cba0584eb7a369032d08b4e503" style="border-collapse: collapse; width: 90%; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; text-align: left;">

                <tr>
                  <td style="vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); border-top: 2px solid rgb(0, 0, 0); width: 1%;" colspan="1">&#160;</td>
                  <td style="vertical-align: top; border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); border-top: 2px solid rgb(0, 0, 0);" colspan="2">
                    <div style="text-align: center; color: rgb(0, 0, 0); font-variant: small-caps; font-weight: bold;"><u>Table 2</u></div>
                  </td>
                </tr>
                <tr>
                  <td style="width: 1%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);" colspan="1">&#160;</td>
                  <td style="width: 74%; vertical-align: top; border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
                    <div style="text-align: center; color: rgb(0, 0, 0); font-weight: bold;"><u>Sales Milestone Event</u></div>
                  </td>
                  <td style="width: 15%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
                    <div style="text-align: center; color: rgb(0, 0, 0); font-weight: bold;"><u>Sales Milestone Payment</u></div>
                  </td>
                </tr>
                <tr>
                  <td style="width: 1%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);" colspan="1">&#160;</td>
                  <td style="width: 74%; vertical-align: top; border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
                    <div>Net Sales of all Licensed Products in the Territory in a Calendar Year are greater than $[***].</div>
                  </td>
                  <td style="width: 15%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
                    <div style="text-align: center;"><font style="color: rgb(0, 0, 0);">$</font>[***]</div>
                  </td>
                </tr>
                <tr>
                  <td style="width: 1%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);" colspan="1">&#160;</td>
                  <td style="width: 74%; vertical-align: top; border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
                    <div>Net Sales of all Licensed Products in the Territory in a Calendar Year are greater than $[***].</div>
                  </td>
                  <td style="width: 15%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
                    <div style="text-align: center;"><font style="color: rgb(0, 0, 0);">$</font>[***]</div>
                  </td>
                </tr>
                <tr>
                  <td style="width: 1%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);" colspan="1">&#160;</td>
                  <td style="width: 74%; vertical-align: top; border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
                    <div>Net Sales of all Licensed Products in the Territory in a Calendar Year are greater than $[***].</div>
                  </td>
                  <td style="width: 15%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
                    <div style="text-align: center;"><font style="color: rgb(0, 0, 0);">$</font>[***]</div>
                  </td>
                </tr>
                <tr>
                  <td style="width: 1%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);" colspan="1">&#160;</td>
                  <td style="width: 74%; vertical-align: top; border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
                    <div>Net Sales of all Licensed Products in the Territory in a Calendar Year are greater than $[***].</div>
                  </td>
                  <td style="width: 15%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
                    <div style="text-align: center;"><font style="color: rgb(0, 0, 0);">$</font>[***]</div>
                  </td>
                </tr>
                <tr>
                  <td style="width: 1%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);" colspan="1">&#160;</td>
                  <td style="width: 74%; vertical-align: top; border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
                    <div>Net Sales of all Licensed Products in the Territory in a Calendar Year are greater than $[***].</div>
                  </td>
                  <td style="width: 15%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
                    <div style="text-align: center;"><font style="color: rgb(0, 0, 0);">$</font>[***]</div>
                  </td>
                </tr>
                <tr>
                  <td style="width: 1%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);" colspan="1">&#160;</td>
                  <td style="width: 74%; vertical-align: top; border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
                    <div>Net Sales of all Licensed Products in the Territory in a Calendar Year are greater than $[***].</div>
                  </td>
                  <td style="width: 15%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
                    <div style="text-align: center;"><font style="color: rgb(0, 0, 0);">$</font>[***]</div>
                  </td>
                </tr>
                <tr>
                  <td style="width: 1%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);" colspan="1">&#160;</td>
                  <td style="width: 74%; vertical-align: top; border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
                    <div>Net Sales of all Licensed Products in the Territory in a Calendar Year are greater than $[***].</div>
                  </td>
                  <td style="width: 15%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
                    <div style="text-align: center;"><font style="color: rgb(0, 0, 0);">$</font>[***]</div>
                  </td>
                </tr>
                <tr>
                  <td style="width: 1%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);" colspan="1">&#160;</td>
                  <td style="width: 74%; vertical-align: top; border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
                    <div>Net Sales of all Licensed Products in the Territory in a Calendar Year are greater than $[***].</div>
                  </td>
                  <td style="width: 15%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
                    <div style="text-align: center;"><font style="color: rgb(0, 0, 0);">$</font>[***]</div>
                  </td>
                </tr>
                <tr>
                  <td style="width: 1%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);" colspan="1">&#160;</td>
                  <td style="width: 74%; vertical-align: top; border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
                    <div>Net Sales of all Licensed Products in the Territory in a Calendar Year are greater than $[***].</div>
                  </td>
                  <td style="width: 15%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
                    <div style="text-align: center;"><font style="color: rgb(0, 0, 0);">$</font>[***]</div>
                  </td>
                </tr>
                <tr>
                  <td style="width: 1%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);" colspan="1">&#160;</td>
                  <td style="width: 74%; vertical-align: top; border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
                    <div>Net Sales of all Licensed Products in the Territory in a Calendar Year are greater than $[***].</div>
                  </td>
                  <td style="width: 15%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
                    <div style="text-align: center;"><font style="color: rgb(0, 0, 0);">$</font>[***]</div>
                  </td>
                </tr>

            </table>
            <div><br>
            </div>
            <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
              <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">44</font></div>
              <div style="page-break-after: always;" id="DSPFPageBreak">
                <hr noshade="noshade" style="border-width: 0px; clear: both; margin: 4px 0px; width: 100%; height: 2px; color: #000000; background-color: #000000;"></div>
            </div>
            <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold;">11.4</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160; <font style="font-weight: bold;"><u>Limitations on Milestone Payments; Exceptions; Notice</u></font>.</div>
            <div style="text-align: justify; text-indent: 36pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;">11.4.1</font>&#160;&#160;&#160; Each milestone payment set forth in <font style="font-variant: small-caps;"><u>Table 1</u></font> and <font style="font-variant: small-caps;"><u>Table</u></font><u> 2</u> above will be paid only once upon the first achievement of the milestone event by a Licensed Product, regardless of the number of Licensed Products that achieve such milestone event or how many
              times a single Licensed Product achieves such milestone event, and any subsequent or repeated achievement of the same milestone event, whether by the same Licensed Product or by a Licensed Product different from the first Licensed Product
              used in the same milestone event, shall not result in any additional payment obligation by AstraZeneca under <u>Section </u><u>11.2</u>&#160;or <u>Section</u><u> 11.3</u>, as applicable.</div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;"> <br>
              </font></div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;">11.4.2</font>&#160;&#160;&#160;&#160; The sales of Licensed Products arising from named patient, compassionate use, or other similar programs will not be considered for purposes
              of determining whether a milestone event listed in <font style="font-variant: small-caps;"><u>Table</u></font><u> 1</u> or <font style="font-variant: small-caps;"><u>Table</u></font><u> 2</u> has been achieved.</div>
            <div style="text-align: justify; text-indent: 72pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;">11.4.3</font>&#160;&#160;&#160; If multiple milestone events are achieved simultaneously by the same occurrence, then the milestone payments for all such milestone events
              will be due simultaneously. If multiple sales milestone events are achieved in the same Calendar Year, then the milestone payments for all such milestone events will be due for such Calendar Year.</div>
            <div style="text-align: justify; text-indent: 72pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;">11.4.4</font>&#160;&#160;&#160;&#160; Each time a milestone event is achieved under this <u>Article 11</u>, AstraZeneca will send Akcea written notice thereof (except with
              respect to milestone event #7 set forth in <font style="font-variant: small-caps;"><u>Table 1,</u></font> in which case [***]) (a) with respect to Development and regulatory milestone events set forth in <font style="font-variant: small-caps;"><u>Table 1</u></font>, within [***] following the date of achievement of such milestone event and (b) with respect to sales milestone events set forth in <font style="font-variant: small-caps;"><u>Table 2</u>,</font> within
              [***] following the end of the month in which such sales-based milestone events occur, and in each case ((a) and (b)), the applicable milestone payment will be due within [***] after receipt by AstraZeneca of an invoice from Akcea (except
              with respect to milestone event #7 set forth in <font style="font-variant: small-caps;"><u>Table 1</u></font>, which will be due within [***] of [***]).</div>
            <div style="text-align: justify; text-indent: 72pt;"> <br>
            </div>
            <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
              <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">45</font></div>
              <div style="page-break-after: always;" id="DSPFPageBreak">
                <hr noshade="noshade" style="border-width: 0px; clear: both; margin: 4px 0px; width: 100%; height: 2px; color: #000000; background-color: #000000;"></div>
            </div>
            <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold;">11.5</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160; <font style="font-weight: bold;"><u>U.S. Royalties</u></font>.</div>
            <div style="text-align: justify; text-indent: 36pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;">11.5.1</font>&#160;&#160;&#160;&#160; <font style="font-weight: bold;"><u>US. Royalty Rates</u></font>. In further consideration of the licenses and other rights granted to
              AstraZeneca, subject to the terms and conditions of this Agreement, including <u>Section 3.6.2</u> and <u>Section </u><u>11.5.2</u>, on a Calendar Quarter-by-Calendar Quarter basis, AstraZeneca will pay to Akcea royalties at the U.S.
              Royalty Rates (set forth in <font style="font-variant: small-caps;"><u>Table 3</u></font> below) (&#8220;<font style="font-weight: bold; font-style: italic;">U.S. Royalty Rates</font>&#8221;) on the aggregate Net Sales resulting from the sale of
              Licensed Products in the U.S. during each Calendar Quarter (collectively, &#8220;<font style="font-weight: bold; font-style: italic;">U.S. Royalties</font>&#8221;), which U.S. Royalty Rate for a given Calendar Year will be determined [***] as follows:</div>
            <div style="text-align: justify; text-indent: 72pt;"> <br>
            </div>
            <table cellspacing="0" cellpadding="0" border="0" align="center" id="zaa01d8f7a4ad4e21b6a19dada980fd93" style="border-collapse: collapse; width: 90%; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; text-align: left;">

                <tr>
                  <td style="vertical-align: top; border-top: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); border-left: 2px solid rgb(0, 0, 0); width: 1%;" colspan="1">&#160;</td>
                  <td style="vertical-align: top; border-top: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);" colspan="2">
                    <div style="text-align: center; color: rgb(0, 0, 0); font-variant: small-caps; font-weight: bold;"><u>Table 3</u></div>
                  </td>
                </tr>
                <tr>
                  <td style="width: 1%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);" colspan="1">&#160;</td>
                  <td style="width: 44%; vertical-align: top; border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
                    <div style="text-align: center;">[***]</div>
                  </td>
                  <td style="width: 45%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
                    <div style="text-align: center; color: rgb(0, 0, 0); font-weight: bold;"><u>U.S. Royalty Rate</u></div>
                  </td>
                </tr>
                <tr>
                  <td style="width: 1%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);" colspan="1">&#160;</td>
                  <td style="width: 44%; vertical-align: top; border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
                    <div>[***]</div>
                  </td>
                  <td style="width: 45%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
                    <div style="text-align: center;">[***]%</div>
                  </td>
                </tr>
                <tr>
                  <td style="width: 1%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);" colspan="1">&#160;</td>
                  <td style="width: 44%; vertical-align: top; border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
                    <div>[***]</div>
                  </td>
                  <td style="width: 45%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
                    <div style="text-align: center;">[***]%</div>
                  </td>
                </tr>
                <tr>
                  <td style="width: 1%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);" colspan="1">&#160;</td>
                  <td style="width: 44%; vertical-align: top; border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
                    <div>[***]</div>
                  </td>
                  <td style="width: 45%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
                    <div style="text-align: center;">[***]%</div>
                  </td>
                </tr>
                <tr>
                  <td style="width: 1%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);" colspan="1">&#160;</td>
                  <td style="width: 44%; vertical-align: top; border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
                    <div>[***]</div>
                  </td>
                  <td style="width: 45%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
                    <div style="text-align: center;">[***]<font style="color: rgb(0, 0, 0);">%</font></div>
                  </td>
                </tr>
                <tr>
                  <td style="width: 1%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);" colspan="1">&#160;</td>
                  <td style="width: 44%; vertical-align: top; border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
                    <div>[***]</div>
                  </td>
                  <td style="width: 45%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
                    <div style="text-align: center;">[***]<font style="color: rgb(0, 0, 0);">%</font></div>
                  </td>
                </tr>
                <tr>
                  <td style="width: 1%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);" colspan="1">&#160;</td>
                  <td style="width: 44%; vertical-align: top; border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
                    <div>[***]</div>
                  </td>
                  <td style="width: 45%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
                    <div style="text-align: center;">[***]<font style="color: rgb(0, 0, 0);">%</font></div>
                  </td>
                </tr>
                <tr>
                  <td style="width: 1%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);" colspan="1">&#160;</td>
                  <td style="width: 44%; vertical-align: top; border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
                    <div>[***]</div>
                  </td>
                  <td style="width: 45%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
                    <div style="text-align: center;">[***]<font style="color: rgb(0, 0, 0);">%</font></div>
                  </td>
                </tr>
                <tr>
                  <td style="width: 1%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);" colspan="1">&#160;</td>
                  <td style="width: 44%; vertical-align: top; border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
                    <div>[***]</div>
                  </td>
                  <td style="width: 45%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
                    <div style="text-align: center;">[***]<font style="color: rgb(0, 0, 0);">%</font></div>
                  </td>
                </tr>
                <tr>
                  <td style="width: 1%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);" colspan="1">&#160;</td>
                  <td style="width: 44%; vertical-align: top; border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
                    <div>[***]</div>
                  </td>
                  <td style="width: 45%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
                    <div style="text-align: center;">[***]<font style="color: rgb(0, 0, 0);">%</font></div>
                  </td>
                </tr>
                <tr>
                  <td style="width: 1%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);" colspan="1">&#160;</td>
                  <td style="width: 44%; vertical-align: top; border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
                    <div>[***]</div>
                  </td>
                  <td style="width: 45%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
                    <div style="text-align: center;">[***]<font style="color: rgb(0, 0, 0);">%</font></div>
                  </td>
                </tr>
                <tr>
                  <td style="width: 1%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);" colspan="1">&#160;</td>
                  <td style="width: 44%; vertical-align: top; border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
                    <div>[***]</div>
                  </td>
                  <td style="width: 45%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
                    <div style="text-align: center;">[***]</div>
                  </td>
                </tr>

            </table>
            <div><br>
            </div>
            <div style="text-align: justify;">For clarity, the U.S. Royalty Rate will be determined [***]. On a Calendar Year-by-Calendar Year basis no later than [***] prior to the start of each Calendar Year, AstraZeneca will [***]. No royalties are due
              on Net Sales of Licensed Products arising from named patient, compassionate use and other programs providing for the delivery of Licensed Product at no cost.</div>
            <div><br>
            </div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;">11.5.2</font>&#160;&#160;&#160; [***]. Within [***] after the end of each Calendar Year, AstraZeneca shall (a) [***], (b) [***], and (c) [***]. If the [***] for a Calendar
              Year is [***]. If the [***] for a Calendar Year is [***]. In addition, within [***] after the end of each Calendar Year, AstraZeneca will provide Akcea with a good faith, non-binding estimate of the [***].</div>
            <div style="text-align: justify; text-indent: 72pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;">11.5.3</font>&#160;&#160;&#160; <font style="font-weight: bold;"><u>U.S. Royalty Reports; Payment of U.S. Royalties</u></font>. Following the First Commercial Sale of any
              Licensed Product in the U.S., unless and until the Opt-Out Date occurs (and for the Calendar Quarter in which the Opt-Out Date occurs), AstraZeneca will furnish to Akcea a detailed written report within [***] after the end of each Calendar
              Quarter during a Calendar Year showing, on a Licensed Product-by-Licensed Product basis, the Net Sales of each Licensed Product in the U.S. and the U.S. Royalties payable under this Agreement with respect to such Calendar Quarter. After
              receipt of such written report, Akcea will submit an invoice to AstraZeneca with respect to the U.S. Royalties payable under this Agreement with respect to such Calendar Quarter. Such U.S. Royalties will be due and payable within [***] after
              AstraZeneca&#8217;s receipt of such invoice. In addition, beginning with the Calendar Quarter in which the First Commercial Sale for the Licensed Product is made in the U.S. and for each Calendar Quarter thereafter, within [***] following the end
              of each such Calendar Quarter, AstraZeneca will provide Akcea a preliminary, non-binding written report estimating the total Net Sales of, and U.S. Royalties payable to Akcea for, Licensed Products projected for such Calendar Quarter.
              Additionally, within [***] after the end of each Calendar Year after the First Commercial Sale of a Licensed Product in the U.S., AstraZeneca shall provide to Akcea a non-binding [***] sales forecast by Calendar Quarter, solely for Akcea&#8217;s
              planning purposes.</div>
            <div style="text-align: justify; text-indent: 72pt;"> <br>
            </div>
            <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
              <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">46</font></div>
              <div style="page-break-after: always;" id="DSPFPageBreak">
                <hr noshade="noshade" style="border-width: 0px; clear: both; margin: 4px 0px; width: 100%; height: 2px; color: #000000; background-color: #000000;"></div>
            </div>
            <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold;">11.6</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160; <font style="font-weight: bold;"><u>ROW Royalties</u></font>.</div>
            <div style="text-align: justify; text-indent: 36pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;">11.6.1</font>&#160;&#160;&#160; <font style="font-weight: bold;"><u>ROW Royalty Rates</u></font>. In further consideration of the licenses and other rights granted to
              AstraZeneca, during the Royalty Term, subject to the terms and conditions of this Agreement (including this <u>Article 11</u>), AstraZeneca will pay to Akcea royalties at the ROW Territory royalty rates (set forth in <font style="font-variant: small-caps;"><u>Table 4</u></font> below) (&#8220;<font style="font-weight: bold; font-style: italic;">ROW Royalty Rates</font>&#8221;) on the aggregate Net Sales resulting from the sale of each Licensed Product (a) in the ROW
              Territory and (b) [***] ((a) and (b), &#8220;<font style="font-weight: bold; font-style: italic;">ROW Net Sales</font>&#8221;), in each case ((a) and (b)), during each Calendar Year (collectively, &#8220;<font style="font-weight: bold; font-style: italic;">ROW</font><font style="font-style: italic;">&#160;</font><font style="font-weight: bold; font-style: italic;">Royalties</font>&#8221;):</div>
            <div style="text-align: justify; text-indent: 72pt;"> <br>
            </div>
            <table cellspacing="0" cellpadding="0" border="0" align="center" id="zab67914c60ab47b38b506e7027fb4c64" style="border-collapse: collapse; width: 80%; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; text-align: left;">

                <tr>
                  <td style="vertical-align: bottom; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0);" rowspan="1" colspan="4">
                    <div style="text-align: center; font-variant: small-caps; font-weight: bold;"><u>Table 4</u></div>
                  </td>
                </tr>
                <tr>
                  <td style="width: 10%; vertical-align: bottom; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
                    <div style="text-align: center; font-weight: bold;">Royalty</div>
                    <div style="text-align: center; font-weight: bold;">Tier</div>
                  </td>
                  <td style="width: 1%; vertical-align: bottom; border-left: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);" colspan="1">&#160;</td>
                  <td style="width: 54%; vertical-align: bottom; border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
                    <div style="font-weight: bold;">ROW Net Sales of Licensed Products in a Calendar Year</div>
                  </td>
                  <td style="width: 15%; vertical-align: bottom; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
                    <div style="text-align: center; font-weight: bold;">ROW</div>
                    <div style="text-align: center; font-weight: bold;">Royalty</div>
                    <div style="text-align: center; font-weight: bold;">Rate</div>
                  </td>
                </tr>
                <tr>
                  <td style="width: 10%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
                    <div style="text-align: center;">1.</div>
                  </td>
                  <td style="width: 1%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);" colspan="1">&#160;</td>
                  <td style="width: 54%; vertical-align: top; border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
                    <div>For the portion of ROW Net Sales of a Licensed Product in a Calendar Year less than $[***]</div>
                  </td>
                  <td style="width: 15%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
                    <div style="text-align: center;">[***]%</div>
                  </td>
                </tr>
                <tr>
                  <td style="width: 10%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
                    <div style="text-align: center;">2.</div>
                  </td>
                  <td style="width: 1%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);" colspan="1">&#160;</td>
                  <td style="width: 54%; vertical-align: top; border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
                    <div>For the portion of ROW Net Sales of a Licensed Product in a Calendar Year greater than or equal to $[***] but less than $[***]</div>
                  </td>
                  <td style="width: 15%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
                    <div style="text-align: center;">[***]%</div>
                  </td>
                </tr>
                <tr>
                  <td style="width: 10%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
                    <div style="text-align: center;">3.</div>
                  </td>
                  <td style="width: 1%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);" colspan="1">&#160;</td>
                  <td style="width: 54%; vertical-align: top; border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
                    <div>For the portion of ROW Net Sales of a Licensed Product in a Calendar Year greater than or equal to $[***] but less than $[***]</div>
                  </td>
                  <td style="width: 15%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
                    <div style="text-align: center;">[***]%</div>
                  </td>
                </tr>
                <tr>
                  <td style="width: 10%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
                    <div style="text-align: center;">4.</div>
                  </td>
                  <td style="width: 1%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);" colspan="1">&#160;</td>
                  <td style="width: 54%; vertical-align: top; border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
                    <div>For the portion of ROW Net Sales of a Licensed Product in a Calendar Year greater than or equal to $[***] but less than $[***]</div>
                  </td>
                  <td style="width: 15%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
                    <div style="text-align: center;">[***]%</div>
                  </td>
                </tr>
                <tr>
                  <td style="width: 10%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
                    <div style="text-align: center;">5.</div>
                  </td>
                  <td style="width: 1%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);" colspan="1">&#160;</td>
                  <td style="width: 54%; vertical-align: top; border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
                    <div>For the portion of ROW Net Sales of a Licensed Product in a Calendar Year greater than or equal to $[***]</div>
                  </td>
                  <td style="width: 15%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
                    <div style="text-align: center;">[***]%</div>
                  </td>
                </tr>

            </table>
            <div><br>
            </div>
            <div style="text-align: justify; text-indent: 36pt;">ROW Net Sales in a Calendar Year will be calculated by [***] during the Royalty Term. Each ROW Royalty Rate set forth in <font style="font-variant: small-caps;"><u>Table 4</u></font> above
              shall apply only to that portion of the Net Sales of all Licensed Products in the ROW Territory during a given Calendar Year that falls within the indicated royalty tier. No ROW Royalties are due on Net Sales of Licensed Products arising from
              named patient, compassionate use and other programs providing for the delivery of Licensed Product at no cost. The sales of Licensed Products arising from named patient, compassionate use, or other similar programs will not be considered a
              First Commercial Sale for purposes of calculating the Royalty Term. ROW Royalties will be payable on a Licensed Product-by-Licensed Product and country-by-country basis during the Royalty Term for such Licensed Product in such country until
              the expiration of the Royalty Term for such Licensed Product in such country. [***]. AstraZeneca will provide reports and payments to Akcea consistent with <u>Section 11.7</u>.</div>
            <div style="text-align: justify; text-indent: 36pt;"> <br>
            </div>
            <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
              <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">47</font></div>
              <div style="page-break-after: always;" id="DSPFPageBreak">
                <hr noshade="noshade" style="border-width: 0px; clear: both; margin: 4px 0px; width: 100%; height: 2px; color: #000000; background-color: #000000;"></div>
            </div>
            <div style="text-align: justify; text-indent: 36pt;">Notwithstanding any provision to the contrary set forth in this Agreement, all references to the ROW Territory in this <u>Section 11.6</u>, <u>Section 11.7</u>, <u>Section 11.8</u> and <u>Section

                11.9</u> [***].</div>
            <div style="text-align: justify; text-indent: 36pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;">11.6.2</font>&#160;&#160;&#160;&#160; <font style="font-weight: bold;"><u>Opt-Out Scenario One Royalty and ROW Royalty Deductions</u></font>.</div>
            <div style="text-align: justify; text-indent: 72pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 108pt;">(a)&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160; <font style="font-weight: bold;">Expiration of Valid Claims and Exclusivity</font>. If on a country-by-country and Licensed Product-by-Licensed Product basis, (i) the last Valid
              Claim of the Akcea Patent Rights or Joint Patent Rights Covering [***] such Licensed Product in such country has expired, (ii) the last Valid Claim of the Akcea Patent Rights or Joint Patent Rights listed in the Orange Book and Covering such
              Licensed Product in such country has expired or a Generic Product is being sold in such country, and (iii) the Regulatory Exclusivity Period in such country with respect to such Licensed Product has expired or a Generic Product is being sold
              in such country, then the Opt-Out Scenario One Royalty Rates or the ROW Royalty Rates, as applicable, used to calculate the Opt-Out Scenario One Royalties or the ROW Royalties, as applicable, with respect to such Licensed Product in such
              country shall by reduced to [***]% of the Opt-Out Scenario One Royalty Rates agreed to by the Parties or the ROW Royalty Rates set forth in <font style="font-variant: small-caps;"><u>Table</u></font><u> 4</u>, as applicable.</div>
            <div style="text-align: justify; text-indent: 108pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 108pt;">(b)&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160; <font style="font-weight: bold;">Opt-Out Scenario One Royalties and ROW Royalties After Generic Intrusion</font>. If, on a country-by-country and Licensed Product-by-Licensed
              Product basis, at any time during the Royalty Term, Generic Intrusion occurs in a given country with respect to a Licensed Product (including in the U.S. if Akcea exercised the Opt-Out Right), then the Opt-Out Scenario One Royalty Rates or
              the ROW Royalty Rates, as applicable, used to calculate Opt-Out Scenario One Royalties or the ROW Royalties, as applicable, for such Licensed Product in such country shall be reduced to [***]% of the Opt-Out Scenario One Royalty Rates agreed
              to by the Parties or the ROW Royalty Rates set forth in <font style="font-variant: small-caps;"><u>Table</u></font><u> 4</u>, as applicable.</div>
            <div style="text-align: justify; text-indent: 108pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 108pt;">(c)&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160; <font style="font-weight: bold;">Compulsory Licenses</font>. If a Governmental Authority requires AstraZeneca or any of its Affiliates or its or their Sublicensees to grant a
              compulsory license to a Third Party (each, a &#8220;<font style="font-weight: bold; font-style: italic;">Compulsory Sublicensee</font>&#8221;) permitting such Third Party to make and sell a Licensed Product in a country, (i) such Compulsory Sublicensee
              will not be considered a Sublicensee for the purpose of this Agreement, and (ii) such grant will be permitted and deemed consented to by Akcea under <u>Section 8.3</u>. At such time as AstraZeneca or any of its Affiliates or its or their
              Sublicensees enters into a sublicense with a Compulsory Sublicensee, in lieu of the Opt-Out Scenario One Royalty Rates agreed to by the Parties or the ROW Royalty Rates set forth in <font style="font-variant: small-caps;"><u>Table</u></font><u>
                4</u>, as applicable, the Parties will discuss, and mutually agree upon, the sharing between Akcea and AstraZeneca of the consideration received by AstraZeneca under such compulsory license, [***]; <font style="font-style: italic;">provided

              </font>that no such sharing will occur until [***].</div>
            <div style="text-align: justify; text-indent: 108pt;"> <br>
            </div>
            <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
              <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">48</font></div>
              <div style="page-break-after: always;" id="DSPFPageBreak">
                <hr noshade="noshade" style="border-width: 0px; clear: both; margin: 4px 0px; width: 100%; height: 2px; color: #000000; background-color: #000000;"></div>
            </div>
            <div style="text-align: justify; text-indent: 108pt;">(d)&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160; <font style="font-weight: bold;">Stacking</font>. AstraZeneca shall be entitled to credit against the ROW Royalties due to Akcea under <u>Section</u><u> 11.6</u>&#160;and sales
              milestone payments due to Akcea under <u>Section</u><u> 11.3</u>&#160;in a given Calendar Quarter [***]% of (i) [***] due by AstraZeneca, or any of its Affiliates or its or their Sublicensees, to a Third Party (or to Akcea under <u>Section
                5.3.1(b)</u>) for a license or other right with respect to any Patent Right, Know-How or other intellectual property [***] to Exploit a Licensed Compound or Licensed Product, including any AstraZeneca Third Party Product-Specific License,
              and (ii) [***], excluding, in each case ((i) and (ii)), [***] (&#8220;<font style="font-weight: bold; font-style: italic;">Third Party Payments</font>&#8221;), and in each case ((i) and (ii)), [***]; <font style="font-style: italic;">provided</font>
              that with respect to any Third Party Payments that are attributable to Akcea&#8217;s breach of its representations and warranties hereunder or for judgements related to Additional Core IP, AstraZeneca shall be entitled to deduct [***]% of such
              Third Party Payments, excluding amounts for which Akcea has indemnified AstraZeneca pursuant to <u>Section 15.2</u>. Notwithstanding the foregoing, for purposes of this <u>Section 11.6.2(d)</u>, Third Party Payments will not include, and
              AstraZeneca will not be entitled to credit, any amounts that are shared by the Parties as Other Operating Expenses pursuant to <u>Section 11.8.2(b)</u>.</div>
            <div style="text-align: justify; text-indent: 108pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold;">11.7</font>&#160;&#160;&#160;&#160;&#160;&#160; <font style="font-weight: bold;"><u>Royalty Reports; Payment of Royalties</u></font>. Following the First Commercial Sale of any Licensed
              Product in any country in the ROW Territory or the U.S. if Akcea exercised the Opt-Out Right in accordance with <u>Section 3.6</u>, AstraZeneca will furnish to Akcea a written report within [***] after the end of each Calendar Quarter during
              a Calendar Year showing, on a Licensed Product-by-Licensed Product and country-by-country basis, the Net Sales of each Licensed Product in each country and the ROW Royalties and Opt-Out Scenario One Royalties payable under this Agreement with
              respect to such Calendar Quarter. After receipt of such written report, Akcea will submit an invoice to AstraZeneca with respect to the ROW Royalties and Opt-Out Scenario One Royalties payable under this Agreement with respect to such
              Calendar Quarter. Such ROW Royalties and Opt-Out Scenario One Royalties will be due and payable within [***] after AstraZeneca&#8217;s receipt of such invoice. In addition, beginning with the Calendar Quarter in which the First Commercial Sale for
              the Licensed Product is made in the ROW Territory or the U.S. if Akcea exercised the Opt-Out Right in accordance with <u>Section 3.6</u> and for each Calendar Quarter thereafter, within [***] following the end of each such Calendar Quarter,
              AstraZeneca will provide Akcea a preliminary, non-binding written report estimating the total Net Sales of, and ROW Royalties and Opt-Out Scenario One Royalties payable to Akcea for, Licensed Products projected for such Calendar Quarter.
              Additionally, during the Royalty Term, within [***] of the end of each Calendar Year, AstraZeneca shall provide to Akcea a non-binding [***] sales forecast by Calendar Quarter, solely for Akcea&#8217;s planning purposes.</div>
            <div style="text-align: justify; text-indent: 36pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold;">11.8</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160; <font style="font-weight: bold;"><u>Third Party Licenses</u></font>.</div>
            <div style="text-align: justify; text-indent: 36pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;">11.8.1</font>&#160;&#160;&#160;&#160; <font style="font-weight: bold;"><u>Notice of Third Party IP</u></font>. If a Party identifies any Third Party intellectual property rights
              that such Party or any of its Affiliates or sublicensees deems [***] in order to Exploit a Licensed Compound or Licensed Product in the Territory, then such Party shall promptly provide written notice to the other Party identifying such Third
              Party intellectual property rights.</div>
            <div style="text-align: justify; text-indent: 72pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;">11.8.2</font>&#160;&#160;&#160;&#160; <font style="font-weight: bold;"><u>Product IP</u></font>. AstraZeneca, its Affiliates and its and their Sublicensees shall have the sole
              right to obtain a license to Exploit the Licensed Compounds and Licensed Products under any Third Party intellectual property rights that are [***] to Exploit a Licensed Product or a Licensed Compound, except for any Additional Core IP (each
              such license, an &#8220;<font style="font-weight: bold; font-style: italic;">AstraZeneca Third Party Product-Specific License</font>&#8221;).</div>
            <div style="text-align: justify; text-indent: 72pt;"> <br>
            </div>
            <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
              <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">49</font></div>
              <div style="page-break-after: always;" id="DSPFPageBreak">
                <hr noshade="noshade" style="border-width: 0px; clear: both; margin: 4px 0px; width: 100%; height: 2px; color: #000000; background-color: #000000;"></div>
            </div>
            <div style="text-align: justify; text-indent: 108pt;">(a)&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160; Subject to <u>Section</u><u> 11.6.2(d)</u>&#160;and <u>Section 11.8.2(b)</u>, if AstraZeneca elects to obtain an AstraZeneca Third Party Product-Specific License, AstraZeneca, or
              its applicable Affiliate or Sublicensee, shall pay all amounts due under such AstraZeneca Third Party Product-Specific Licenses.</div>
            <div style="text-align: justify; text-indent: 108pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 108pt;">(b)&#160; &#160; &#160;&#160;&#160;&#160; Unless and until Akcea has exercised the Opt-Out Right in accordance with <u>Section 3.6</u>, AstraZeneca will, prior to entering into any AstraZeneca Third Party
              Product-Specific License with respect to the U.S., provide notice to the JSC of any AstraZeneca Third Party Product-Specific License granting rights to any intellectual property rights that it has determined are [***] to Exploit a Licensed
              Product or a Licensed Compound in the U.S., which notice will include (i) any payment obligations directly related to the potential agreement in the U.S. and (ii) a copy of such proposed AstraZeneca Third Party Product-Specific License. The
              JSC shall review and discuss such proposal. AstraZeneca will [***] any comments provided by Akcea on such potential agreement, but will have the sole right to determine whether to obtain such AstraZeneca Third Party Product-Specific License
              and the terms of such agreement after discussion at the JSC. If AstraZeneca elects to obtain such AstraZeneca Third Party Product-Specific License, then any financial obligations under such AstraZeneca Third Party Product-Specific License
              that are reasonably allocable to the Exploitation of a Licensed Product in the U.S. will [***].</div>
            <div style="text-align: justify; text-indent: 108pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;">11.8.3</font>&#160;&#160;&#160;&#160; <font style="font-weight: bold;"><u>Additional </u><u>Core IP</u></font>.</div>
            <div style="text-align: justify; text-indent: 72pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 108pt;">(a)&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;Akcea and its Affiliates shall have the first right to obtain and shall be responsible for obtaining a license under any Additional Core IP. If Akcea or its Affiliate obtains a
              license under any Additional Core IP, then [***] or its applicable Affiliate shall pay [***] under such license and such license will be considered a Future In-License Agreement.</div>
            <div style="text-align: justify; text-indent: 108pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 108pt;">(b)&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;If Akcea or its Affiliates decline to obtain a license under any Additional Core IP pursuant to <u>Section </u><u>11.8.3(a)</u> within [***] of receiving notice pursuant to <u>Section

                11.8.1</u>, then AstraZeneca shall have the second right to obtain a license under such Third Party intellectual property rights. In such case, if AstraZeneca elects to obtain a license under any such Additional Core IP, then, subject to <u>Section</u><u>
                11.6.2(d)</u><u>,</u> [***] shall pay [***] under such license agreement (except as set forth in <u>Section </u><u>11.8.3(c)</u>).</div>
            <div style="text-align: justify; text-indent: 108pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 108pt;">(c)&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160; If AstraZeneca elects to obtain a license under any Additional Core IP that is [***] to Exploit the Licensed Product or the Licensed Compound in the U.S. and Akcea has not
              exercised the Opt-Out Right in accordance with <u>Section 3.6</u>, then any financial obligations under such license that are reasonably allocable to the Exploitation of the Licensed Product in the U.S. will [***].</div>
            <div style="text-align: justify; text-indent: 108pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;">11.8.4</font>&#160;&#160;&#160;&#160; <font style="font-weight: bold;"><u>Future In-License Agreements</u></font>. Akcea shall, and shall cause its Affiliates to, ensure that
              all Future In-License Agreements are consistent with the terms and conditions of this Agreement in all material respects and [***], except to the extent that (a) [***] or (b) [***]. Akcea or its applicable Affiliate shall pay [***] under any
              Future In-License Agreement.</div>
            <div style="text-align: justify; text-indent: 72pt;"> <br>
            </div>
            <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
              <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">50</font></div>
              <div style="page-break-after: always;" id="DSPFPageBreak">
                <hr noshade="noshade" style="border-width: 0px; clear: both; margin: 4px 0px; width: 100%; height: 2px; color: #000000; background-color: #000000;"></div>
            </div>
            <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold;">11.9</font>&#160;&#160;&#160;&#160;&#160;&#160; <font style="font-weight: bold;"><u>Minimum Payments</u></font>. During the Royalty Term, in no event will the aggregate royalty reductions
              under <u>Section 11.6.2</u> collectively reduce the Opt-Out Scenario One Royalties or the ROW Royalties payable to Akcea on Net Sales of a Licensed Product in any given Calendar Quarter to an amount that is less than [***]% of the amount of
              Opt-Out Scenario One Royalties or the ROW Royalties, respectively, that would otherwise be due under this Agreement. Notwithstanding the foregoing[***].</div>
            <div style="text-align: justify; text-indent: 36pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold;">11.10</font>&#160;&#160;&#160;&#160;&#160; <font style="font-weight: bold;"><u>Other Operating Expenses</u>.</font></div>
            <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold;"> <br>
              </font></div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;">11.10.1</font>&#160; <font style="font-weight: bold;"><u>Share Ratios</u></font>. The Parties will share the Other Operating Expenses incurred with respect to
              Exploitation of the Licensed Products for the U.S. prior to the Opt-Out Date as follows: Akcea will bear [***]% and AstraZeneca will bear [***]% of all Other Operating Expenses incurred.</div>
            <div style="text-align: justify; text-indent: 72pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;">11.10.2</font>&#160; <font style="font-weight: bold;"><u>Shared Other Operating Expenses Payment Reconciliation</u></font>. Unless and until the Opt-Out Date
              occurs (and for the Calendar Quarter in which the Opt-Out Date occurs), the following shall apply: No later than [***] after the end of each Calendar Quarter, each Party will deliver to the other Party a written report that sets forth in
              detail the actual Other Operating Expenses incurred by or on behalf of such Party during such Calendar Quarter (such report of actual expenses, the &#8220;<font style="font-weight: bold; font-style: italic;">Other Operating Expenses Cost Share
                Notice</font>&#8221;). Each Party will provide the other Party with supporting documentation of such Other Operating Expenses if reasonably requested by the other Party. For each such Calendar Quarter, no later than [***] after receipt of the
              Other Operating Expenses Cost Share Notice for such Calendar Quarter from each Party, the Party that incurred less than its allocation of Other Operating Expenses during such Calendar Quarter will make a balancing payment to the other Party
              to effect the cost-sharing ratios set forth in <u>Section 11.10.1</u>, to the extent the amounts set forth in the Other Operating Expenses Cost Share Notices are undisputed. Any dispute regarding amounts set forth in an Other Operating
              Expenses Cost Share Notice will be promptly referred to the JSC for resolution, and if the JSC determines that any disputed amount should be included in the applicable Other Operating Expenses Cost Share Notice, the Party that incurred less
              than its allocation of Other Operating Expenses during such Calendar Quarter (taking into account any balancing payments previously made for such Calendar Quarter pursuant to the immediately preceding sentence) will make a balancing payment
              to the other Party to effect the cost-sharing ratios set forth in <u>Section </u><u>11.10.1</u>&#160;within [***] of the JSC determination.</div>
            <div style="text-align: justify; text-indent: 72pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold;">11.11</font>&#160;&#160;&#160;&#160;&#160; <font style="font-weight: bold;"><u>Accounting</u></font>.</div>
            <div style="text-align: justify; text-indent: 36pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;">11.11.1</font>&#160;&#160; <font style="font-weight: bold;"><u>General Principles Regarding Eligible Expenses</u></font>.</div>
            <div style="text-align: justify; text-indent: 72pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 108pt;">(a)&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160; <font style="font-weight: bold;">Consistency with Accounting Treatment</font>. The Parties acknowledge and agree that expenses will not be reflected in Eligible Expenses unless
              and until such expenses are recognized by such Party in its statements of profit and loss which are included in its financial statements in accordance with its Accounting Standards, except as expressly provided in the definition of Eligible
              Expenses.</div>
            <div style="text-align: justify; text-indent: 108pt;"> <br>
            </div>
            <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
              <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">51</font></div>
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            </div>
            <div style="text-align: justify; text-indent: 108pt;">(b)&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;<font style="font-weight: bold;">General Allocation Principles</font>.</div>
            <div style="text-align: justify; text-indent: 108pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 144pt;">(i)&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160; The allocation method for all Eligible Expenses that are not solely related to the Licensed Product as part of the Development Plan and Budget, U.S. Commercialization Plan and
              Budget, and U.S. Medical Affairs Plan and Budget will be applied in accordance with the incurring Party&#8217;s Accounting Standards, consistently applied across its products.</div>
            <div style="text-align: justify; text-indent: 144pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 144pt;">(ii)&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160; Included FTE Costs and Expenses will only be included in Eligible Expenses through FTE Costs and will not be separately charged.</div>
            <div style="text-align: justify; text-indent: 144pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 144pt;">(iii)&#160;&#160;&#160;&#160;&#160;&#160;&#160; Out-of-Pocket Costs will exclude general and administrative expenses including individuals who perform general and administrative activities within Development,
              Commercialization and Medical Affairs activities, except as expressly provided in the definition of Eligible Expenses.</div>
            <div style="text-align: justify; text-indent: 144pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 144pt;">(iv)&#160;&#160;&#160;&#160;&#160;&#160;&#160; Out-of-Pocket Costs that are associated with the Licensed Product will be directly charged as Eligible Expenses without any markup or overhead added.</div>
            <div style="text-align: justify; text-indent: 144pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;">11.11.2</font>&#160;&#160; <font style="font-weight: bold;"><u>Records</u></font>. Each Party agrees to keep, and to require its Affiliates and, with respect to
              AstraZeneca, use Commercially Reasonable Efforts to cause its Sublicensees, to keep, complete and accurate records for a minimum period of [***] after the relevant payment is owed pursuant to this Agreement, setting forth Eligible Expenses,
              COGS, Net Sales of the Licensed Products, and other amounts payable to the other Party hereunder in sufficient detail to enable amounts owed or payable to the other Party hereunder to be determined.</div>
            <div style="text-align: justify; text-indent: 72pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;">11.11.3</font>&#160;&#160; <font style="font-weight: bold;"><u>Audits</u></font>.</div>
            <div style="text-align: justify; text-indent: 72pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 108pt;">(a)&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160; Each Party further agrees, that during the Term and for a period of [***] thereafter, upon not less than [***] prior written notice, to permit, and to cause its Affiliates to
              permit, examination of such books and records relating to the Licensed Product by an independent accounting firm of nationally recognized standing selected by the other Party and reasonably acceptable to such audited Party for the purpose of
              verifying the accuracy of the accrual of any milestone payments, the calculation and reporting of Net Sales of the Licensed Products, the correctness of any milestone or royalty payment made under this Agreement and the calculation of
              Eligible Expenses (and cost sharing thereof), for any period within the preceding [***].<font style="font-weight: bold; font-style: italic;">&#160;</font>Such independent accounting firm shall be subject to appropriate confidentiality provisions
              substantially equivalent to those of this Agreement. Such audit will not be performed more frequently than [***] period, and will be conducted during normal business hours, in the location where such books and records are normally kept, and
              otherwise in a manner that minimizes any interference to the audited Party&#8217;s business operations. The independent accounting firm will only share the results of the audit, not the underlying records, with the auditing Party. The auditing
              Party will provide the audited Party with a copy of the results of the audit promptly following the auditing Party&#8217;s receipt thereof.</div>
            <div style="text-align: justify; text-indent: 108pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 108pt;">(b)&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;Such examination is to be made at the expense of the auditing Party, except if the results of the audit reveal an underpayment or overcharge by the audited Party of [***]% or
              more during the period being audited, then the reasonable fees and expenses for such examination will be paid by the audited Party.</div>
            <div style="text-align: justify; text-indent: 108pt;"> <br>
            </div>
            <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
              <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">52</font></div>
              <div style="page-break-after: always;" id="DSPFPageBreak">
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            </div>
            <div style="text-align: justify; text-indent: 108pt;">(c)&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;If any audit establishes that the audited Party underpaid or overcharged any amounts due to or from, as applicable, the auditing Party under this Agreement, then, unless
              disputed pursuant to <u>Section</u><u> 11.11.3(d)</u>, the audited Party shall pay the auditing Party any such deficiency or refund any such overcharged amount within [***] after receipt of a copy of the results of the audit and written
              notice thereof. If any audit establishes that the audited Party overpaid or undercharged any amounts due to or from, as applicable, the auditing Party under this Agreement, then, unless disputed pursuant to <u>Section</u><u> 11.11.3(d)</u>,
              the audited Party may offset all such excess payments or undercharged amounts, against any outstanding or future amounts payable by the audited Party to the auditing Party under this Agreement until the audited Party has received full credit
              for all such excess payments or undercharged amounts; <font style="font-style: italic;">provided</font> that if no outstanding or future amounts are payable by the audited Party to the auditing Party under this Agreement, the auditing Party
              shall pay the audited Party any such excess payment or undercharged amount within [***] after receipt of a copy of the results of the audit and written notice thereof. Interest, as set forth in <u>Section 11.15</u>, will be due on any
              amounts owed pursuant to this <u>Section 11.11.3(c)</u> or <u>Section 11.11.3(d)</u> if [***].</div>
            <div style="text-align: justify; text-indent: 108pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 108pt;">(d)&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;<font style="font-weight: bold;">Audit Dispute</font>. In the event of a dispute with respect to any audit under this <u>Section</u><u> 11.11.3</u>, Akcea and AstraZeneca shall
              work in good faith to resolve the dispute. If the Parties are unable to reach a mutually acceptable resolution of any such dispute within [***], the dispute shall be submitted for resolution to a certified public accounting firm jointly
              selected by each Party&#8217;s certified public accountants or to such other Person as the Parties shall mutually agree (the &#8220;<font style="font-weight: bold; font-style: italic;">Auditor</font>&#8221;). The decision of the Auditor shall be final and the
              costs of such arbitration as well as the initial audit shall be borne between the Parties in such manner as the Auditor shall determine. Not later than [***] after such decision and in accordance with such decision, either (i) the audited
              Party shall pay any underpaid or overcharged amounts (and any interest thereon as set forth in <u>Section 11.15</u> only if required pursuant to the last sentence of <u>Section 11.11.3(c)</u>)&#160;or (ii) the auditing Party shall reimburse any
              excess payment or undercharged amount (and any interest thereon as set forth in <u>Section 11.15</u> only if required pursuant to the last sentence of <u>Section 11.11.3(c)</u>).</div>
            <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold;"> <br>
              </font></div>
            <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold;">11.12</font>&#160;&#160;&#160;&#160; <font style="font-weight: bold;"><u>Methods of Payments</u></font>. All payments due from either Party under this Agreement will be paid in
              Dollars by wire transfer to a U.S. denominated bank account designated in writing by the payee and will be non-creditable (except as otherwise expressly provided in <u>Section 2.4.1(b)(ii)</u>, <u>Section 2.4.1(b)(iii)</u>, <u>Section
                2.5.4,</u>&#160;<u>Section 11.11.3(c)</u>), irrevocable and non-refundable, <font style="font-style: italic;">provided</font> that the foregoing shall not preclude either Party from claiming the amount of any such payment as Losses in
              connection with any right or remedy sought by such Party in the event of an actual or threatened breach of this Agreement.</div>
            <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold;"> <br>
              </font></div>
            <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold;">11.13</font>&#160;&#160;&#160;&#160;&#160; <font style="font-weight: bold;"><u>Taxes</u></font>. The provisions of this <u>Section 11.13</u> are to be read in conjunction with the
              provisions of <u>Section 17.3</u>.</div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;"> <br>
              </font></div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;">11.13.1</font>&#160; <font style="font-weight: bold;"><u>Taxes On Income</u></font>. Each Party alone will be solely responsible for paying any and all taxes
              (other than withholding taxes required by applicable Law to be paid by AstraZeneca or Akcea (as the case may be)) levied on account of, or measured in whole or in part by reference to, the income of such Party.</div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;"> <br>
              </font></div>
            <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
              <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">53</font></div>
              <div style="page-break-after: always;" id="DSPFPageBreak">
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            </div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;">11.13.2</font>&#160;&#160; <font style="font-weight: bold;"><u>Indirect Taxes</u></font>.</div>
            <div style="text-align: justify; text-indent: 108pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 108pt;">(a)&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;All payments are exclusive of Indirect Taxes. If any Indirect Taxes are chargeable in respect of any payments, the paying Party will pay such Indirect Taxes at the applicable
              rate in respect of such payments following receipt, where applicable, of an Indirect Taxes invoice in the appropriate form issued by the receiving Party in respect of those payments.</div>
            <div style="text-align: justify; text-indent: 108pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 108pt;">(b)&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160; The Parties will issue invoices for all amounts payable under this Agreement consistent with Indirect Tax requirements and irrespective of whether the sums may be netted for
              settlement purposes. If such amounts of Indirect Taxes are refunded by the applicable Governmental Authority or other fiscal authority subsequent to payment, the Party receiving such refund will transfer such amount to the paying Party within
              [***] of receipt. The Parties agree to reasonably cooperate to provide any information required by the Party pursuing a refund of Indirect Taxes paid.</div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;"> <br>
              </font></div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;">11.13.3</font>&#160;&#160; <font style="font-weight: bold;"><u>Withholding Tax</u></font>. To the extent the paying Party is required to deduct and withhold taxes on
              any payment, the paying Party will pay the amounts of such taxes to the proper Governmental Authority for the account of the receiving Party and remit the net amount to the receiving Party in a timely manner. The paying Party will promptly
              furnish the receiving Party with proof of payment of such taxes. If documentation is necessary in order to secure an exemption from, or a reduction in, any withholding taxes, the Parties will provide such documentation to the extent they are
              entitled to do so. In accordance with the procedures set forth in <u>Section </u><u>15.4</u>, the receiving Party will also indemnify the paying Party for any tax, interest or penalties imposed on the paying Party if the paying Party
              improperly reduces or eliminates withholding tax based upon representations made by the receiving Party.</div>
            <div style="text-align: justify; text-indent: 72pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;">11.13.4</font>&#160;&#160; <font style="font-weight: bold;"><u>Tax Cooperation</u></font>. At least [***] prior to the date a given payment is due under this
              Agreement, the non-paying Party will provide the paying Party with any and all tax forms that may be reasonably necessary in order for the paying Party to lawfully not withhold tax or to withhold tax at a reduced rate with respect to such
              payment under an applicable bilateral income tax treaty. Following the paying Party&#8217;s timely receipt of such tax forms from the non-paying Party, the paying Party will not withhold tax or will withhold tax at a reduced rate under an
              applicable bilateral income tax treaty, if appropriate under applicable Law. The non-paying Party will provide any such tax forms to the paying Party upon request and in advance of the due date. Each Party will provide the other with
              reasonable assistance to enable the recovery, as permitted by applicable Law, of withholding taxes resulting from payments made under this Agreement, such recovery to be for the benefit of the Party who would have been entitled to receive the
              money but for the application of withholding tax under this <u>Section 11.13</u>.</div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;"> <br>
              </font></div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;">11.13.5</font>&#160;&#160; <font style="font-weight: bold;"><u>Prevention of Facilitation of Tax Evasion</u></font>.</div>
            <div style="text-align: justify; text-indent: 108pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 108pt;">(a)&#160;&#160;&#160;&#160;&#160;&#160;&#160; Each Party represents, warrants and undertakes that neither it nor its Affiliates shall commit a tax evasion facilitation offence under Part 3 of the UK Criminal Finances Act 2017
              in connection with or attributable to this Agreement or the transactions contemplated hereby.</div>
            <div style="text-align: justify; text-indent: 108pt;"> <br>
            </div>
            <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
              <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">54</font></div>
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            </div>
            <div style="text-align: justify; text-indent: 108pt;">(b)&#160;&#160;&#160;&#160;&#160;&#160;&#160; Each Party shall promptly report to the other Party any apparent breach of <u>Section</u><u> 11.13.5(a)</u>&#160;and shall (i) answer, in reasonable detail, any written or oral
              inquiry from the other Party related to its and its Affiliates compliance with <u>Section</u><u> 11.13.5(a)</u>, (ii) facilitate the interview of employees of such Party by the other Party (or any agent of such Party) at any reasonable time
              specified by the inquiring Party related to such Party&#8217;s compliance with <u>Section</u><u> 11.13.5(a)</u>&#160;and (iii) co-operate with the inquiring Party and any Governmental Authority in relation to any investigation relating to the matters
              referred to in <u>Section</u><u> 11.13.5(a)</u>, in all cases, as reasonably required to enable that other Party to comply with its undertaking in <u>Section </u><u>11.13.5(a)</u>.</div>
            <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold;"> <br>
              </font></div>
            <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold;">11.14</font>&#160;&#160;&#160;&#160; <font style="font-weight: bold;"><u>Currency Exchange</u></font>. Notwithstanding anything to the contrary in the Agreement, conversion of
              sales recorded in local currencies to Dollars will be performed using AstraZeneca&#8217;s, its Affiliate&#8217;s or its or their Sublicensee&#8217;s, as applicable, Exchange Rate. &#8220;<font style="font-weight: bold; font-style: italic;">Exchange Rate</font>&#8221;
              means the IFRS-compliant rate as used by AstraZeneca Plc for the purpose of preparing its consolidated financial statements on any date, as may be adjusted from time to time, which, as of the Execution Date, is the rate of exchange as
              published by Reuters as prevailing at 8.00 am (GMT) taken on the 25th day of the month prior to such date, where that day is a Business Day, or if the 25th day of the month is not a Business Day, the first Business Day following the 25th day
              of the month.</div>
            <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold;"> <br>
              </font></div>
            <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold;">11.15</font>&#160;&#160;&#160;&#160;&#160; <font style="font-weight: bold;"><u>Interest</u></font>. If any undisputed payment due to either Party under this Agreement is not paid
              when due, then such paying Party shall pay interest thereon (before and after any judgment) at an annual rate (but with interest accruing on a daily basis) of [***] the U.S. effective federal funds rate, as adjusted each Business Day and
              published by the Federal Reserve Bank of New York through its website (https://apps.newyorkfed.org/markets/autorates/fed%20funds) (or in the event that the U.S. effective federal funds rate is no longer an applicable reference rate, such
              reasonably equivalent alternative as may be selected by AstraZeneca in its reasonable discretion), such interest to run from the date on which payment of such undisputed sum became due until payment thereof in full together with such
              interest. Notwithstanding the previous sentence, the payable interest rate shall never be less than [***].</div>
            <div style="text-align: center; font-weight: bold;"> <br>
            </div>
            <div style="text-align: center; font-weight: bold;">ARTICLE 12</div>
            <div style="text-align: center; font-weight: bold;">INTELLECTUAL PROPERTY</div>
            <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold;"> <br>
              </font></div>
            <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold;">12.1</font>&#160;&#160;&#160;&#160;&#160;&#160; <font style="font-weight: bold;"><u>Ownership of Inventions; Disclosure</u><u>; Cross-License</u></font>.</div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;"> <br>
              </font></div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;">12.1.1</font>&#160;&#160;&#160; <font style="font-weight: bold;"><u>Existing IP</u></font>. Nothing in this Agreement will affect Akcea&#8217;s ownership of the Licensed
              Technology existing as of the Execution Date or AstraZeneca&#8217;s ownership of AstraZeneca IP existing as of the Execution Date, which in each case will remain owned by the Party having such rights.</div>
            <div style="text-align: justify; text-indent: 72pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;">12.1.2</font>&#160;&#160;&#160; <font style="font-weight: bold;"><u>Ownership</u></font>.<br>
              <br>
            </div>
            <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
              <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">55</font></div>
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            </div>
            <div style="text-align: justify; text-indent: 108pt;">(a)&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;<font style="font-weight: bold;">AstraZeneca Program Technology</font>. As between the Parties, AstraZeneca is the sole owner of any Know-How conceived, discovered, invented or
              created solely by or on behalf of AstraZeneca or its Affiliates or its or their Sublicensees under or in connection with this Agreement, any Patent Rights that claim or Cover inventions made solely by or on behalf of AstraZeneca or its
              Affiliates or its or their Sublicensees under or in connection with this Agreement (collectively, the &#8220;<font style="font-weight: bold; font-style: italic;">AstraZeneca Program Technology</font>&#8221;), and any Trademark(s) for the Licensed
              Product, and will own and retain all of its rights, title and interest thereto, subject to any rights or licenses expressly granted by AstraZeneca to Akcea under this Agreement.</div>
            <div style="text-align: justify; text-indent: 108pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 108pt;">(b)&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160; <font style="font-weight: bold;">Akcea Program Technology</font>. As between the Parties, Akcea is the sole owner of any Know-How conceived, discovered, invented or created
              solely by or on behalf of Akcea or its Affiliates under or in connection with this Agreement and any Patent Rights that claim or Cover inventions made solely by or on behalf of Akcea or its Affiliates under or in connection with this
              Agreement (collectively, the &#8220;<font style="font-weight: bold; font-style: italic;">Akcea Program Technology</font>&#8221;), and will own and retain all of its rights, title and interest thereto, subject to any rights or licenses expressly granted
              by Akcea to AstraZeneca under this Agreement.</div>
            <div style="text-align: justify; text-indent: 108pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 108pt;">(c)&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;<font style="font-weight: bold;">Joint Program Technology</font>. As between the Parties, the Parties will jointly own any Know-How conceived, discovered, invented or created
              jointly by or on behalf of both Akcea or its Affiliates, on the one hand, and AstraZeneca or its Affiliates, on the other hand, under or in connection with this Agreement (&#8220;<font style="font-weight: bold; font-style: italic;">Joint Know-How</font>&#8221;)

              and any Patent Rights that claim or Cover inventions made jointly by or on behalf of both Akcea or its Affiliates, on the one hand, and AstraZeneca or its Affiliates, on the other hand, under or in connection with this Agreement (&#8220;<font style="font-weight: bold; font-style: italic;">Joint Patent Rights</font>&#8221;, and collectively with any Joint Know-How, the &#8220;<font style="font-weight: bold; font-style: italic;">Joint Program Technology</font>&#8221;). Subject to the licenses
              granted under this Agreement and the exclusivity obligations set forth in <u>Article 9</u>, each Party will be free to practice and Exploit, either itself or through the grant of licenses to Third Parties (which Third Party licenses may be
              further sublicensed), the Joint Program Technology throughout the world without restriction, without the need to obtain further consent from or provide notice to the other Party, and without any duty to account or otherwise make any payment
              of any compensation to the other Party. Each Party shall promptly disclose to the other Party in writing, and shall cause its Affiliates and its and their licensees and (sub)licensees/Sublicensees to so disclose, the conception, discovery,
              invention or creation of any Joint Know-How or Joint Patent Rights.</div>
            <div style="text-align: justify; text-indent: 108pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 108pt;">(d)&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160; <font style="font-weight: bold;">United States Law</font>. The determination of whether Know-How is conceived, discovered, invented or created by a Party for the purpose of
              allocating proprietary rights (including Patent Right, copyright, or other intellectual property rights) therein, shall, for purposes of this Agreement, be made in accordance with applicable Law in the United States (without regard to
              conflict of laws) as such law exists as of the Execution Date irrespective of where such conception, discovery, invention, or creation occurs.<br>
              <br>
            </div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;">12.1.3</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;<font style="font-weight: bold;"><u>Cross-License</u></font>.</div>
            <div style="text-align: justify; text-indent: 72pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 108pt;">(a)&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;Subject to the terms and conditions of this Agreement and effective as of the Closing Date, Akcea hereby grants to AstraZeneca, and AstraZeneca accepts, a non-exclusive,
              royalty-free, fully-paid, perpetual, irrevocable, non-transferable (except in accordance with <u>Section</u><u> 17.3</u>), sublicensable license under the Akcea Program Technology that is conceived, discovered, invented or created in the
              performance of Development or Commercialization activities for which the Parties share Eligible Expenses under this Agreement for any and all purposes.</div>
            <div style="text-align: justify; text-indent: 108pt;"> <br>
            </div>
            <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
              <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">56</font></div>
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            </div>
            <div style="text-align: justify; text-indent: 108pt;">(b)&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;Subject to the terms and conditions of this Agreement and effective as of the Closing Date, AstraZeneca hereby grants to Akcea, and Akcea accepts, a non-exclusive, royalty-free,
              fully-paid, perpetual, irrevocable, non-transferable (except in accordance with <u>Section</u><u> 17.3</u>), sublicensable license under the AstraZeneca Program Technology that is conceived, discovered, invented or created in the performance
              of Development or Commercialization activities for which the Parties share Eligible Expenses under this Agreement for any and all purposes.</div>
            <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold;"> <br>
              </font></div>
            <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold;">12.2</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160; <font style="font-weight: bold;"><u>Filing, Prosecution and Maintenance of Patents</u></font>.</div>
            <div style="text-align: justify; text-indent: 36pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;">12.2.1</font>&#160;&#160;&#160;&#160; <font style="font-weight: bold;"><u>Patent Rights</u></font>.</div>
            <div style="text-align: justify; text-indent: 72pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 108pt;">(a)&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160; <font style="font-weight: bold;">Akcea Core Technology Patent Rights and Akcea Manufacturing Patent Rights</font>. As between the Parties, Akcea will control and be responsible
              for Prosecuting and Maintaining (i) the Akcea Core Technology Patent Rights, and (ii) Akcea Manufacturing Patent Rights. Notwithstanding the foregoing, (x) except with respect to the Akcea Product-Specific Patent Rights and Joint Patent
              Rights as provided herein and as provided in clause (y) below, Akcea will not, and will ensure that its Affiliates and (sub)licensees do not, Prosecute and Maintain any claim in a Patent Right specifically claiming the Licensed Compound or
              the Exploitation thereof, and (y) with respect to any Akcea Core Technology Patent Rights that include a claim directed specifically to the Licensed Compound and that have been filed and are being Prosecuted and Maintained as of the Execution
              Date, Akcea will, or will cause its Affiliates to, file divisionals or pursue other similar procedures with respect thereto in a manner so that any such claims are included in Akcea Product-Specific Patent Rights, and to the extent Akcea is
              unable to do so, Akcea and AstraZeneca will promptly discuss in good faith and, unless otherwise agreed by the Parties, Akcea will, and will cause its Affiliates and (sub)licensees to, cancel such claims and promptly notify AstraZeneca
              thereof, in each case, so that no Akcea Core Technology Patent Right includes any such claims.</div>
            <div style="text-align: justify; text-indent: 108pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 108pt;">(b)&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;<font style="font-weight: bold;">Akcea Product-Specific Patent Rights</font>. Following the Closing Date (and so long as the applicable license to AstraZeneca under <u>Section
                8.1</u> is in effect), AstraZeneca will control and be responsible for Prosecuting and Maintaining the Akcea Product-Specific Patent Rights in the Territory.</div>
            <div style="text-align: justify; text-indent: 108pt;"> <br>
            </div>
            <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
              <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">57</font></div>
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            </div>
            <div style="text-align: justify; text-indent: 108pt;">(c)&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;<font style="font-weight: bold;">Joint Program Technology</font>. In the event the Parties make any Joint Know-How, the Parties will promptly meet to discuss and determine,
              based on mutual consent, whether to seek patent protection thereon. Neither Party will file any Joint Patent Right without mutual consent. If the Parties decide to seek patent protection for any Joint Know-How, then [***] will have the first
              right, but not the obligation, for Prosecuting and Maintaining any Joint Patent Right in the Territory in accordance with the provisions of <u>Section 12.2.2</u>. Where [***] declines to exercise its first right to file on a Joint Patent
              Right that the Parties have agreed to file, [***] shall have the right for Prosecuting and Maintaining such Joint Patent Right in accordance with the provisions of <u>Section 12.2.2</u>. The non-filing Party will reimburse the filing Party
              for [***]% of the costs incurred by the filing Party in Prosecuting and Maintaining such Joint Patent Rights, which reimbursement will be made pursuant to, and within [***] of, invoices (including reasonable supporting documentation)
              submitted by the filing Party to the non-filing Party no more often than once per Calendar Quarter. The non-prosecuting Party will cooperate with the prosecuting Party in taking reasonable measures to control costs and non-prosecuting Party
              shall be responsible for [***]% of (i) any fees or costs related to any correspondence of outside counsel with or instructions to outside counsel by such Party (or any of such Party&#8217;s representatives) which is independent of joint prosecution
              efforts, or (ii) any patent office fees, and associated counsel/agent fees and costs, for extensions which are not incurred at the request of, and not due to the actions of, the prosecuting Party.<font style="font-weight: bold; font-style: italic;">&#160;</font>If either Party (the &#8220;<font style="font-weight: bold; font-style: italic;">Declining Party</font>&#8221;) at any time declines to participate in the Prosecution and Maintenance of any Joint Patent Right or share in the costs of
              Prosecution and Maintenance of any Joint Patent Right in a country, on a country-by-country basis, the Declining Party will provide the other Party (the &#8220;<font style="font-weight: bold; font-style: italic;">Continuing Party</font>&#8221;) with
              [***] prior written notice to such effect, in which event, the Declining Party will (A) have no responsibility with respect to the Prosecution and Maintenance of the applicable Joint Patent Right in such country after the end of such [***]
              period, (B) have no responsibility for any expenses incurred in connection with the Prosecution and Maintenance of such Joint Patent Right in such country after the end of such [***] period and (C) if the Continuing Party elects to continue
              such Prosecution and Maintenance, then the Declining Party, upon the Continuing Party&#8217;s request, will execute such documents and perform such acts, at the Continuing Party&#8217;s expense, as may be reasonably necessary (1) to assign to the
              Continuing Party all of the Declining Party&#8217;s right, title and interest in and to such Joint Patent Right in such country and (2) to permit the Continuing Party to Prosecute and Maintain such Joint Patent Right in such country at its sole
              expense. Where such Joint Patent Right is assigned to AstraZeneca as the Continuing Party, it will be deemed to be AstraZeneca Patent Rights (to the extent it meets the definition of AstraZeneca Patent Rights) and AstraZeneca Program
              Technology, and will be subject to the applicable license grants to Akcea under this Agreement; and where such Joint Patent Right is assigned to Akcea as the Continuing Party, it will be deemed to be Licensed Technology (to the extent it
              meets the definition of Licensed Technology) and Akcea Program Technology, and will be subject to the applicable license grants to AstraZeneca under this Agreement.</div>
            <div style="text-align: justify; text-indent: 108pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 108pt;">(d)&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;<font style="font-weight: bold;">AstraZeneca Patent Rights</font>. AstraZeneca will control and be responsible for Prosecuting and Maintaining the AstraZeneca Patent Rights.</div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;"> <br>
              </font></div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;">12.2.2</font>&#160;&#160;&#160; <font style="font-weight: bold;"><u>Other Matters Pertaining to Prosecution and Maintenance of Patents</u></font>. Except with respect to
              AstraZeneca Patent Rights:</div>
            <div style="text-align: justify; text-indent: 72pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 108pt;">(a)&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;Each Party will keep the other Party informed as to material developments with respect to the Prosecution and Maintenance of the Patent Rights for which such Party has
              responsibility for Prosecution and Maintenance pursuant to <u>Section 12.2.1</u>, including by providing copies of any material correspondence that such Party provides to or receives from any patent office, including notice of all
              interferences, reissues, re-examinations, <font style="font-style: italic;">inter partes</font> reviews, post-grant reviews, oppositions or requests for Patent Term Extensions, and all patent-related filings, and by providing the other Party
              the timely opportunity to have reasonable input into the strategic aspects of such Prosecution and Maintenance.</div>
            <div style="text-align: justify; text-indent: 108pt;"> <br>
            </div>
            <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
              <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">58</font></div>
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            </div>
            <div style="text-align: justify; text-indent: 108pt;">(b)&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;With respect to Prosecution and Maintenance activities under <u>Section 12.2.1(b)</u> or <u>Section 12.2.1(c)</u>, AstraZeneca may use counsel of its own choice reasonably
              acceptable to Akcea (for clarity, it is agreed that AstraZeneca may use internal patent counsel and agents, filing clerks, and paralegals employed by AstraZeneca) for Prosecuting and Maintaining and coordinating worldwide filings of such
              Patent Rights. At AstraZeneca&#8217;s request, Akcea will cooperate and assist AstraZeneca and outside counsel and agents in the Prosecution and Maintenance of such Patent Rights. Subject to <u>Section</u><u> 12.9</u>, if AstraZeneca elects (i)
              not to file and prosecute patent applications for an Akcea Product-Specific Patent Right (&#8220;<font style="font-weight: bold; font-style: italic;">AstraZeneca Prosecuted Patents</font>&#8221;) in a particular country, (ii) not to continue the
              prosecution (including any interferences, oppositions, reissue proceedings, or re-examinations) or maintenance of any AstraZeneca Prosecuted Patent in a particular country, or (iii) not to file and prosecute patent applications for the
              AstraZeneca Prosecuted Patent in a particular country following a written request from Akcea to file and prosecute in such country, then AstraZeneca will so notify Akcea promptly in writing of its intention not less than [***] before an
              action is required to enable Akcea to meet any deadlines by which an action must be taken to establish or preserve any such Patent Right in such country; and Akcea will have the right, but not the obligation, to file, prosecute and maintain
              such AstraZeneca Prosecuted Patent in the applicable country at its own expense with counsel of its own choice; <font style="font-style: italic;">provided</font> that Akcea shall ensure that its filing, prosecution and maintenance of such
              AstraZeneca Prosecuted Patent in such country is consistent with AstraZeneca&#8217;s Prosecution and Maintenance of such AstraZeneca Prosecuted Patent in other countries and is not reasonably likely to adversely affect the scope, validity or
              enforceability of such AstraZeneca Prosecuted Patent in other countries or any of the other Patent Rights being Prosecuted and Maintained by AstraZeneca under this Agreement. In such a case, AstraZeneca will cooperate with Akcea to file for,
              or continue to prosecute and maintain such AstraZeneca Prosecuted Patent in such country in Akcea&#8217;s own name, but only to the extent that AstraZeneca is not required to take any position with respect to such abandoned AstraZeneca Prosecuted
              Patent that is inconsistent with AstraZeneca&#8217;s Prosecution and Maintenance of such AstraZeneca Prosecuted Patent in other countries or that would be reasonably likely to adversely affect the scope, validity or enforceability of any of such
              AstraZeneca Prosecuted Patent in other countries or the other Patent Rights being Prosecuted and Maintained by AstraZeneca under this Agreement. Notwithstanding anything to the contrary in this Agreement, if Akcea assumes responsibility for
              the prosecution and maintenance of the any such AstraZeneca Prosecuted Patent under this <u>Section 12.2.2(b)</u>, then Akcea will have no obligation to notify AstraZeneca if Akcea intends to abandon such AstraZeneca Prosecuted Patent.</div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;"> <br>
              </font></div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;">12.2.3</font>&#160;&#160;&#160;&#160; <font style="font-weight: bold;"><u>Patent Costs</u></font>. Except as set forth in <u>Section 12.2.1(c)</u> and <u>Section 12.2.2 </u>or

              to the extent costs are included in the definition of an Eligible Commercialization Expense, each Party will be responsible for all patent costs incurred by such Party after the Closing Date in all countries designated by it in the
              Prosecution and Maintenance of Patent Rights for which such Party is responsible under <u>Article 12</u>.</div>
            <div style="text-align: justify; text-indent: 72pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold;">12.3</font>&#160;&#160;&#160;&#160;&#160;&#160; <font style="font-weight: bold;"><u>Defense of Claims Brought by Third Parties; Oppositions</u></font>.</div>
            <div style="text-align: justify; text-indent: 36pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;">12.3.1</font>&#160;&#160;&#160;&#160; <font style="font-weight: bold;"><u>Licensed Compound</u></font>. If a Third Party initiates a proceeding against a Party claiming a Patent
              Right owned by or licensed to such Third Party is infringed by the Exploitation of any Licensed Compound or Licensed Product in the Territory, then AstraZeneca will have the first right, but not the obligation, to defend against any such
              proceeding at its sole cost and expense (except to the extent shared as Third Party Payments under this Agreement). If AstraZeneca elects to defend against such proceeding, then AstraZeneca will have the sole right to direct the defense and
              to elect whether to settle such claim (but, prior to Akcea&#8217;s exercise of the Opt-Out Right, only with the prior written consent of Akcea for any such claims that are related to the U.S., not to be unreasonably withheld, conditioned or
              delayed). AstraZeneca will keep Akcea apprised of the progress of such proceeding. If AstraZeneca elects not to defend against a proceeding, then AstraZeneca will so notify Akcea in writing within [***] after AstraZeneca first receives
              written notice of the initiation of such proceeding, and Akcea will have the right, but not the obligation, to defend against such a proceeding at its sole cost and expense and thereafter Akcea will have the sole right to direct the defense
              thereof, including the right to settle such claim, but only with the prior written consent of AstraZeneca, which consent will not be unreasonably withheld, delayed or conditioned. In any event, the Party not defending such proceeding will
              reasonably assist the other Party and cooperate in any such litigation at the defending Party&#8217;s request and expense. Each Party may at its own expense and with its own counsel join any defense initiated or directed by the other Party under
              this <u>Section </u><u>12.3.1</u>. Each Party will provide the other Party with prompt written notice of the commencement of any such proceeding under this <u>Section </u><u>12.3.1</u>, and such Party will promptly furnish the other Party
              with a copy of each communication relating to the alleged infringement that is received by such Party.</div>
            <div style="text-align: justify; text-indent: 72pt;"> <br>
            </div>
            <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
              <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">59</font></div>
              <div style="page-break-after: always;" id="DSPFPageBreak">
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            </div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;">12.3.2</font>&#160;&#160;&#160; <font style="font-weight: bold;"><u>Interferences, Reissues, Re-Examinations and Oppositions</u></font>. If a Third Party initiates a
              proceeding related to an interference, reissue, re-examination or opposition of an Akcea Product-Specific Patent Right or Joint Patent Right in the Territory, the Party responsible for Prosecution and Maintenance pursuant to <u>Section
                12.2.1</u> will, by written notice to the other Party, either (a) control the defense of such proceeding or (b) give the other Party the right to control the defense of such proceeding, in each case ((a) and (b)), solely to the extent such
              proceeding relates to an interference, reissue, re-examination or opposition of an Akcea Product-Specific Patent Right or Joint Patent Right, <font style="font-style: italic;">provided</font> that if the Party responsible for Prosecution and
              Maintenance pursuant to <u>Section 12.2.1</u> makes no such election within [***], then the other Party will have the right, but not the obligation, to control the defense of such proceeding, at such other Party&#8217;s sole expense. In any event,
              the Party not defending such proceeding will reasonably assist the other Party and cooperate in any such litigation at the defending Party&#8217;s request and expense. Each Party may at its own expense and with its own counsel join any defense
              initiated or directed by the other Party under this <u>Section 12.3.2</u>. Each Party will provide the other Party with prompt written notice of the commencement of any such proceeding under this <u>Section 12.3.2</u>, and such Party will
              promptly furnish the other Party with a copy of each communication relating to the alleged infringement that is received by such Party.</div>
            <div style="text-align: justify; text-indent: 72pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold;">12.4</font>&#160;&#160;&#160;&#160;&#160;&#160; <font style="font-weight: bold;"><u>Enforcement of Patents Against Competitive Infringement</u></font>. With respect to infringement,
              unauthorized use, misappropriation or threatened infringement by a Third Party of any Akcea Product-Specific Patent Rights or Joint Patent Rights by reason of the Exploitation of a product that binds to TTR anywhere in the Territory (&#8220;<font style="font-weight: bold; font-style: italic;">Competitive Infringement</font>&#8221;), the Parties will handle such Competitive Infringement in accordance with the remainder of this <u>Section 12.4</u>.</div>
            <div style="text-align: justify; text-indent: 36pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;">12.4.1</font>&#160;&#160;&#160; <font style="font-weight: bold;"><u>Duty to Notify of Competitive Infringement</u></font>. If either Party learns of a Competitive
              Infringement by a Third Party in the Territory, then such Party will promptly notify the other Party in writing and will provide such other Party with available evidence of such Competitive Infringement; <font style="font-style: italic;">provided,

                however</font>, that for cases of Competitive Infringement under <u>Section </u><u>12.4.5</u> below, such written notice will be given within [***] after learning of such Competitive Infringement.</div>
            <div style="text-align: justify; text-indent: 72pt;"> <br>
            </div>
            <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
              <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">60</font></div>
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            </div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;">12.4.2</font> &#160; <font style="font-weight: bold;"><u>Control of Competitive Infringement Proceedings</u></font>. AstraZeneca will have the first right, but
              not the obligation, to institute, prosecute, and control and settle a proceeding with respect to a Competitive Infringement, including as a defense or counterclaim in connection with any proceeding regarding Third Party infringement under <u>Section</u><u>
                12.3.1</u>, by counsel of its own choice at its own cost and expense (except to the extent included in the definition of Other Operating Expenses), and Akcea will have the right, at its own cost and expense, to be represented in that action
              by counsel of its own choice (which amounts shall not be included in Other Operating Expenses), <font style="font-style: italic;">however</font>, AstraZeneca will have the right to control (including the right to settle) such litigation. If
              AstraZeneca fails to initiate a proceeding within a period of [***] after receipt of written notice of such Competitive Infringement (subject to a [***] extension to conclude negotiations, if AstraZeneca has commenced good faith negotiations
              with an alleged infringer for elimination of such Competitive Infringement within such [***] period), then Akcea will have the right to initiate and control a proceeding with respect to such Competitive Infringement by counsel of its own
              choice at its own cost and expense (except to the extent included in the definition of Other Operating Expenses), and AstraZeneca will have the right to be represented in any such action by counsel of its own choice at its own cost and
              expense (which amounts shall not be included in Other Operating Expenses). Notwithstanding the foregoing, if [***]; <font style="font-style: italic;">provided, however</font>, that [***].</div>
            <div style="text-align: justify; text-indent: 72pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;">12.4.3</font>&#160;&#160;&#160;&#160; <font style="font-weight: bold;"><u>Joinder; Cooperation</u></font>.</div>
            <div style="text-align: justify; text-indent: 72pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 108pt;">(a)&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160; If a Party initiates a proceeding in accordance with this <u>Section 12.4</u>, then the other Party agrees to be joined as a party plaintiff where necessary and to give the
              first Party reasonable assistance and authority to file and prosecute the proceeding. Subject to <u>Section </u><u>12.4.4</u>, the costs and expenses of each Party incurred pursuant to this <u>Section </u><u>12.4.3(a)</u> will be borne by
              the Party initiating such proceeding.</div>
            <div style="text-align: justify; text-indent: 108pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 108pt;">(b)&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;If one Party initiates a proceeding in accordance with this <u>Section 12.4</u>, then the other Party may join such proceeding as a party plaintiff where necessary for such
              other Party to seek lost profits with respect to such infringement.</div>
            <div style="text-align: justify; text-indent: 108pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;">12.4.4</font>&#160;&#160;&#160;&#160; <font style="font-weight: bold;"><u>Share of Recoveries</u></font>. Any damages or other monetary awards recovered with respect to a
              proceeding brought pursuant to <u>Section 12.4</u> will be shared as follows:</div>
            <div style="text-align: justify; text-indent: 72pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 108pt;">(a)&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160; the amount of such recovery will first be applied to the Parties&#8217; reasonable Out-of-Pocket Costs incurred in connection with such proceeding, except that such Out-of-Pocket Costs
              that were shared between the Parties as Other Operating Expenses and for which reconciliation payments have been made pursuant to Section 11.10 will be applied to each Party to the extent of its respective share of such Other Operating
              Expenses (and provided that amounts will be allocated <font style="font-style: italic;">pro rata</font> if insufficient to cover the totality of such Out-of-Pocket Costs);</div>
            <div style="text-align: justify; text-indent: 108pt;"> <br>
            </div>
            <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
              <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">61</font></div>
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            </div>
            <div style="text-align: justify; text-indent: 108pt;">(b)&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160; if Akcea has not exercised its Opt-Out Right, then the amount of such recovery that relates to a Competitive Infringement in the U.S. will then be shared by the Parties, with
              AstraZeneca receiving [***]% of such remaining proceeds and Akcea receiving [***]% of such remaining proceeds; and</div>
            <div style="text-align: justify; text-indent: 108pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 108pt;">(c)&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;any other proceeds (either because such proceeds were the result of a Competitive Infringement outside the U.S. or because Akcea has exercised its Opt-Out Right) will be
              allocated as follows: (i) [***] or (ii) [***].</div>
            <div style="text-align: justify; text-indent: 108pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;">12.4.5</font>&#160;&#160;&#160; <font style="font-weight: bold;"><u>35 USC &#167; 271(e)(2) Infringement</u></font>. Notwithstanding anything to the contrary in this <u>Section
                12.4</u>, for a Competitive Infringement under 35 USC &#167;<font style="font-weight: bold;">&#160;</font>271(e)(2), the time period set forth in <u>Section </u><u>12.4.2</u> during which AstraZeneca will have the initial right to bring a
              proceeding will be shortened to a total of [***], so that, to the extent Akcea has the right, pursuant to such <u>Section </u><u>12.4.2</u> to initiate a proceeding if AstraZeneca does not initiate a proceeding, Akcea will have such right
              if AstraZeneca does not initiate a proceeding within [***] after AstraZeneca&#8217;s receipt of written notice of such Competitive Infringement.</div>
            <div style="text-align: justify; text-indent: 72pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold;">12.5</font>&#160;&#160;&#160;&#160;&#160;&#160; <font style="font-weight: bold;"><u>Settlement</u></font>. Notwithstanding anything to the contrary in this <u>Article 12</u>, neither
              Party may enter a settlement, consent judgment or other voluntary final disposition of a suit under this <u>Article 12</u> that (a) disclaims, limits the scope of, admits the invalidity or unenforceability of, or grants a license, covenant
              not to sue or similar immunity under a Patent Right Controlled by the other Party or its Affiliates (<font style="font-style: italic;">provided</font> that, with respect to AstraZeneca as the settling Party, the foregoing shall not apply to
              Akcea Product-Specific Patent Rights), or (b) imposes any costs or liability on, or involves any admission of wrongdoing by the other Party or its Affiliates, in each case without first obtaining the written consent of the other Party; <font style="font-style: italic;">provided</font> that a settlement of Competitive Infringement that would or may result in reduced payments hereunder shall not, in and of itself, be deemed to require the consent of such other Party.</div>
            <div style="text-align: justify; text-indent: 36pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold;">12.6</font>&#160;&#160;&#160;&#160;&#160;&#160; <font style="font-weight: bold;"><u>Patent Listing</u></font>. AstraZeneca will have the sole right, at its discretion (except as set forth
              in this <u>Section 12.6</u>), to list, with the applicable Regulatory Authorities commencing on the Closing Date and during the remainder of the Term, all applicable Akcea Patent Rights. Prior to such listings, the Parties will meet to
              evaluate and identify all applicable Patent Rights, and AstraZeneca will have the right to review, where reasonable, original records relating to any invention for which Patent Rights are being considered by AstraZeneca for any such listing.
              Notwithstanding the preceding sentence, AstraZeneca will retain final decision-making authority as to the listing of all applicable Akcea Patent Rights for the Licensed Product that are not Akcea Core Technology Patent Rights or Akcea
              Manufacturing Patent Rights, regardless of which Party owns such Patent Rights, and AstraZeneca may not list any Akcea Core Technology Patent Rights or Akcea Manufacturing Patent Rights unless the Parties mutual agree to do so, or unless
              otherwise required by applicable Law.</div>
            <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold;"> <br>
              </font></div>
            <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold;">12.7</font>&#160;&#160;&#160;&#160;&#160;&#160; <font style="font-weight: bold;"><u>Joint Research Agreement under the Leahy-Smith America Invents Act</u></font>. If a Party intends to
              invoke its rights under 35 U.S.C. &#167; 102(c) of the Leahy-Smith America Invents Act, then it will notify the other Party and neither Party will make an election under such provision when exercising its rights under this <u>Article 12</u>
              without the prior written consent of the other Party (such consent not to be unreasonably withheld, conditioned or delayed), and the Parties will use reasonable efforts to cooperate and coordinate their activities with such Party with respect
              to any submissions, filings or other activities in support thereof. The Parties acknowledge and agree that this Agreement is a &#8220;joint research agreement&#8221; as defined in 35 U.S.C. &#167; 100(h).</div>
            <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold;"> <br>
              </font></div>
            <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
              <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">62</font></div>
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            </div>
            <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold;">12.8</font>&#160;&#160;&#160;&#160;&#160;&#160; <font style="font-weight: bold;"><u>Additional Rights and Exceptions</u></font>. Other than as expressly set forth in this <u>Article 12</u>,
              as between the Parties, Akcea retains the sole right to (a) Prosecute and Maintain (i) Akcea Core Technology Patent Rights and (ii) Akcea Manufacturing Patent Rights during the Term, and (b) control any enforcement of Akcea Core Technology
              Patent Rights and Akcea Manufacturing Patent Rights, <font style="font-style: italic;">provided</font> that if under clause (b) the enforcement of Akcea Core Technology Patent Rights or Akcea Manufacturing Patent Rights is believed in
              AstraZeneca&#8217;s reasonable opinion to potentially impact Net Sales and such an Akcea Core Technology Patent Right or Akcea Manufacturing Patent Right is the only Akcea Patent Right Covering the Licensed Product at the time of such enforcement
              proceeding, then AstraZeneca has the second right, but no obligation, to enforce such patents, <font style="font-style: italic;">so long as</font> AstraZeneca, in connection with any such enforcement proceeding, also enforces any relevant
              AstraZeneca Patent Rights. Any damages or other monetary awards recovered with respect to a proceeding brought pursuant to clause (b) of this <u>Section 12.8</u> that impacts Net Sales will be shared as follows:</div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;"> <br>
              </font></div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;">12.8.1</font>&#160;&#160;&#160; any recoveries will first be applied to reimburse each Party&#8217;s reasonable Out-of-Pocket Costs incurred in connection therewith (which amounts
              will be allocated <font style="font-style: italic;">pro rata</font> if insufficient to cover the totality of such Out-of-Pocket Costs); and</div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;"> <br>
              </font></div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;">12.8.2</font>&#160;&#160;&#160; any remaining recoveries will be [***].</div>
            <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold;"> <br>
              </font></div>
            <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold;">12.9</font>&#160;&#160;&#160;&#160;&#160;&#160; <font style="font-weight: bold;"><u>Patent Term Extension</u></font>. Notwithstanding <u>Section</u><u> 12.2.2(b)</u>, the Parties will
              cooperate with each other in gaining Patent Term Extension with respect to Akcea Product-Specific Patent Rights wherever applicable to the Licensed Product, and AstraZeneca will determine which Akcea Product-Specific Patent Rights will be
              extended and will have the exclusive right, but not the obligation, to seek such Patent Term Extension, in Akcea&#8217;s or Ionis&#8217;s name, if so required.</div>
            <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold;"> <br>
              </font></div>
            <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold;">12.10</font>&#160;&#160;&#160;&#160; <font style="font-weight: bold;"><u>UPC</u></font>. With respect to any Akcea Product-Specific Patent Rights, AstraZeneca will have the
              right to determine whether to opt in or opt out (and to opt in again) of the Unified Patent Court system and if requested by AstraZeneca, Akcea will promptly do all things reasonably necessary and execute all documents required to give effect
              to such decision(s), provided that [***].</div>
            <div style="text-align: center; font-weight: bold;"> <br>
            </div>
            <div style="text-align: center; font-weight: bold;">ARTICLE 13</div>
            <div style="text-align: center; font-weight: bold;">CONFIDENTIALITY</div>
            <div style="text-align: center; font-weight: bold;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold;">13.1</font>&#160;&#160;&#160;&#160;&#160;&#160; <font style="font-weight: bold;"><u>Confidentiality; Exceptions</u></font>. Except to the extent expressly authorized by this Agreement or
              otherwise agreed in writing, the Parties agree that the receiving Party and its Affiliates (the &#8220;<font style="font-weight: bold; font-style: italic;">Receiving Party</font><font style="font-weight: bold;">&#8221;</font>) will keep confidential and
              will not publish or otherwise disclose or use for any purpose, other than as provided for in this Agreement, any confidential or proprietary information or materials, patentable or otherwise, in any form (written, oral, photographic,
              electronic, magnetic or otherwise) that is disclosed to it by the other Party or its Affiliates (the &#8220;<font style="font-weight: bold; font-style: italic;">Disclosing Party</font>&#8221;), including trade secrets, Know-How, inventions or
              discoveries, proprietary information, data of a financial, commercial or technical nature, formulae, processes, techniques and information relating to the Disclosing Party&#8217;s past, present or future marketing, financial or Exploitation
              activities of any product or potential product or useful technology of the Disclosing Party or the pricing thereof (collectively, &#8220;<font style="font-weight: bold; font-style: italic;">Confidential Information</font>&#8221;), except to the extent
              that it can be established by the Receiving Party that such Confidential Information:</div>
            <div style="text-align: justify; text-indent: 36pt;"> <br>
            </div>
            <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
              <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">63</font></div>
              <div style="page-break-after: always;" id="DSPFPageBreak">
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            </div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;">13.1.1</font>&#160;&#160;&#160; was in the lawful knowledge and possession of the Receiving Party prior to the time it was first disclosed to the Receiving Party by the
              Disclosing Party, or was otherwise developed independently by the Receiving Party without reference to any of the Disclosing Party&#8217;s Confidential Information, as evidenced by written records kept in the ordinary course of business, or other
              documentary proof of actual use by the Receiving Party;<font style="font-style: italic;"> provided</font> that the foregoing exception shall not apply with respect to Akcea Product-Specific IP or Joint Know-How;</div>
            <div style="text-align: justify; text-indent: 72pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;">13.1.2</font>&#160;&#160;&#160; was generally available to the public or otherwise part of the public domain at the time of its first disclosure to the Receiving Party by
              the Disclosing Party;</div>
            <div style="text-align: justify; text-indent: 72pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;">13.1.3</font>&#160;&#160;&#160; became generally available to the public or otherwise part of the public domain after its disclosure to the Receiving Party by the Disclosing
              Party and other than through any act or omission of the Receiving Party in breach of this Agreement; or</div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;"> <br>
              </font></div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;">13.1.4</font>&#160;&#160;&#160; was disclosed to the Receiving Party, other than under an obligation of confidentiality, by a Third Party who had no obligation to the
              Disclosing Party not to disclose such information to others.</div>
            <div style="text-align: justify; text-indent: 72pt;"> <br>
            </div>
            <div style="text-align: justify;">The Receiving Party will protect all Confidential Information against unauthorized disclosure to Third Parties with the same degree of care as the Receiving Party uses for its own similar information, but in no
              event less than a reasonable degree of care. The Joint Know-How and the terms and conditions of this Agreement and following the Closing Date, the Akcea Product-Specific IP shall be deemed to be the Confidential Information of both of the
              Parties hereto and shall be deemed to have been disclosed by Akcea to AstraZeneca, on the one hand, and by AstraZeneca to Akcea, on the other hand; <font style="font-style: italic;">provided</font> that if this Agreement is earlier
              terminated in accordance with <u>Section 16.2</u>, then the Akcea Product-Specific IP will thereafter be deemed to be Confidential Information of Akcea only.</div>
            <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold;"> <br>
              </font></div>
            <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold;">13.2</font>&#160;&#160;&#160;&#160;&#160;&#160; <font style="font-weight: bold;"><u>Prior Confidentiality Agreement Superseded</u></font>. This Agreement supersedes the Mutual
              Confidential Disclosure Agreement executed by Ionis and AstraZeneca on March 5, 2021 (including any and all amendments thereto). All information exchanged by the Parties under such Mutual Confidential Disclosure Agreement is deemed
              Confidential Information hereunder and subject to the terms of this <u>Article 13</u>.</div>
            <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold;"> <br>
              </font></div>
            <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
              <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">64</font></div>
              <div style="page-break-after: always;" id="DSPFPageBreak">
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            </div>
            <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold;">13.3</font>&#160;&#160;&#160;&#160;&#160;&#160; <font style="font-weight: bold;"><u>Authorized Disclosure</u></font>. The Receiving Party may only use the Confidential Information of the
              Disclosing Party for exercising its rights and performing its obligations under this Agreement and may only disclose Confidential Information of the Disclosing Party as follows: (a) to the extent required to its Affiliates and its and their
              respective directors, officers, employees, agents, existing or prospective sublicensees, permitted assignees, consultants and representatives who reasonably need to know such Confidential Information in order to advise or assist the Receiving
              Party in connection with the performance of its obligations or rights granted or reserved in this Agreement and under appropriate confidentiality provisions substantially equivalent to those of this Agreement, <font style="font-style: italic;">provided </font>that Confidential Information may be disclosed by a Receiving Party to a governmental entity or agency without requiring such entity or agency to enter into a confidentiality agreement; (b) to the extent reasonably
              necessary to file or prosecute patent, copyright and trademark applications or to obtain or maintain Regulatory Approvals as permitted under this Agreement; (c) as required by applicable Law or in response to a valid Order of a court of
              competent jurisdiction; <font style="font-style: italic;">provided, however</font>, that if a Receiving Party is required by Law or in response to a valid Order of a court to make any such disclosure of a Disclosing Party&#8217;s Confidential
              Information it will, except where impracticable, give reasonable advance notice to the Disclosing Party of such disclosure requirement, limit disclosure to only the Confidential Information requested to be disclosed and, if requested by the
              Disclosing Party, cooperate with the Disclosing Party to secure confidential treatment of such Confidential Information required to be disclosed; (d) in communication with existing or prospective investors, lenders, financing sources,
              professional advisors, acquirers, merger partners, subcontractors, licensees or Inbound Licensors (to the extent required by the applicable In-License Agreement) on a need to know basis, in each case under appropriate confidentiality
              provisions substantially equivalent to those of this Agreement; (e) to the extent mutually agreed to in writing by the Parties; or (f) (i) with respect to AstraZeneca as the Receiving Party, as may be necessary or useful in connection with
              the Exploitation of the Licensed Compound and Licensed Product, and (ii) with respect to Akcea as the Receiving Party, as may be necessary or useful in connection with the performance of its Development activities pursuant to the Development
              Plan and Budget or its Co-Commercialization and Medical Affairs Activities. The confidentiality and non-use obligations set forth under this Agreement will survive the termination or expiration of this Agreement for a period of five years.</div>
            <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold;"> <br>
              </font></div>
            <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold;">13.4</font>&#160;&#160;&#160;&#160;&#160;&#160; <font style="font-weight: bold;"><u>Press Release; Disclosure of Agreement</u></font>.&#160;On or promptly after the Execution Date, each Party
              will issue a press release of the execution of this Agreement, the content of which shall be mutually agreed to in writing by the Parties.<font style="font-weight: bold; font-style: italic;">&#160;</font>Subject to <u>Section 13.5</u>, neither
              Party may issue any other press release or other public disclosure regarding this Agreement or its terms or the Parties&#8217; activities hereunder, or any results or data arising hereunder, except (a) with the other Party&#8217;s prior written consent
              (such consent not to be unreasonably withheld, conditioned or delayed), or (b) for any disclosure that is, in the opinion of the disclosing Party&#8217;s counsel, reasonably necessary to comply with applicable securities exchange listing
              requirements or other applicable Laws. Each Party will provide to the other Party a copy of any public announcement regarding this Agreement or the subject matter hereof (including any filing with the United States Securities and Exchange
              Commission (or any stock exchange, including Nasdaq, or any similar regulatory agency in any country other than the United States)), as practicable under the circumstances, reasonably prior to its scheduled release (and in any event less than
              [***] prior to the anticipated date of disclosure). Each Party will have the right to expeditiously review and recommend changes to any such announcement, and, except as otherwise required by securities exchange listing requirements or
              applicable Law, the Party whose announcement has been reviewed will remove any Confidential Information of the reviewing Party that the reviewing Party reasonably deems to be inappropriate for disclosure and will give due consideration to any
              reasonable comments by the reviewing Party relating to such announcement, including the provisions of this Agreement for which confidential treatment should be sought. For clarity, the Parties hereby acknowledge and agree that each Party may
              file this Agreement under the Securities Act in the United States and that the Parties will each use reasonable efforts to obtain confidential treatment of the commercial terms and sensitive technical and any other portions of this Agreement
              that such other Party requests be kept confidential. Notwithstanding the foregoing, to the extent information regarding this Agreement has already been publicly disclosed, each Party (other than a Party that had caused such information to
              become publicly disclosed in breach of this <u>Article 13</u>) may subsequently disclose the same information to the public without the consent of the other Party, <font style="font-style: italic;">provided</font> that such information
              remains accurate at the time of such subsequent disclosure.</div>
            <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold;"> <br>
              </font></div>
            <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
              <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">65</font></div>
              <div style="page-break-after: always;" id="DSPFPageBreak">
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            </div>
            <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold;">13.5</font>&#160;&#160;&#160;&#160;&#160;&#160; <font style="font-weight: bold;"><u>Publications</u></font>. Except as expressly permitted in this <u>Section 13.5</u>, neither Party nor
              its Affiliates or sublicensees will publish or publicly disclose the scientific results of any of the activities conducted with respect to the Licensed Compound or Licensed Product without the prior written consent of the other Party. The
              Parties recognize that it may be useful or required to publish or publicly disclose the results of Exploitation activities conducted with respect to the Licensed Compound or Licensed Product, and each Party (and its Affiliates and
              sublicensees) will be free to publish or publicly disclose such results, including on its clinical trials registry or on a government-sponsored database such as www.clinicaltrials.gov, subject to the prior review by the other Party for
              patentability and protection of its Confidential Information as described in this <u>Section 13.5</u> and, in the case of [***] as the publishing Party, only with [***] prior written consent (not to be unreasonably withheld, conditioned or
              delayed). The Party that desires to publish such results will provide the other Party with a copy of such proposed abstract, manuscript, or presentation no less than [***] ([***] in the case of abstracts) prior to its intended submission for
              publication. The reviewing Party will respond in writing promptly and in no event later than [***] ([***] in the case of abstracts) after receipt of the proposed material, with one or more of the following: (a) comments on the proposed
              material, which the publishing Party will consider in good faith, (b) a specific statement of concern, based upon the need to seek patent protection or to block publication if the reviewing Party determines that the proposed disclosure
              contains or describes intellectual property that should be maintained as a trade secret to protect the Licensed Product or any Exploitation activities conducted under this Agreement, or (c) an identification of the reviewing Party&#8217;s
              Confidential Information that is contained in the material reviewed. In the event of concern over patent protection or whether maintaining a trade secret would be a priority, the publishing Party agrees not to submit such publication or to
              make such presentation that contains such information until the reviewing Party is given a reasonable period of time, and in no event more than [***], to seek patent protection for any material in such publication or presentation which it
              believes is patentable or to resolve any other issues. All publications made by either Party shall be consistent with the publication strategy included in the U.S. Medical Affairs Plan and Budget. Notwithstanding anything herein to the
              contrary, Akcea and, its Affiliates may publish or publicly disclose any scientific data or results with respect to the Clinical Trial that is ongoing as of the Execution Date for [***] without the prior consent of AstraZeneca; <font style="font-style: italic;">provided</font> that (i) prior to publication by Akcea and its Affiliates (if applicable), AstraZeneca will have the right to review and approve the content of such publications, which approval of the contents
              will not be unreasonably withheld, conditioned or delayed and (ii) Akcea shall ensure such publication is made within [***] after Completion of such Clinical Trial.</div>
            <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold;"> <br>
              </font></div>
            <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
              <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">66</font></div>
              <div style="page-break-after: always;" id="DSPFPageBreak">
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            </div>
            <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold;">13.6</font> &#160; &#160;&#160;&#160; <font style="font-weight: bold;"><u>Remedies</u></font>. Each Party will be entitled to seek, in addition to any other right or remedy it
              may have, at Law or in equity, a temporary injunction, without the posting of any bond or other security, enjoining or restraining the other Party from any violation or threatened violation of this <u>Article 13</u>.</div>
            <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold;"> <br>
              </font></div>
            <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold;">13.7</font>&#160;&#160;&#160;&#160;&#160;&#160; <font style="font-weight: bold;"><u>Ongoing Obligation for Confidentiality</u></font>. Upon the effective date of termination of this
              Agreement, upon the Disclosing Party&#8217;s request, the Receiving Party shall destroy or return (as requested by the Disclosing Party) any Confidential Information of the Disclosing Party (in the event of termination of this Agreement with
              respect to one or more Terminated Territories but not in its entirety, solely to the extent relating specifically and exclusively to such Terminated Territories), except that the Receiving Party (a) may retain a single copy of the
              Confidential Information for the sole purpose of (i) ascertaining its rights and responsibilities in respect of such Confidential Information and (ii) exercising its rights that expressly survive the expiration or termination of this
              Agreement and (b) shall not be required to destroy any computer files stored securely by the Receiving Party that are created by automatic system back up.</div>
            <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold;"> <br>
              </font></div>
            <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold;">13.8</font>&#160;&#160;&#160;&#160;&#160;&#160; <font style="font-weight: bold;"><u>Use of Name; Acknowledgment</u></font>. Except as otherwise set forth in this <u>Section </u><u>13.8</u>,
              neither Party will use the other Party&#8217;s name, logo or Trademark in a press release or other publication or other form of publicity without first obtaining the prior consent of the Party to be named. Each Party will acknowledge in any press
              release, public presentation or publication regarding the collaboration or the Licensed Product, the other Party&#8217;s role in discovering and developing the Licensed Product, that the Licensed Product is under license from Ionis and otherwise
              acknowledge the contributions from the other Party, and each Party&#8217;s stock ticker symbol (e.g.. Nasdaq: IONS; NYSE: AZN). Ionis may include the Licensed Product (and identify AstraZeneca as its partner for the Licensed Product) in Ionis&#8217; drug
              pipeline.</div>
            <div style="text-align: center; font-weight: bold;"> <br>
            </div>
            <div style="text-align: center; font-weight: bold;">ARTICLE 14</div>
            <div style="text-align: center; font-weight: bold;">REPRESENTATIONS AND WARRANTIES</div>
            <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold;"> <br>
              </font></div>
            <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold;">14.1</font>&#160;&#160;&#160;&#160;&#160;&#160; <font style="font-weight: bold;"><u>Representations and Warranties of the Parties</u></font>. Each Party hereby represents and warrants to
              the other Party, as of the Execution Date and as of the Closing Date, that:</div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;"> <br>
              </font></div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;">14.1.1</font>&#160;&#160;&#160;&#160; such Party is duly organized, validly existing and in good standing under the Laws of the jurisdiction of its incorporation and has full
              corporate power and authority to enter into and deliver this Agreement and to carry out the provisions hereof;</div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;"> <br>
              </font></div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;">14.1.2</font>&#160;&#160;&#160;&#160; such Party has taken all necessary action on its part required by applicable Law and its organizational documents to authorize the execution
              and delivery of this Agreement and the performance of its obligations hereunder;</div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;"> <br>
              </font></div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;">14.1.3</font>&#160;&#160;&#160; this Agreement has been duly and validly executed and delivered on behalf of such Party, and, assuming due and valid authorization, execution
              and delivery by the other Party, constitutes a legal, valid, and binding obligation, enforceable against it in accordance with the terms hereof, subject to bankruptcy, insolvency, moratorium or other similar Laws affecting or relating the
              enforcement of creditors&#8217; rights generally, and general principles of equity;</div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;"> <br>
              </font></div>
            <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
              <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">67</font></div>
              <div style="page-break-after: always;" id="DSPFPageBreak">
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            </div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;">14.1.4</font>&#160;&#160;&#160; the execution, delivery and performance of this Agreement by such Party does not conflict with any agreement or any provision thereof, or any
              instrument or understanding, oral or written, to which it is a party or by which it is bound, nor violate any Law or regulation of any Governmental Authority having jurisdiction over such Party;</div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;"> <br>
              </font></div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;">14.1.5</font>&#160;&#160;&#160; except as contemplated by <u>Section 10.2</u>, all consents, approvals and authorizations from all Governmental Authorities or other Third
              Parties required to be obtained by such Party in connection with this Agreement have been obtained;</div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;"> <br>
              </font></div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;">14.1.6</font>&#160;&#160;&#160; such Party is not debarred under the United States Federal Food, Drug and Cosmetic Act or comparable applicable Laws; and</div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;"> <br>
              </font></div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;">14.1.7</font>&#160;&#160;&#160; (a) none of a Party&#8217;s officers, directors and employees, and to each Party&#8217;s Knowledge, any other Person acting on its behalf, has directly
              or indirectly given, offered or promised to give money or anything of value to any Government Official in an effort to influence any Government Official or any other Person in a corrupt or improper effort to obtain or retain business or any
              commercial advantage, such as a permit or license to do business, or accepted such a payment, and (b) all Persons acting on its behalf have materially complied with all applicable Laws in connection with conducting its business operations,
              including the U.S. Foreign Corrupt Practices Act, laws implementing the Convention on Combating Bribery of Foreign Public Officials in International Business Transactions and local Laws prohibiting bribery, kickbacks, or other unlawful or
              improper means of obtaining business or commercial advantages, in each case ((a) and (b)), (i) as to Akcea, with respect to the Licensed Compound or Licensed Product, and (ii) as to AstraZeneca, that would, in the reasonable view of
              AstraZeneca, have a material adverse effect on Akcea.</div>
            <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold;"> <br>
              </font></div>
            <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold;">14.2</font>&#160;&#160;&#160;&#160;&#160;&#160; <font style="font-weight: bold;"><u>Representations and Warranties of Akcea</u></font>. Akcea hereby represents and warrants to
              AstraZeneca, as of the Execution Date and as of the Closing Date, and covenants, that:</div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;"> <br>
              </font></div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;">14.2.1</font>&#160;&#160;&#160; Akcea has all rights, authorizations and consents necessary to grant all rights and licenses it purports to grant to AstraZeneca with respect
              to the Licensed Technology under this Agreement, in each case, free and clear of any rights of any Third Party that would be in conflict with the licenses and other rights it purports to grant to AstraZeneca under this Agreement and has
              obtained the prior written consent of Ionis as required under the Ionis/Akcea Agreement with respect to the grant of such rights and licenses;</div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;"> <br>
              </font></div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;">14.2.2</font>&#160;&#160;&#160; Akcea has sufficient legal or beneficial title and ownership or right to license (or sublicense as the case may be) with respect to the
              Licensed Technology as is necessary to fulfill its obligations under this Agreement and to grant the licenses (or sublicenses as the case may be) to AstraZeneca pursuant to this Agreement;</div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;"> <br>
              </font></div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;">14.2.3</font>&#160;&#160;&#160; there is no (a) action, suit, claim, demand, dispute, proceeding, arbitration, inquiry, investigation or other legal action of any nature,
              civil, criminal, regulatory or otherwise, pending or, to Akcea&#8217;s Knowledge, threatened, against Akcea or any of its Affiliates or (b) judgement or settlement against or owed by Akcea or any of its Affiliates, in each case ((a) and (b)) in
              connection with the Licensed Technology, the Licensed Compound, or the Licensed Product or relating to the transactions contemplated by this Agreement (including any claim alleging that the Exploitation of the Licensed Compound or Licensed
              Product in the Territory infringes or misappropriates any intellectual property rights of a Third Party);</div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;"> <br>
              </font></div>
            <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
              <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">68</font></div>
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            </div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;">14.2.4</font>&#160;&#160;&#160; all officers, employees and contractors of Akcea or its Affiliates that are inventors of any of the inventions claimed in the Akcea Patent
              Rights or that have performed Development, Manufacturing or other Exploitation activities on behalf of Akcea or its Affiliates, as applicable, have entered into written agreements pursuant to which such Persons are obligated to assign all
              rights, title, and interests in and to any such inventions developed by them, whether or not patentable, to Akcea or such Affiliate, respectively, as the sole owner thereof;</div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;"> <br>
              </font></div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;">14.2.5</font>&#160;&#160;&#160; to Akcea&#8217;s Knowledge, no officer, employee or contractor of Akcea or its Affiliates is, or during the Term will be, subject to any agreement
              that requires such individual to assign any interest in any Licensed Technology to any Third Party;</div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;"> <br>
              </font></div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;">14.2.6</font>&#160;&#160;&#160; there are no additional licenses or rights (beyond those granted to AstraZeneca under this Agreement) under any intellectual property owned
              or Controlled by Akcea that would be required in order for AstraZeneca to Exploit the Licensed Compound and the Licensed Product that is being clinically Developed as of the Execution Date;</div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;"> <br>
              </font></div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;">14.2.7</font>&#160;&#160; the Licensed Technology constitutes all of the Patent Rights and Know-How owned or otherwise Controlled by Akcea and its Affiliates that are
              necessary to Exploit the Licensed Compound and the Licensed Product that is being clinically Developed as of the Execution Date;</div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;"> <br>
              </font></div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;">14.2.8</font>&#160;&#160;&#160; neither Akcea nor its Affiliates has previously assigned, transferred, conveyed, or otherwise encumbered its rights, title, or interests in
              or to the Licensed Technology in a manner that conflicts with any rights granted to AstraZeneca hereunder with respect to the Licensed Compound or the Licensed Product;</div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;"> <br>
              </font></div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;">14.2.9</font>&#160;&#160;&#160; other than the PTC Agreement, the Prior Agreements and the Permitted Licenses, neither Akcea nor any of its Affiliates is a party to any
              agreement with a Third Party that limits any of the rights and licenses that would be granted to AstraZeneca under this Agreement absent such agreement;</div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;"> <br>
              </font></div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;">14.2.10</font>&#160; (a) <u>Schedule </u><u>1.11</u> (Akcea Core Technology Patent Rights), <u>Schedule 1.18</u> (Akcea Manufacturing Patent Rights) and <u>Schedule

                1.23</u> (Akcea Product-Specific Patent Rights) set forth true, correct, and complete lists of all Patent Rights owned, licensed or otherwise Controlled by Akcea or any of its Affiliates that relate to the Licensed Compound or the Licensed
              Product, (b) except as otherwise indicated in <u>Schedule </u><u>1.11</u> (Akcea Core Technology Patent Rights), <u>Schedule 1.18</u> (Akcea Manufacturing Patent Rights) or <u>Schedule 1.23</u> (Akcea Product-Specific Patent Rights), each
              issued Akcea Patent Right is in full force and effect and each issued or pending Akcea Patent Right has been filed and prosecuted in good faith, and (c) Akcea or its Affiliates have timely paid all application, registration, maintenance and
              renewal fees payable with respect to such Patent Rights that are pending or granted and all necessary documents and certificates have been filed with the relevant agencies for the purpose of maintaining such Patent Rights;</div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;"> <br>
              </font></div>
            <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
              <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">69</font></div>
              <div style="page-break-after: always;" id="DSPFPageBreak">
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            </div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;">14.2.11</font>&#160; to Akcea&#8217;s Knowledge, no Third Party (a) is infringing, misappropriating or violating any Akcea Core Technology Patent Rights or Akcea
              Manufacturing Patent Rights (and there is no claim by Akcea that a Third Party is or was infringing, misappropriating or violating any Akcea Core Technology Patent Rights or Akcea Manufacturing Patent Rights) or misappropriating any Know-How
              included in the Akcea Core Technology IP or Akcea Manufacturing IP, in each case, with respect to a Competitive Oligo, (b) is infringing, misappropriating or violating any Akcea Product-Specific Patent Rights (and there is no claim by Akcea
              that a Third Party is or was infringing, misappropriating or violating any Akcea Product-Specific Patent Rights) or misappropriating any Know-How included in the Akcea Product-Specific IP, and (c) has challenged or threatened to challenge the
              inventorship, ownership, Akcea&#8217;s right to use, scope, validity or enforceability of any Akcea Patent Rights (including, by way of example, through the institution or written threat of institution of interferences, derivation, post-grant
              review, opposition, nullity, reexamination, reissue, revocation, <font style="font-style: italic;">inter partes</font> or similar invalidity proceedings before the United States Patent and Trademark Office or any analogous foreign
              Governmental Authority);</div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;"> <br>
              </font></div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;">14.2.12</font>&#160; Akcea has set forth on <u>Schedule </u><u>1.94</u> (Existing In-License Agreements) a true, correct, and complete list of all agreements
              pursuant to which a Third Party has granted Akcea or its Affiliates a license under any Know-How or Patent Rights that are necessary to Exploit the Licensed Compound or the Licensed Product, and all such Patent Rights and Know-How are
              included in the Licensed Technology. All Existing In-License Agreements are in full force and effect, and Akcea has provided AstraZeneca with true and complete copies of each such Existing In-License Agreement and all amendments thereto.
              Neither Akcea, its Affiliates nor, to Akcea&#8217;s Knowledge, the counterparty to an Existing In-License Agreement is in default with respect to a material obligation under such Existing In-License Agreement, and none of such parties has claimed
              or, to Akcea&#8217;s Knowledge, has grounds upon which to claim that the other party is in default with respect to a material obligation under any Existing In-License Agreement;</div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;"> <br>
              </font></div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;">14.2.13</font>&#160; neither Akcea nor its Affiliates have received any written claim alleging, and do not have Knowledge of any claim or any fact or circumstance
              indicating, that Exploitation of the Licensed Compound and Licensed Product infringe any Patent Rights or misappropriate or otherwise violate other intellectual property rights of a Third Party;</div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;"> <br>
              </font></div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;">14.2.14</font>&#160; no Licensed Technology has been created pursuant to, and is not subject to, any funding agreement with any government or Governmental
              Authority or any Third Party, and is not subject to the requirements of the Bayh-Dole Act or any similar provision of any applicable Law. No funding, facilities or personnel of any Governmental Authority were used, directly or indirectly, to
              develop or create, in whole or in part, any Licensed Technology;</div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;"> <br>
              </font></div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;">14.2.15</font>&#160;&#160; to Akcea&#8217;s Knowledge, no additional licenses or other intellectual property rights are required from any Third Party to conduct activities
              under the Development Plan and Budget as it exists on the Execution Date;</div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;"> <br>
              </font></div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;">14.2.16</font>&#160;&#160; each Regulatory Filing filed by Akcea or its Affiliates with respect to the Licensed Compound or the Licensed Product prior to the Execution
              Date and the Closing Date was true, complete and accurate in all material respects and timely filed;</div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;"> <br>
              </font></div>
            <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
              <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">70</font></div>
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            </div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;">14.2.17</font>&#160; any and all Regulatory Filings filed by Akcea or its Affiliates with respect to the Licensed Compound or the Licensed Product have been
              provided to AstraZeneca in an appropriate electronic format prior to the Execution Date. Neither Akcea nor its Affiliates or licensees has received any written notice or allegation from any Regulatory Authority regarding (a) any actual,
              alleged, possible, or potential violation of or failure to comply with any Law with respect to Regulatory Filings for the Licensed Product, or (b) any actual, proposed, or potential revocation, withdrawal, suspension, cancellation,
              termination, or modification of any Regulatory Filing for the Licensed Product, and, to Akcea&#8217;s Knowledge, there is no reasonable basis for any such notice or allegation;</div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;"> <br>
              </font></div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;">14.2.18</font>&#160;&#160; all preclinical and clinical investigations of the Licensed Product sponsored by Akcea or its Affiliates and all other Licensed Product
              Development activities of Akcea or its Affiliates have been and are being conducted in material compliance with applicable protocols, procedures, Laws, rules, regulations and guidances, including cGCP and applicable protocols, procedures,
              Laws, rules, regulations and guidances restricting the use and disclosure of individually identifiable health information. Neither Akcea nor its Affiliates has received any written notice from the FDA, the EMA or any other Regulatory
              Authority performing functions similar to those performed by those with respect to any ongoing clinical or pre-clinical studies or tests of the Licensed Product requiring the termination, suspension or material modification of such studies or
              tests, and no Governmental Authority has commenced any action to place a clinical hold order on, or otherwise terminate or suspend, any ongoing Clinical Trial of the Licensed Product conducted by or on behalf of Akcea or its Affiliates;</div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;"> <br>
              </font></div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;">14.2.19</font>&#160; all inventory of any API, drug product and packaged Clinical Trial material for the Licensed Product transferred from Akcea to AstraZeneca
              hereunder (a) meets and was Manufactured in accordance with all specifications and all applicable Laws and other regulatory requirements (including cGMP where applicable), (b) is free from contamination, diluents and defects in materials and
              workmanship, and (c) is not adulterated or misbranded;</div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;"> <br>
              </font></div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;">14.2.20</font>&#160; to Akcea&#8217;s Knowledge, neither Akcea nor any of its Affiliates has committed any act, or omitted to commit any act, that may cause the Akcea
              Patent Rights to expire prematurely or be declared invalid or unenforceable;</div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;"> <br>
              </font></div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;">14.2.21</font>&#160; to Akcea&#8217;s Knowledge, true, complete and correct copies of all material information with respect to the safety and efficacy of the Licensed
              Compound and the Licensed Product that are not otherwise publicly available have been provided to AstraZeneca;</div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;"> <br>
              </font></div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;">14.2.22</font>&#160;&#160; to Akcea&#8217;s Knowledge, there is no material omission from, or material misrepresentation in, [***] as of the Execution Date;</div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;"> <br>
              </font></div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;">14.2.23</font>&#160;&#160; neither Akcea nor any of its Affiliates has provided the Licensed Compound or the Licensed Product to a Third Party under the Prior
              Agreements or the Existing In-License Agreements;</div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;"> <br>
              </font></div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;">14.2.24</font>&#160; no consents from the Inbound Licensors under the In-License Agreements are required to enter into this Agreement and to grant the licenses to
              AstraZeneca hereunder, other than the consent from Ionis contained in that certain Letter Agreement by and among AstraZeneca, Akcea and Ionis, dated as of the Execution Date; and</div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;"> <br>
              </font></div>
            <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
              <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">71</font></div>
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            </div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;">14.2.25</font>&#160; neither Akcea nor its Affiliates has, regarding or related to the Licensed Compound, the Licensed Product or the Akcea Product-Specific IP,
              been subject to a corporate integrity agreement, deferred prosecution agreement, consent decree, monitoring agreement, settlement agreement or other similar agreement or Order mandating or prohibiting future or past activities.</div>
            <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold;"> <br>
              </font></div>
            <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold;">14.3</font>&#160;&#160;&#160;&#160;&#160;&#160; <font style="font-weight: bold;"><u>Covenants of the Parties</u></font>. From and after the Execution Date through the expiration or
              earlier termination of this Agreement, each Party covenants to the other Party as follows:</div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;"> <br>
              </font></div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;">14.3.1</font>&#160;&#160;&#160; such Party will not, during the Term, employ or use the services of any Person that is debarred, in connection with the Exploitation of the
              Licensed Products. If such Party becomes aware of the debarment or threatened debarment of any Person providing services to such Party that are directly or indirectly related to activities under this Agreement, including such Party itself or
              its Affiliates or Sublicensees, such Party will promptly notify the other Party in writing;</div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;"> <br>
              </font></div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;">14.3.2</font>&#160;&#160;&#160; during the Term, such Party will take reasonable precautions to preserve the confidentiality of the Know-How contained in the Licensed
              Technology, subject to <u>Article 13</u> (including authorized disclosures in <u>Section</u><u> 13.3</u>) (with, for the purposes of this <u>Section 14.3.2</u>, the exceptions to confidentiality available for a Receiving Party also
              applying to Akcea <font style="font-style: italic;">mutatis mutandis)</font>;</div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;"> <br>
              </font></div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;">14.3.3</font>&#160;&#160;&#160; (a) Akcea shall not, and shall cause its Affiliates not to, incur or permit to exist, with respect to any Licensed Technology, and (b)
              AstraZeneca shall not, and shall cause its Affiliates not to, incur or permit to exist, with respect to any AstraZeneca IP, in each case ((a) and (b)), any lien, encumbrance, charge, security interest, mortgage, liability, assignment, grant
              of license or other obligation that is or would be inconsistent with the licenses and other rights granted to the other Party under this Agreement.</div>
            <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold;"> <br>
              </font></div>
            <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold;">14.4</font>&#160;&#160;&#160;&#160;&#160;&#160; <font style="font-weight: bold;"><u>Covenants of Akcea</u></font>. From and after the Execution Date through the expiration or earlier
              termination of this Agreement, Akcea covenants to AstraZeneca as follows:</div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;"> <br>
              </font></div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;">14.4.1</font>&#160;&#160;&#160; Akcea will not enter into any agreement or other obligation with any Third Party, or amend an existing agreement with a Third Party, in each
              case, that would have an adverse effect on Akcea&#8217;s ability to grant the licenses (or sublicenses as the case may be) granted to AstraZeneca, or perform its obligations, under this Agreement; and</div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;"> <br>
              </font></div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;">14.4.2</font>&#160;&#160;&#160; with respect to any changes resulting from Akcea&#8217;s obligations under the last sentence of <u>Section 12.2.1(a)</u> and otherwise upon
              AstraZeneca&#8217;s reasonable written request (such request not to be submitted to Akcea more than once every Calendar Year), Akcea will promptly update <u>Schedule </u><u>1.11</u> (Akcea Core Technology Patent Rights), <u>Schedule 1.18</u>
              (Akcea Manufacturing Patent Rights) and <u>Schedule 1.23</u> (Akcea Product-Specific Patent Rights), and submit such amended Schedules to AstraZeneca;</div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;"> <br>
              </font></div>
            <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
              <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">72</font></div>
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            </div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;">14.4.3</font>&#160;&#160;&#160; Akcea and its Affiliates, as applicable, will at all times have obtained the necessary consents from the Inbound Licensors under the
              In-License Agreements to enter into this Agreement and to grant the licenses to AstraZeneca hereunder, and, upon AstraZeneca&#8217;s written request, will provide to AstraZeneca written evidence of same;</div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;"> <br>
              </font></div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;">14.4.4</font>&#160;&#160; neither Akcea nor its Affiliates will amend, modify, terminate, or waive any rights under any In-License Agreement, Prior Agreement or any
              agreement with an Authorized CMO listed on <u>Schedule 8.3.2</u>, in each case, in a manner that would adversely affect AstraZeneca&#8217;s rights or obligations under this Agreement without AstraZeneca&#8217;s prior written consent;</div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;"> <br>
              </font></div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;">14.4.5</font>&#160;&#160;&#160; neither Akcea nor its Affiliates will commit any acts or permit the occurrence of any omissions that would cause or result in the termination
              of any In-License Agreement or any agreement with an Authorized CMO listed on <u>Schedule 8.3.2</u> that is Manufacturing the API or drug product or Licensed Product being used to conduct the ongoing Phase 3 Clinical Trials as of the
              Execution Date, which termination would adversely affect AstraZeneca&#8217;s rights or obligations under this Agreement, without AstraZeneca&#8217;s prior written consent. Akcea or Ionis, as applicable, will notify AstraZeneca in writing within [***]
              after any such termination of any such agreement;</div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;"> <br>
              </font></div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;">14.4.6</font>&#160;&#160;&#160; Akcea or its Affiliates shall be and remain solely responsible for fulfilling and performing at its cost and expense, any and all obligations
              under each In-License Agreement, each Prior Agreement, and each agreement with an Authorized CMO listed on <u>Schedule</u><u> 8.3.2</u><u>,</u> including timely, full and complete payment of any and all amounts due thereunder or in
              connection therewith to the other parties thereto, and will otherwise remain, and cause its Affiliates to otherwise remain, in compliance in all material respects with all such agreements;</div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;"> <br>
              </font></div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;">14.4.7</font>&#160;&#160;&#160; Akcea will furnish AstraZeneca with copies of all notices received by Akcea or any of its Affiliates relating to any alleged breach or
              default by Akcea or any of its Affiliates under any In-License Agreement, Prior Agreement or agreement with an Authorized CMO listed on <u>Schedule</u><u> 8.3.2</u>, in each case, that would reasonably be expected to adversely affect
              AstraZeneca&#8217;s rights hereunder, promptly after receipt thereof and thereafter furnish AstraZeneca with copies of all correspondence and summaries of material discussions between the applicable parties to the In-License Agreement or Prior
              Agreement relating to the alleged breach, including any proposed resolution of the matter; and</div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;"> <br>
              </font></div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;">14.4.8</font>&#160;&#160;&#160; Akcea will promptly furnish AstraZeneca with true and complete copies of all Future In-License Agreements and all amendments to the
              In-License Agreements and Prior Agreements arising after the Execution Date.</div>
            <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold;"> <br>
              </font></div>
            <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold;">14.5</font>&#160;&#160; &#160; &#160; <font style="font-weight: bold;"><u>Disclaimer</u></font>. EXCEPT AS OTHERWISE EXPRESSLY SET FORTH IN THIS AGREEMENT, NEITHER PARTY MAKES
              ANY REPRESENTATION OR EXTENDS ANY WARRANTY OF ANY KIND, EITHER EXPRESS OR IMPLIED, INCLUDING ANY WARRANTY THAT ANY PATENTS ARE VALID OR ENFORCEABLE, AND EXPRESSLY DISCLAIMS ALL IMPLIED WARRANTIES OF MERCHANTABILITY, FITNESS FOR A PARTICULAR
              PURPOSE AND NON-INFRINGEMENT. BOTH PARTIES HEREBY ACKNOWLEDGE AND AGREE THAT THE OTHER PARTY MAKES (AND HAS MADE) NO REPRESENTATION OR WARRANTY, EITHER EXPRESS OR IMPLIED, AT LAW OR IN EQUITY, THAT THE COMPOUND OR PRODUCT WILL BE SUCCESSFUL,
              THAT IT WILL BE ABLE TO SUCCESSFULLY ACHIEVE THE MILESTONE EVENTS SET FORTH IN <u>ARTICLE 11</u> OR THAT IT WILL BE ABLE TO ACHIEVE ANY AMOUNT OF NET SALES, AND EACH PARTY SPECIFICALLY DISCLAIMS THAT IT IS RELYING UPON OR HAS RELIED UPON ANY
              SUCH REPRESENTATIONS OR WARRANTIES THAT MAY HAVE BEEN MADE BY ANY PERSON.</div>
            <div style="text-align: justify; text-indent: 36pt;"> <br>
            </div>
            <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
              <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">73</font></div>
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            </div>
            <div style="text-align: center; font-weight: bold;">ARTICLE 15</div>
            <div style="text-align: center; font-weight: bold;">INDEMNIFICATION; INSURANCE</div>
            <div style="text-align: center; font-weight: bold;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold;">15.1</font>&#160;&#160;&#160;&#160;&#160;&#160; <font style="font-weight: bold;"><u>Indemnification by AstraZeneca</u></font>. AstraZeneca will defend, and indemnify and hold harmless,
              Akcea and its Affiliates and its and their respective directors, officers, employees, agents, representatives, successors and assigns (collectively, the &#8220;<font style="font-weight: bold; font-style: italic;">Akcea Indemnified Parties</font>&#8221;),
              from and against any and all liabilities, damages, losses, costs and expenses, including interest penalties and reasonable attorneys&#8217; fees and expenses (collectively, &#8220;<font style="font-weight: bold; font-style: italic;">Losses</font>&#8221;), to
              the extent arising out of or resulting from any Third Party suits, claims, actions, proceedings or demands (&#8220;<font style="font-weight: bold; font-style: italic;">Third Party Claims</font>&#8221;) to the extent based upon:</div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;"> <br>
              </font></div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;">15.1.1</font>&#160;&#160;&#160; any breach of any representation, warranty or covenant made by AstraZeneca in this Agreement;</div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;"> <br>
              </font></div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;">15.1.2</font>&#160;&#160;&#160; the Exploitation of the Licensed Compound or Licensed Product by AstraZeneca or its Affiliates or its or their Sublicensees or
              subcontractors, other than Losses shared pursuant to <u>Section 15.3</u>; or</div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;"> <br>
              </font></div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;">15.1.3</font>&#160;&#160;&#160; the gross negligence or willful misconduct of AstraZeneca or any of the AstraZeneca Indemnified Parties in the exercise of their rights or
              performance of their obligations hereunder;</div>
            <div style="text-align: justify;"><font style="font-style: italic;">provided </font>that, in the case of each of <u>Sections 15.1.1</u> through <u>15.1.3</u> above, AstraZeneca will not be obligated to so defend, and indemnify and hold
              harmless, the Akcea Indemnified Parties for any Third Party Claim to the extent that such Third Party Claim is based upon an action or omission for which Akcea would have an obligation to indemnify the AstraZeneca Indemnified Parties under <u>Section

                15.2.1</u>, Section <u>15.2.2</u> or <u>Section 15.2.4</u> if such Loss were incurred by an AstraZeneca Indemnified Party.</div>
            <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold;"> <br>
              </font></div>
            <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold;">15.2</font>&#160;&#160;&#160;&#160; <font style="font-weight: bold;"><u>Indemnification by Akcea</u></font>. Akcea will defend, and indemnify and hold harmless, AstraZeneca and
              its Affiliates and its and their Sublicensees and its and their respective directors, officers, employees, agents, representatives, successors and assigns (collectively, the &#8220;<font style="font-weight: bold; font-style: italic;">AstraZeneca
                Indemnified Parties</font>&#8221;), from and against any and all Losses, to the extent arising out of or resulting from any Third Party Claims to the extent based upon:</div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;"> <br>
              </font></div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;">15.2.1</font>&#160;&#160;&#160; any breach of any representation, warranty or covenant made by Akcea in this Agreement;</div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;"> <br>
              </font></div>
            <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
              <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">74</font></div>
              <div style="page-break-after: always;" id="DSPFPageBreak">
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            </div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;">15.2.2</font>&#160;&#160;&#160; the Exploitation of the Licensed Compound or Licensed Product by Akcea or its Affiliates or subcontractors prior to the Closing Date;</div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;"> <br>
              </font></div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;">15.2.3</font>&#160;&#160;&#160; the Exploitation, including the Co-Commercialization and Medical Affairs Activities (if any), of the Licensed Compound or Licensed Product by
              Akcea or its Affiliates or subcontractors during the Term and after termination of this Agreement, other than Losses shared pursuant to <u>Section 15.3</u>; or</div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;"> <br>
              </font></div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;">15.2.4</font>&#160;&#160;&#160; the gross negligence or willful misconduct of Akcea or any of the Akcea Indemnified Parties in the exercise of their rights or performance of
              their obligations hereunder;</div>
            <div style="text-align: justify;"><font style="font-style: italic;">provided </font>that, in the case of each of <u>Sections 15.2.1</u> through <u>15.2.4</u> above, Akcea will not be obligated to so defend, and indemnify and hold harmless,
              the AstraZeneca Indemnified Parties for any Third Party Claim to the extent that such Third Party Claim is based upon an action or omission for which AstraZeneca would have an obligation to indemnify the Akcea Indemnified Parties under <u>Section</u><u>
                15.1.1</u> or <u>Section 15.1.3</u>&#160;if such Loss were incurred by an Akcea Indemnified Party.</div>
            <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold;"> <br>
              </font></div>
            <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold;">15.3</font>&#160;&#160;&#160;&#160;&#160; <font style="font-weight: bold;"><u>Losses in the U.S</u></font>. All<font style="font-weight: bold;">&#160;</font>Losses incurred by either
              Party arising from any Third Party Claim relating to the Exploitation of a Licensed Product in the U.S. after the Closing Date and prior to the Opt-Out Date (if any) during the Term will be shared by the Parties as an Other Operating Expense
              in accordance with <u>Section 11.10</u>, <font style="font-style: italic;">provided</font> that such Other Operating Expenses will not include Losses of a Party or its Affiliate to the extent such Losses are: (a) caused by a breach of this
              Agreement by a Party or Affiliate; or (b) caused by the gross negligence or willful misconduct of a Party or its Affiliate, and any such Losses described in clause (a) or (b) will not be shared by the Parties. If either Party learns of any
              Third Party Claim with respect to Losses covered by this <u>Section </u><u>15.3</u>, such Party shall provide the other Party with prompt written notice thereof. The Parties shall confer with respect to how to respond to such Third Party
              Claim and how to handle such Third Party Claim in an efficient manner. In the absence of such an agreement, each Party shall have the right to take such action as it deems appropriate.</div>
            <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold;"> <br>
              </font></div>
            <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold;">15.4</font>&#160;&#160;&#160;&#160;&#160;&#160; <font style="font-weight: bold;"><u>Procedure</u></font>.</div>
            <div style="text-align: justify; text-indent: 36pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;">15.4.1</font>&#160;&#160; <font style="font-weight: bold;"><u>Notice of Claim</u></font>. All indemnification claims provided for in <u>Section</u><u> 15.1 </u>and <u>Section</u><u>
                15.2</u>&#160;will be made solely by such Party to this Agreement (the &#8220;<font style="font-weight: bold; font-style: italic;">Indemnified Party</font>&#8221;). The Indemnified Party will give the indemnifying Party prompt written notice (an &#8220;<font style="font-weight: bold; font-style: italic;">Indemnification Claim Notice</font>&#8221;) of any Losses or the discovery of any fact upon which the Indemnified Party intends to base a request for indemnification under <u>Section</u><u> 15.1 </u>or

              <u>Section </u><u>15.2</u>, but in no event will the indemnifying Party be liable for any Losses to the extent such Losses result from any delay in providing such notice. Each Indemnification Claim Notice must contain a description of the
              claim and the nature and amount of such Loss (to the extent that the nature and amount of such Loss is known at such time). The Indemnified Party will furnish promptly to the indemnifying Party copies of all papers and official documents
              received in respect of any Losses and Third Party Claims.</div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;"> <br>
              </font></div>
            <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
              <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">75</font></div>
              <div style="page-break-after: always;" id="DSPFPageBreak">
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            </div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;">15.4.2</font>&#160;&#160;&#160; <font style="font-weight: bold;"><u>Control of Defense</u></font>. At its option, the indemnifying Party may assume the defense of any Third
              Party Claim by giving written notice to the Indemnified Party within [***] after the indemnifying Party&#8217;s receipt of an Indemnification Claim Notice. The assumption of the defense of a Third Party Claim by the indemnifying Party will not be
              construed as an acknowledgment that the indemnifying Party is liable to indemnify the Indemnified Party in respect of the Third Party Claim, nor will it constitute a waiver by the indemnifying Party of any defenses it may assert against the
              Indemnified Party&#8217;s claim for indemnification. Upon assuming the defense of a Third Party Claim, the indemnifying Party may appoint as lead counsel in the defense of the Third Party Claim any legal counsel selected by the indemnifying Party.
              In the event the indemnifying Party assumes the defense of a Third Party Claim, the Indemnified Party will as soon as is reasonably possible deliver to the indemnifying Party all original notices and documents (including court papers)
              received by the Indemnified Party in connection with the Third Party Claim. Should the indemnifying Party assume the defense of a Third Party Claim, except as provided in this <u>Section</u><u> 15.4.2</u>, the Indemnified Party will be
              responsible for the legal costs or expenses subsequently incurred by such Indemnified Party in connection with the analysis, defense or settlement of the Third Party Claim.</div>
            <div style="text-align: justify; text-indent: 72pt;"> <br>
            </div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;">15.4.3</font>&#160;&#160; <font style="font-weight: bold;"><u>Right to Participate in Defense</u></font>. Without limiting <u>Section</u><u> 15.4.2</u>, any
              Indemnified Party will be entitled to participate in, but not control, the defense of such Third Party Claim and to employ counsel of its choice for such purpose; <font style="font-style: italic;">provided, however</font>, that such
              employment will be at the Indemnified Party&#8217;s own cost and expense unless (a) the employment thereof has been specifically authorized by the indemnifying Party in writing, (b) the indemnifying Party has failed to assume the defense and employ
              counsel in accordance with <u>Section</u><u> 15.4.2</u>&#160;(in which case the Indemnified Party will control the defense), or (c) the interests of the Indemnified Party and the indemnifying Party with respect to such Third Party Claim are
              sufficiently adverse to prohibit the representation by the same counsel of both Parties under applicable Law, ethical rules or equitable principles in which case the indemnifying Party will be responsible for any such costs and expenses of
              counsel for the Indemnified Party.</div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;"> <br>
              </font></div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;">15.4.4</font>&#160;&#160;&#160; <font style="font-weight: bold;"><u>Settlement</u></font>. With respect to any Third Party Claims relating solely to the payment of money
              damages in connection with a Third Party Claim and that will not admit liability or violation of Law on the part of the Indemnified Party or result in the Indemnified Party&#8217;s becoming subject to injunctive or other relief or otherwise
              adversely affecting the business of the Indemnified Party in any manner (such as granting a license or admitting the invalidity of a Patent Right Controlled by an Indemnified Party), and as to which the indemnifying Party will have
              acknowledged in writing the obligation to indemnify the Indemnified Party hereunder, the indemnifying Party will have the sole right to consent to the entry of any judgment, enter into any settlement or otherwise dispose of such Loss, on such
              terms as the indemnifying Party, in its sole discretion, will deem appropriate. With respect to all other Losses in connection with Third Party Claims, where the indemnifying Party has assumed the defense of the Third Party Claim in
              accordance with <u>Section</u><u> 15.4.2</u>, the indemnifying Party will have authority to consent to the entry of any judgment, enter into any settlement or otherwise dispose of such Loss provided it obtains the prior written consent of
              the Indemnified Party (which consent will not be unreasonably withheld, conditioned or delayed). The indemnifying Party will not be liable for any settlement, consent to entry of judgment, or other disposition of a Loss by an Indemnified
              Party that is reached without the written consent of the indemnifying Party. Regardless of whether the indemnifying Party chooses to defend or prosecute any Third Party Claim, no Indemnified Party will admit any liability with respect to or
              settle, compromise or discharge, any Third Party Claim without the prior written consent of the indemnifying Party, such consent not to be unreasonably withheld, conditioned or delayed.</div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;"> <br>
              </font></div>
            <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
              <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">76</font></div>
              <div style="page-break-after: always;" id="DSPFPageBreak">
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            </div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;">15.4.5</font>&#160;&#160;&#160; <font style="font-weight: bold;"><u>Cooperation</u></font>. Regardless of whether the indemnifying Party chooses to defend or prosecute any
              Third Party Claim, the Indemnified Party will, and will cause each other Indemnified Party to, cooperate in the defense or prosecution thereof and will furnish such records, information and testimony, provide such witnesses and attend such
              conferences, discovery proceedings, hearings, trials and appeals as may be reasonably requested in connection therewith. Such cooperation will include affording to the indemnifying Party access during normal business hours to, and reasonable
              retention by the Indemnified Party of, records and information that are reasonably relevant to such Third Party Claim, and making Indemnified Parties and other employees and agents available on a mutually convenient basis to provide
              additional information and explanation of any material provided hereunder, and the indemnifying Party will reimburse the Indemnified Party for all its reasonable Out-Of-Pocket Costs in connection therewith.</div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;"> <br>
              </font></div>
            <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold;">15.4.6</font>&#160;&#160;&#160; <font style="font-weight: bold;"><u>Costs and Expenses</u></font>. Except as provided above in this <u>Section</u><u> 15.4</u>, the costs
              and expenses, including attorneys&#8217; fees and expenses, incurred by the Indemnified Party in connection with any claim will be reimbursed [***] by the indemnifying Party, without prejudice to the indemnifying Party&#8217;s right to contest the
              Indemnified Party&#8217;s right to indemnification and subject to refund in the event the indemnifying Party is ultimately held not to be obligated to indemnify the Indemnified Party.</div>
            <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold;"> <br>
              </font></div>
            <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold;">15.5</font>&#160;&#160;&#160;&#160;&#160; <font style="font-weight: bold;"><u>Insurance</u></font>. Each Party will maintain with insurers with a minimum &#8220;A-&#8221; AM Best rating, at its
              own cost, reasonable insurance against liability and other risks associated with its activities and obligations under this Agreement, including its Development, Manufacturing, Commercialization and other Exploitation activities, as
              applicable, and its indemnification obligations hereunder, in such amounts (subject to such deductibles, which are the sole responsibility of the named insured) and on such terms as are reasonable and customary for prudent practices for a
              company of similar size and of similar resources as such Party for the activities to be conducted by it under this Agreement. Each Party will promptly furnish to the other Party evidence of such insurance prior to the Closing Date and
              annually thereafter. Each Party will provide a minimum of [***] written notice of any cancellation, with no replacement policy, to the other Party. All insurance of a Party will be primary and non-contributing to any insurance carried by the
              other Party, to the extent of the first Party&#8217;s indemnification obligations. Notwithstanding the foregoing, AstraZeneca may self-insure, in whole or in part, the insurance requirements described in this <u>Section</u><u> 15.5</u>.</div>
            <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold;"> <br>
              </font></div>
            <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold;">15.6</font>&#160;&#160;&#160;&#160;&#160; <font style="font-weight: bold;"><u>Damages Waiver</u></font>. EXCEPT FOR (A) CLAIMS OF A THIRD PARTY THAT ARE SUBJECT TO INDEMNIFICATION
              UNDER THIS <u>ARTICLE 15</u> OR <u>SECTION 11.13.3</u>. (B) CLAIMS ARISING OUT OF A PARTY&#8217;S WILLFUL MISCONDUCT, (C) A PARTY&#8217;S BREACH OF <u>SECTION 9.2</u> OR (D) CLAIMS ARISING OUT OF A PARTY&#8217;S BREACH OF ITS CONFIDENTIALITY OBLIGATIONS
              UNDER THIS AGREEMENT, NEITHER PARTY NOR ANY OF ITS AFFILIATES WILL BE LIABLE TO THE OTHER PARTY TO THIS AGREEMENT OR ITS AFFILIATES FOR ANY INCIDENTAL, CONSEQUENTIAL, SPECIAL, PUNITIVE OR OTHER INDIRECT DAMAGES OR LOST OR IMPUTED PROFITS OR
              ROYALTIES, LOST DATA OR COST OF PROCUREMENT OF SUBSTITUTE GOODS OR SERVICES, WHETHER LIABILITY IS ASSERTED IN CONTRACT, TORT (INCLUDING NEGLIGENCE AND STRICT PRODUCT LIABILITY), INDEMNITY OR CONTRIBUTION, AND IRRESPECTIVE OF WHETHER THAT
              PARTY OR ANY REPRESENTATIVE OF THAT PARTY HAS BEEN ADVISED OF, OR OTHERWISE MIGHT HAVE ANTICIPATED THE POSSIBILITY OF, ANY SUCH LOSS OR DAMAGE.</div>
          </div>
          <div><br>
          </div>
        </div>
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  <div>
    <div style="text-align: center; font-weight: bold; font-size: 10pt;">ARTICLE 16</div>
    <div style="text-align: center; font-weight: bold; font-size: 10pt;">TERM AND TERMINATION<a name="TERMANDTERMINATION"><!--Anchor--></a></div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; font-size: 10pt;">16.1</font><font style="font-size: 10pt;">&#160;&#160; <a name="Term."><!--Anchor--></a>&#160;&#160;&#160; <font style="font-weight: bold;"><u>Term</u></font>. The term of
        this Agreement will commence as of the Closing Date and, unless terminated earlier, shall (a) with respect to the ROW Territory, on a Licensed Product-by-Licensed Product and country-by-country basis, continue until the expiration of the Royalty
        Term for such Licensed Product in such country and (b) with respect to the U.S., (i) if Akcea does not exercise its Opt-Out Right, until the Parties (and their Affiliates and its and their sublicensees) cease all Development, Commercialization and
        Medical Affairs activities for the Licensed Product in the U.S. and (ii) if Akcea exercises its Opt-Out Right, until expiration of the Royalty Term for such Licensed Product in the U.S. (the &#8220;<font style="font-weight: bold; font-style: italic;">Term</font>&#8221;).


        If the Closing Date has not occurred by the [***] following the Execution Date, then this Agreement may be terminated by either Party upon written notice to the other Party, <font style="font-style: italic;">provided</font> that a Party shall not
        be entitled to terminate this Agreement pursuant to this sentence if such Party is in breach of this Agreement and such breach has caused the Closing Date to not occur by such date.</font></div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; font-size: 10pt;">16.2</font><font style="font-size: 10pt;">&#160;&#160;&#160;&#160;&#160;&#160; <font style="font-weight: bold;"><u>Termination</u></font>.</font></div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold; font-size: 10pt;">16.2.1</font><font style="font-size: 10pt;">&#160;&#160;&#160; <font style="font-weight: bold;"><u>Termination for Material Breach</u></font>.</font></div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: justify; text-indent: 108pt; font-size: 10pt;">(a)&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;If a Party (the &#8220;<font style="font-weight: bold; font-style: italic;">Breaching Party</font>&#8221;) materially breaches this Agreement (including any material breach of such
      Party&#8217;s diligence obligations pursuant to <u>Section 2.1</u> or <u>Section </u><u>3.1.1</u>, as applicable), in addition to any other right and remedy the other Party (the &#8220;<font style="font-weight: bold; font-style: italic;">Non-Breaching Party</font>&#8221;)



      may have, the Non-Breaching Party may terminate this Agreement in its entirety upon written notice to the Breaching Party if the Breaching Party, after receiving written notice identifying such material breach in reasonable detail (a &#8220;<font style="font-weight: bold; font-style: italic;">Default</font><font style="font-style: italic;">&#160;</font><font style="font-weight: bold; font-style: italic;">Notice</font>&#8221;), fails to cure such material breach within [***] after delivery of the
      Default Notice (or within [***] after delivery of the Default Notice if such material breach is solely based on the Breaching Party&#8217;s failure to pay any amounts due hereunder) (such [***] or [***] period, as applicable, the &#8220;<font style="font-weight: bold; font-style: italic;">Cure Period</font>&#8221;); <font style="font-style: italic;">provided</font> that (i) if such breach (other than a payment breach) cannot be cured within the Cure Period, if the Breaching Party commences actions to cure such
      breach within the Cure Period and thereafter diligently continues such actions, then the termination shall not become effective unless and until the Breaching Party fails to diligently continue such actions, and (ii) with respect to any alleged
      breach by the Breaching Party of its diligence obligations set forth in <u>Section</u><u> 2.1</u>&#160;or <u>Section</u><u> 3.1.1</u>, as applicable, the Non-Breaching Party shall first provide written notice thereof to the Breaching Party, and the
      Parties shall meet and confer to discuss and resolve the matter in good faith, and attempt to devise a mutually agreeable plan to address any outstanding issues for not less than [***] (or such longer period as may be mutually agreed by the Parties)
      before the Non-Breaching Party may issue any Default Notice with respect to such alleged breach (for clarity, the Cure Period shall not commence prior to the conclusion of such good faith discussions and the subsequent issuance of a Default Notice by
      Non-Breaching Party).</div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
      <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">78</font></div>
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    </div>
    <div style="text-align: justify; text-indent: 108pt; font-size: 10pt;">(b)&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;Notwithstanding <u>Section</u><u> 16.2.1(a)</u>, if the material breach and failure to cure contemplated in <u>Section</u><u> 16.2.1(a)</u>&#160;is with respect to
      AstraZeneca&#8217;s diligence obligations under <u>Section</u><u> 2.1</u>&#160;or <u>Section</u><u> 3.1.1</u>&#160;with respect to the Development or Commercialization of a Licensed Product, but does not affect, and is not reasonably likely to affect, [***], Akcea
      shall not have the right to terminate this Agreement in its entirety, but shall have the right to terminate this Agreement solely with respect to [***] that are affected by, or reasonably likely to be affected by, such material breach, and this
      Agreement shall remain in full force and effect with respect to [***] that are not affected, or not reasonably likely to be affected.</div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: justify; text-indent: 108pt; font-size: 10pt;">(c)&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;<font style="font-weight: bold;"><u>Disputes Regarding Material Breach</u></font>. Notwithstanding the foregoing, if the Breaching Party disputes in good faith the
      existence, materiality or failure to cure of any alleged uncured material breach, and provides notice to the Non-Breaching Party of such dispute within the relevant Cure Period, then the Non-Breaching Party will not have the right to terminate this
      Agreement in accordance with <u>Section 16.2.1</u>, unless and until (i) it has been determined in accordance with <u>Section 17.1</u> that this Agreement was materially breached by the Breaching Party and (ii) the Breaching Party fails to cure
      such material breach within [***] after such determination. It is understood and acknowledged that during the pendency of such dispute, all the terms and conditions of this Agreement will remain in effect and the Parties will continue to perform all
      of their respective obligations hereunder, including satisfying any payment obligations.</div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold; font-size: 10pt;">16.2.2</font><font style="font-size: 10pt;">&#160;&#160;&#160; <font style="font-weight: bold;"><u>AstraZeneca&#8217;s Termination for Convenience</u></font>. At any
        time following payment by AstraZeneca of the upfront fees under <u>Section 11.1</u>, AstraZeneca will be entitled to terminate this Agreement, on a region-by-region basis, for convenience by providing [***] written notice to Akcea of such
        termination. For purposes of this <u>Section </u><u>16.2.2</u>, &#8220;region&#8221; shall mean each of the U.S. and the ROW Territory.</font></div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
      <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">79</font></div>
      <div style="page-break-after:always;" id="DSPFPageBreak">
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    </div>
    <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold; font-size: 10pt;">16.2.3</font><font style="font-size: 10pt;">&#160;&#160; <font style="font-weight: bold;"><u>Termination for Patent Challenge</u></font>. If AstraZeneca or
        any of its Affiliates (a) commences or actively, directly and voluntarily participates in any action or proceeding (including any patent opposition or re-examination proceeding), or otherwise asserts any claim, challenging or denying the validity
        or enforceability of any claim of any Akcea Patent Right that is licensed to AstraZeneca under this Agreement or (b) actively assists any other person or entity in bringing or prosecuting any action or proceeding (including any patent opposition or
        re-examination proceeding) challenging or denying the validity or enforceability of any claim of any such Akcea Patent Right (each of (a) and (b), a &#8220;<font style="font-weight: bold; font-style: italic;">Patent Challenge</font>&#8221;), then, except as
        otherwise set forth in this <u>Section</u><u> 16.2.3</u>, Akcea shall have the right, in its sole discretion, to give notice to AstraZeneca that Akcea may terminate this Agreement [***] following such notice, and, unless AstraZeneca and its
        Affiliates withdraw or cause to be withdrawn such Patent Challenge(s) (or in the case of<font style="font-style: italic;"> ex-parte</font> proceedings, multi-party proceedings, or other Patent Challenges that AstraZeneca or its Affiliate does not
        have the power to unilaterally withdraw or cause to be withdrawn, AstraZeneca and its Affiliates cease actively assisting any other party to such Patent Challenge and, to the extent AstraZeneca or any of its Affiliates is a party to such Patent
        Challenge, it withdraws from such Patent Challenge) within such [***] period, Akcea shall have the right to terminate this Agreement by providing written notice thereof to AstraZeneca, unless such termination is prohibited under applicable Law.
        Notwithstanding the foregoing, any participation by AstraZeneca or its Affiliates or its or their employees in any claim, challenge or proceeding (i) that has been compelled by a court, patent office, or Third Party (other than any Sublicensee) or
        as required under a pre-existing agreement between AstraZeneca&#8217;s employee(s) or consultant(s) and their prior employer(s) or (ii) that is necessary or reasonably required to assert a cross-claim or a counterclaim or to respond to a court request or
        order or administrative law request or order, including asserting any defense or counterclaim in, or otherwise responding to an action for infringement of intellectual property asserted, filed, or threatened to be filed, against AstraZeneca or its
        Affiliate by Akcea or any of its Affiliates or its (sub)licensees, in each case ((i) and (ii)), shall not constitute active and voluntary participation or active assistance and shall not give rise to Akcea&#8217;s right to terminate this Agreement. In
        addition, Akcea shall not have the right to terminate this Agreement pursuant to this <u>Section</u><u> 16.2.3</u>&#160;if any Affiliate that first becomes an Affiliate of AstraZeneca after the Closing Date was undertaking activities in connection with
        a Patent Challenge prior to such Affiliate first becoming an Affiliate of AstraZeneca if such Affiliate withdraws or causes to be withdrawn such Patent Challenge (or in the case of<font style="font-style: italic;"> ex-parte</font> proceedings,
        multi-party proceedings, or other Patent Challenges that such Affiliate does not have the power to unilaterally withdraw or cause to be withdrawn, ceases actively assisting any other party to such Patent Challenge and, to the extent such Affiliate
        is a party to such Patent Challenge, withdraws from such Patent Challenge) within the earlier to occur of (A) [***] and (B) [***], and in all cases, <font style="font-style: italic;">provided</font>, that neither AstraZeneca nor any AstraZeneca
        Affiliate thereafter continues such Patent Challenge or, knowingly, the provision of any active assistance to any person or entity in respect of the same. Each Sublicense shall contain a provision that is consistent with this <u>Section </u><u>16.2.3</u>
        with respect to Patent Challenges by the applicable Sublicensee. If a Sublicensee commences or actively, directly and voluntarily participates in, or actively assists any other person or entity in bringing or prosecuting any Patent Challenge, and
        fails to withdraw or cause to be withdrawn or cease actively assisting any other party to such Patent Challenge in accordance with the requirements of this <u>Section </u><u>16.2.3</u>, then, subject to the exceptions set forth above (applied <font style="font-style: italic;">mutatis mutandis </font>to Sublicensees), AstraZeneca shall terminate the applicable Sublicense and, <font style="font-style: italic;">provided</font> that AstraZeneca timely terminates such Sublicense, Akcea shall
        not have a termination right under this <u>Section </u><u>16.2.3</u> as a result of such Patent Challenge.</font></div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold; font-size: 10pt;">16.2.4</font><font style="font-size: 10pt;">&#160;&#160;&#160; <font style="font-weight: bold;">Termination for Insolvency</font>. In the event that either Party
        (a) files for protection under bankruptcy or insolvency laws, (b) makes an assignment for the benefit of creditors, (c) appoints or suffers appointment of a receiver or trustee over substantially all of its property that is not discharged within
        [***] after such filing, (d) proposes a written agreement of composition or extension of its debts, (e) proposes or is a party to any dissolution or liquidation, (f) files a petition under any bankruptcy or insolvency act or has any such petition
        filed against it that is not discharged within [***] after the filing thereof or (g) admits in writing to its creditors its inability generally to meet its obligations as they fall due in the general course, then the other Party may terminate this
        Agreement in its entirety effective immediately upon written notice to such Party.</font></div>
    <div style="font-size: 10pt;">&#160;</div>
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      <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">80</font></div>
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    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; font-size: 10pt;">16.3</font><font style="font-size: 10pt;">&#160;&#160;&#160;&#160;&#160; <a name="EffectsofTermination."><!--Anchor--></a>&#160; <font style="font-weight: bold;"><u>Effects of
            Termination</u></font>.</font></div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold; font-size: 10pt;">16.3.1</font><font style="font-size: 10pt;">&#160;&#160;&#160; <font style="font-weight: bold;"><u>In General</u></font>. Without limiting any other legal or
        equitable remedies that either Party may have, if this Agreement is terminated in its entirety pursuant to <u>Section 16.2</u>, then the following will occur:</font></div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: justify; text-indent: 108pt; font-size: 10pt;">(a)&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;except as required to perform activities under this <u>Section 16.3</u>, including the Transition Services, the license grants to AstraZeneca under <u>Section</u><u>
        8.1</u>&#160;and to Akcea under <u>Section</u><u> 8.2</u> will terminate immediately and be of no further force or effect. Subject to <u>Section </u><u>16.3.3</u> and except as required to perform activities under this <u>Section 16.3</u>, including
      the Transition Services, AstraZeneca shall, and, subject to <u>Section </u><u>8.5</u>, shall cause its Affiliates and its and their Sublicensees to, cease selling the Licensed Product.</div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: justify; text-indent: 108pt; font-size: 10pt;">(b)&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;<font style="font-weight: bold;">Reversion License</font>.</div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: justify; text-indent: 144pt; font-size: 10pt;">(i)&#160;&#160;&#160;&#160; &#160; &#160; Except with respect to any termination by AstraZeneca pursuant to <u>Section</u><u> 16.2.1(a)</u>&#160;or <u>Section</u><u> 16.2.4</u>, upon Akcea&#8217;s request, which request
      must be made no later than the later of (A) [***] after the effective date of termination and (B) [***] following written notice by AstraZeneca to Akcea asking Akcea to confirm if Akcea wishes to have AstraZeneca grant the Reversion License, subject
      to the remaining subsections of this <u>Section</u><u> 16.3.1(b)</u>, AstraZeneca agrees to grant and hereby grants to Akcea, effective as of the effective date of such termination, a perpetual, non-exclusive, royalty-bearing (solely as set forth in
      <u>Section 16.3.1(b)(ii)</u>) license under the AstraZeneca Reversion IP<font style="font-weight: bold; font-style: italic;">&#160;</font>Controlled by AstraZeneca or any of its Affiliates as of the effective date of termination that is [***] as of the
      effective date of such termination for the Exploitation of the Licensed Product in the Field in the Terminated Territory to Exploit the Licensed Product in the Field in the Terminated Territory (the &#8220;<font style="font-weight: bold; font-style: italic;">Reversion License</font>&#8221;).<font style="font-weight: bold; font-style: italic;">&#160;</font>For clarity, the Reversion License will exclude any Know-How and Patent Rights that are related to or claim (1) [***] or (2) [***] as of the effective
      date of such termination to Exploit the Licensed Product as it is being Commercialized by AstraZeneca or its Affiliates in the applicable Terminated Territory as of the effective date of termination.</div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: justify; text-indent: 144pt; font-size: 10pt;">(ii)&#160;&#160;&#160;&#160;&#160; &#160; Without limiting Akcea&#8217;s obligations in <u>Section 16.3.1(b)(iii)</u>, the Reversion License shall be royalty-free if the Agreement is terminated by Akcea pursuant to <u>Section







        16.2.1</u> or <u>Section 16.2.4</u>. In all other events of termination, the Reversion License shall be royalty-bearing as follows: (A) if the effective date of the termination occurs prior to [***], then Akcea will pay AstraZeneca [***], or (B)
      if the effective date of termination occurs after [***], then Akcea will pay AstraZeneca [***]. The Reversion License will be granted on the effective date of termination regardless of if the Parties have reached agreement on the [***] terms of such
      Reversion License; <font style="font-style: italic;">provided</font> that [***] will be due [***] as of the effective date of termination on the terms subsequently agreed to by the Parties. Once the Parties have reached agreement on such terms,
      Akcea will pay [***] from the effective date of termination through the date of such agreement within [***] after receipt of an invoice from AstraZeneca. For purposes of this <u>Section</u><u> 16.3.1(b)</u>, the definition of &#8220;Net Sales,&#8221; shall
      apply <font style="font-style: italic;">mutatis mutandis</font> to Akcea&#8217;s obligations to pay royalties under this <u>Section</u><u> 16.3.1(b)</u>&#160;as they apply to AstraZeneca and, solely for such purpose, each reference (and any related
      definitions) to (1) AstraZeneca shall be deemed to be a reference to Akcea, (2) Akcea shall be deemed to be a reference to AstraZeneca and (3) a Sublicensee shall be deemed to be a reference to a licensee or sublicensee of Akcea or its Affiliates.</div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
      <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">81</font></div>
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    </div>
    <div style="text-align: justify; text-indent: 144pt; font-size: 10pt;">(iii)&#160;&#160;&#160;&#160;&#160;&#160;&#160; To the extent that any AstraZeneca Reversion IP that is the subject of the Reversion License is in-licensed by AstraZeneca or any of its Affiliates, AstraZeneca shall
      provide a copy of such in-license or other agreement to Akcea (which copy may be redacted as necessary to comply with its obligations of confidentiality to the counterparty <font style="font-style: italic;">provided</font> that such redactions do
      not undermine Akcea&#8217;s ability to comply with such in-license or understand the [***] if it were to take a sublicense). Akcea will promptly notify AstraZeneca if the Reversion License should include such in-licensed AstraZeneca Reversion IP. If Akcea
      elects to take a sublicense under such in-license as part of the Reversion License, then (A) any license to Akcea under such AstraZeneca Reversion IP pursuant to the Reversion License shall be subject to the terms and conditions of such in-license,
      (B) Akcea shall (1) provide the necessary reporting information to AstraZeneca in sufficient time as reasonably requested by AstraZeneca to enable AstraZeneca to comply with its obligations under such in-license and AstraZeneca&#8217;s obligation to [***]
      pursuant to clause (2), (2) [***] and (3) not, and shall cause its Affiliates and (sub)licensees not to, take or fail to take any action if doing so (or not doing so) would cause AstraZeneca to be in breach of such in-license to the extent that any
      applicable obligations have been disclosed to Akcea and (C) [***]. For any in-licensed AstraZeneca Reversion IP that is the subject to the Reversion License but is also applicable to other products, the Parties shall use good faith efforts to
      appropriately allocate any upfront fees or sales milestones to Akcea&#8217;s or its Affiliate&#8217;s or sublicensee&#8217;s practice of such sublicensed intellectual property that is included in the Reversion License and such other products.</div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: justify; text-indent: 144pt; font-size: 10pt;">(iv)&#160;&#160;&#160;&#160;&#160;&#160;&#160; Except with respect to any termination by AstraZeneca pursuant to <u>Section 16.2.1(a)</u> or <u>Section 16.2.4</u>, upon Akcea&#8217;s request, which request must be made
      no later than the later of (A) [***] and (B) [***], the Parties will negotiate in good faith and on commercially reasonable terms, a perpetual, non-exclusive license under the Know-How and Patents<font style="font-weight: bold; font-style: italic;">&#160;</font>Controlled







      by AstraZeneca or any of its Affiliates (other than Joint Know-How and Joint Patents) as of the effective date of termination that are not included in the Reversion License and that are necessary to Exploit the Licensed Product in the Field in the
      Terminated Territory as such Licensed Product is being clinically Developed by AstraZeneca or its Affiliates in the applicable Terminated Territory as of the effective date of termination.</div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: justify; text-indent: 108pt; font-size: 10pt;">(c)&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160; Except with respect to any termination by AstraZeneca pursuant to <u>Section</u><u> 16.2.1(a)</u>&#160;or <u>Section</u><u> 16.2.4</u>, AstraZeneca and its Affiliates will
      (i) assign to Akcea, upon Akcea&#8217;s request, any contracts (including Supply Agreements) that are solely related to the Licensed Product in the Terminated Territory and freely assignable by AstraZeneca or its Affiliates at [***] AstraZeneca or its
      Affiliates (or for which Akcea agrees to [***]), (ii) use commercially reasonable efforts to obtain the applicable counter-party&#8217;s consent to assign any such contracts that are not freely assignable, (iii) to the extent any contracts (including
      Supply Agreements) related to the Licensed Product in the Terminated Territory are not assigned to Akcea because such contracts are either not solely related to the Licensed Product in the Terminated Territory or not freely assignable, facilitate the
      replication of such agreements between Akcea and such Third Party and (iv) supply Licensed Product to Akcea at [***] to ensure continuity of supply of Licensed Product to patients in the Terminated Territory until the earlier of (1) [***] and (2) the
      assignment or replication of all Supply Agreements related to the Licensed Product in the Terminated Territory pursuant to this <u>Section 16.3.1(c)</u>, or Akcea otherwise entering into supply agreement(s) with Third Parties sufficient to ensure
      such continuity of supply;</div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
      <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">82</font></div>
      <div style="page-break-after:always;" id="DSPFPageBreak">
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    </div>
    <div style="text-align: justify; text-indent: 108pt; font-size: 10pt;">(d)&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;AstraZeneca will provide to Akcea a detailed, fair and accurate description of the status of the Exploitation of the Licensed Product in each country in the Terminated
      Territory through the effective date of termination; and</div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: justify; text-indent: 108pt; font-size: 10pt;">(e)&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;AstraZeneca will, and will ensure that its Affiliates and its and their Sublicensees, execute all documents and take all such further actions as may be reasonably
      requested by Akcea in order to give effect to the foregoing clauses.</div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold; font-size: 10pt;">16.3.2</font><font style="font-size: 10pt;">&#160;&#160;&#160; <font style="font-weight: bold;"><u>In One or More Countries</u></font>.<font style="font-weight: bold; font-style: italic;">&#160;</font>If this Agreement is terminated with respect to one (1) or more countries but not the entire Territory, then, except as set forth below, the provisions of <u>Section</u><u> 16.3.1</u>&#160;shall apply, but only with
        respect to such terminated country or countries (and such country(ies) will be the Terminated Territory for purposes of <u>Section</u><u> 16.3.1</u>), and this Agreement shall continue with respect to the other countries in the Territory:</font></div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: justify; text-indent: 108pt; font-size: 10pt;">(a)&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;<u>Section</u><u> 16.3.1(a)</u>&#160;shall not apply, and the license grants to AstraZeneca under <u>Section</u><u> 8.1</u>&#160;shall automatically be deemed to be amended with
      respect to the Terminated Territory to be non-exclusive and to exclude the right to Commercialize the Licensed Product in the Field in such Terminated Territory and AstraZeneca shall retain a non-exclusive right to Develop and Manufacture Licensed
      Compounds and Licensed Products in the Terminated Territory solely for the purposes of supporting Regulatory Approval or Commercialization of the Licensed Products in the Territory.</div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: justify; text-indent: 108pt; font-size: 10pt;">(b) &#160;&#160; &#160;&#160;&#160; Notwithstanding the Reversion License in <u>Section</u><u> 16.3.1(b)</u>, AstraZeneca reserves the right under the AstraZeneca Reversion IP that is the subject of the
      Reversion License to Develop and Manufacture Licensed Compounds and Licensed Products in the Terminated Territory solely for the purposes of supporting Regulatory Approval or Commercialization of Licensed Products in the Territory.</div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: justify; text-indent: 108pt; font-size: 10pt;">(c)&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160; Promptly after termination of this Agreement with respect to a Licensed Product in the Terminated Territory, the Parties shall enter into an agreement regarding (i) the
      maintenance of the global safety database for Licensed Products, (ii) a process for the exchange of adverse event safety data in a mutually agreed format in order to monitor the safety of Licensed Products and to meet reporting requirements of any
      applicable Regulatory Authorities in the Territory and Terminated Territory, and (iii) coordination of the Development, Manufacture and Commercialization of the Licensed Products in the Terminated Territory, on the one hand, and the Development,
      Manufacture and Commercialization of the Licensed Products in and for the Territory, on the other hand, as needed.</div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
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    </div>
    <div style="text-align: justify; text-indent: 108pt; font-size: 10pt;">(d)&#160;&#160;&#160;&#160;&#160;&#160;&#160; AstraZeneca shall not, and shall not permit any of its Affiliates, and shall use commercially reasonable efforts not to permit any of its and their Sublicensees or
      distributors to, distribute, market, promote, offer for sale or sell any Licensed Products directly or indirectly (i) to any Person for use in the applicable Terminated Territory or (ii) to any Person in the Territory that AstraZeneca or any of its
      Affiliates or any of its or their Sublicensees or distributors knows is likely to distribute, market, promote, offer for sale or sell such Licensed Product for use in the applicable Terminated Territory or assist another Person to do so; <font style="font-style: italic;">provided</font> that if such Terminated Territory includes a country where passive sales cannot be prohibited under applicable Law, then AstraZeneca, its Affiliates and its and their Sublicensees and distributors may, to
      the extent passive sales cannot be prohibited under applicable Law and such passive sales are made in accordance with applicable Law, passively sell any Licensed Product into other jurisdictions that are in the Terminated Territory, but may not
      actively sell or promote any Licensed Product in such Terminated Territory. If AstraZeneca or any of its Affiliates receives or becomes aware of the receipt by a Sublicensee or distributor of any orders for any Licensed Product for use in such
      Terminated Territory, then AstraZeneca or its Affiliates, as applicable, shall use good faith efforts to refer (or instruct its Sublicensee or distributor, as applicable, to refer) such orders to Akcea. AstraZeneca shall cause its Affiliates and its
      and their Sublicensees and distributors to notify Akcea of any receipt of any orders for Licensed Product for use in such Terminated Territory.</div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: justify; text-indent: 108pt; font-size: 10pt;">(e)&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160; Akcea shall not, and shall not permit any of its Affiliates, and shall use commercially reasonable efforts not to permit any of its and their (sub)licensees, or
      distributors to, distribute, market, promote, offer for sale or sell any Licensed Product directly or indirectly (i) to any Person for use in the Territory or (ii) to any Person in such Terminated Territory that Akcea or any of its Affiliates or any
      of its or their (sub)licensees or distributors knows is likely to distribute, market, promote, offer for sale or sell such Licensed Product for use in the Territory or assist another Person to do so; <font style="font-style: italic;">provided</font>
      that if such Terminated Territory includes a country where passive sales cannot be prohibited under applicable Law, then Akcea, its Affiliates and its and their (sub)licensees and distributors may, to the extent passive sales cannot be prohibited
      under applicable Law and such passive sales are made in accordance with applicable Law, passively sell any Licensed Product into other jurisdictions that are in the Territory, but may not actively sell or promote any Licensed Product in the
      Territory. If Akcea or any of its Affiliates receives or becomes aware of the receipt by a (sub)licensee or distributor of any orders for any Licensed Product for use in the Territory, then Akcea or its Affiliates, as applicable, shall use good faith
      efforts to refer (or instruct its (sub)licensee or distributor, as applicable, to refer) such orders to AstraZeneca. Akcea shall cause its Affiliates and its and their (sub)licensees and distributors to notify AstraZeneca of any receipt of any orders
      for any Licensed Product for use in the Territory. </div>
    <div style="font-size: 10pt;">&#160;</div>
    <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
      <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">84</font></div>
      <div id="DSPFPageBreak" style="page-break-after: always;">
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    </div>
    <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold; font-size: 10pt;">16.3.3</font><font style="font-size: 10pt;">&#160;&#160;&#160; <font style="font-weight: bold;"><u>Transition Services</u></font>. Except with respect to any
        termination by AstraZeneca pursuant to <u>Section</u><u> 16.2.1(a)</u>&#160;or <u>Section</u><u> 16.2.4</u>:</font></div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: justify; text-indent: 108pt; font-size: 10pt;">(a)&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;<font style="font-weight: bold;">Transition Plan</font>.</div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: justify; text-indent: 144pt; font-size: 10pt;">(i)&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160; In addition to the effects set forth in <u>Section 16.3.1</u> and <u>Section </u><u>16.3.2</u>, at Akcea&#8217;s reasonable request and at Akcea&#8217;s cost and expense, if this
      Agreement is terminated pursuant to <u>Section 16.2</u>, then AstraZeneca will use Commercially Reasonable Efforts to perform the Transition Services (as defined below) in accordance with the Transition Plan as set forth in this <u>Section 16.3.3</u>.
      Upon Akcea&#8217;s request, the Parties will agree to a transition plan pursuant to <u>Section 16.3.3(a)(ii)</u> that includes all activities that are necessary to (A) if a Licensed Product is being Commercialized in the Terminated Territory, provide
      patients with continued access to the Licensed Product, (B) transition the responsibilities under all Regulatory Approvals and ongoing Clinical Trials for the Licensed Product in the Terminated Territory to Akcea or its designee and (C) transition
      the then-current supply process for the Licensed Product in the Terminated Territory to Akcea or its designee, in each case, as necessary for Akcea to Exploit the Licensed Product in the Terminated Territory as such Licensed Product is being
      clinically Developed or Commercialized by AstraZeneca or its Affiliates in the Terminated Territory as of the effective date of termination<font style="font-weight: bold; font-style: italic;">&#160;</font>(collectively, the &#8220;<font style="font-weight: bold; font-style: italic;">Transition Services</font>&#8221;), which plan, in addition to standard contractual provisions, will also address customer and commercial matters, adverse event reporting, Licensed Product complaints, reimbursement support and
      other patient contact center activities, Medical Affairs, government and managed care contracts, Manufacturing, quality, regulatory, pharmacovigilance/global safety database and post-approval studies and commitments (such plan, the &#8220;<font style="font-weight: bold; font-style: italic;">Transition Plan</font>&#8221;). The Transition Plan shall also (x) set forth responsibility for all monitoring and follow up with respect to subjects/patients that were administered Licensed Products from
      and after the effective date of termination and (y) provide that at Akcea&#8217;s election (1) AstraZeneca shall have the right for [***] after the effective date of such termination with respect to the Terminated Territory to sell or otherwise dispose of
      all Licensed Compounds and Licensed Products then in its inventory and any in-progress inventory, in each case that is intended for sale or disposition in the Terminated Territory, (2) Akcea shall purchase all such inventory and any in-progress
      inventory from AstraZeneca at [***], or (3) a combination of both (1) and (2), in each case to the extent practicable.</div>
    <div style="font-size: 10pt;">&#160;</div>
    <font style="font-size: 10pt;"> &#160; &#160; &#160; &#160; &#160; &#160; &#160; &#160; &#160; &#160; &#160; &#160; &#160; &#160; &#160; &#160; &#160; &#160; &#160; &#160; &#160; &#160; &#160; &#160; &#160; &#160;&#160; &#160; &#160;&#160; (ii)&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160; Akcea may elect to have AstraZeneca perform the Transition Services by providing written notice to AstraZeneca no later than the later of (A) [***]
      following the effective date of the termination and (B) [***] following written notice by AstraZeneca to Akcea asking Akcea to confirm if Akcea wishes to have AstraZeneca perform the Transition Services. If Akcea requests Transition Services, then
      Akcea shall propose a Transition Plan setting forth the Transition Services to be performed by AstraZeneca, including delivery and transition dates, and, for a period of [***] after such request, the Parties will use good faith efforts to negotiate a
      mutually agreeable version of such Transition Plan. If the Parties have not reached agreement on the Transition Plan within [***] after Akcea requests Transition Services, then either Party may refer such matter for resolution pursuant to <u>Schedule



        16.3.3(a)(ii)</u>. If Akcea elects to have AstraZeneca perform the Transition Services but the Parties have not reached agreement on the Transition Plan before the effective date of termination, then AstraZeneca will use Commercially Reasonable
      Efforts to maintain access to the Licensed Product in the Territory for patients that were receiving such Licensed Product through clinical Development or Commercialization as of the effective date of termination until such Transition Plan is either
      agreed upon by the Parties or resolved pursuant to <u>Schedule 16.3.3(a)(ii)</u>.<font style="font-weight: bold; font-style: italic;">&#160;</font>In addition, the Parties will, within [***] after such request, establish a transition committee consisting
      of at least each Party&#8217;s Alliance Managers, a representative from each Party&#8217;s CMC group who was responsible for the Licensed Product prior to the termination, and up to two additional representatives from each Party who are from other relevant
      functional groups to facilitate a smooth transition. While AstraZeneca is providing Transition Services, AstraZeneca and Akcea will mutually agree in writing on talking points and a communication plan to customers, specialty pharmacies, physicians,
      Regulatory Authorities, patient advocacy groups and clinical study investigators, and AstraZeneca will make all such communication to such entities in accordance with the mutually agreed talking points. </font>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
      <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">85</font></div>
      <div style="page-break-after:always;" id="DSPFPageBreak">
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    </div>
    <div style="text-align: justify; text-indent: 144pt; font-size: 10pt;">(iii)&#160;&#160;&#160;&#160; &#160; AstraZeneca will use Commercially Reasonable Efforts to perform the Transition Services in accordance with the Transition Plan for a period not to exceed [***] from the
      effective date of termination (the &#8220;<font style="font-weight: bold; font-style: italic;">Transition Period</font>&#8221;); <font style="font-style: italic;">provided</font> that if the Transition Plan is determined pursuant to the arbitration process set
      forth on <u>Schedule 16.3.3(a)(ii)</u> and the arbitrators select Akcea&#8217;s Arbitration Proposal, then the Transition Period will be extended by the amount of time that elapsed from the time that the determination of the Transition Plan was referred
      for resolution pursuant to <u>Schedule 16.3.3(a)(ii)</u> until the arbitrators selected Akcea&#8217;s Arbitration Proposal. AstraZeneca and Akcea may also mutually agree to extend the Transition Period.</div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: justify; text-indent: 108pt; font-size: 10pt;">(b)&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;<font style="font-weight: bold;">Costs of Transition Services</font>. Akcea will pay [***] to perform the Transition Services. Unless otherwise agreed as part of the
      Transition Plan and subject to the terms and conditions of such Transition Plan, Akcea will own all Net Revenue (as defined in the Transition Plan) derived from the Licensed Product after the effective date of termination and AstraZeneca will remit
      all such Net Revenues to Akcea in accordance with the Transition Plan.</div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: justify; text-indent: 108pt; font-size: 10pt;">(c)&#160;&#160;&#160;&#160;&#160;&#160;&#160; <font style="font-weight: bold;">Responsibility for Transition Services</font>. Akcea or its designee will be sufficiently prepared to, and will, accept the transition
      of Development, Manufacturing and Commercialization activities with respect to the Licensed Product to Akcea or such designee on the timelines set forth in the agreed transition plan for the Transition Services. As between AstraZeneca and Akcea,
      AstraZeneca will have no liability under this Agreement with respect to a failure of, or delay in, the Transition Services to the extent AstraZeneca uses Commercially Reasonable Efforts to perform, and complies with applicable Law in performing, the
      Transition Services or to the extent caused by factors beyond AstraZeneca&#8217;s reasonable control (including any failure or delay by Akcea or its designee in accepting the transition of Development, Manufacturing and Commercialization activities with
      respect to the Licensed Product in the Terminated Territory). If AstraZeneca encounters any delays, then the Parties shall discuss in good faith and agree upon extended timelines for completion of the Transition Services.</div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold; font-size: 10pt;">16.3.4</font><font style="font-size: 10pt;">&#160;&#160;&#160; <font style="font-weight: bold;"><u>Additional Remedies of AstraZeneca in Lieu of Termination of
            this Agreement</u></font>. If AstraZeneca has the right to terminate this Agreement in its entirety pursuant to <u>Section</u><u> 16.2.1(a)</u>&#160;(after giving effect to the applicable Cure Period) or <u>Section</u><u> 16.2.4</u>, then in lieu
        of AstraZeneca terminating pursuant to <u>Section </u><u>16.2.1(a)</u>&#160;or <u>Section</u><u> 16.2.4</u>, as applicable, AstraZeneca shall have the right, as its sole and exclusive remedy for the events giving rise to AstraZeneca&#8217;s termination
        right, to elect, by providing written notice to Akcea, to have this Agreement continue in full force and effect as modified by this <u>Section</u><u> 16.3.4</u>, in which case, such modifications shall be effective as of the date AstraZeneca
        delivers such notice to Akcea:</font></div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: justify; text-indent: 108pt; font-size: 10pt;">(a)&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;all rights and licenses granted to AstraZeneca under <u>Section</u><u> 8.1</u>&#160;shall become perpetual and irrevocable;</div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: justify; text-indent: 108pt; font-size: 10pt;">(b)&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;AstraZeneca&#8217;s obligations to pay milestones and royalties under <u>Section</u><u> 3.6.2(b)(i)</u>, <u>Section</u><u> 11.2</u>, <u>Section</u><u> 11.3</u>, <u>Section</u><u>
        11.5</u>&#160;and <u>Section</u><u> 11.6</u>&#160;shall be reduced to [***]% of the amount that would otherwise have been payable under this Agreement;</div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: justify; text-indent: 108pt; font-size: 10pt;">(c)&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160; If Akcea has not exercised the Opt-Out Right, notwithstanding the expiration of the Second Opt-Out Period (if applicable), Akcea will be deemed to have exercised the
      Opt-Out Right, and the consequences thereof shall apply, subject to <u>Section</u><u> 16.3.4(b)</u>&#160;and except that AstraZeneca will have no obligation to reimburse Akcea for [***]; and</div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
      <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">86</font></div>
      <div style="page-break-after:always;" id="DSPFPageBreak">
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    </div>
    <div style="text-align: justify; text-indent: 108pt; font-size: 10pt;">(d)&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;all other provisions would remain in full force and effect without change.</div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; font-size: 10pt;">16.4</font><font style="font-size: 10pt;">&#160;&#160;&#160;&#160; <a name="AccruedRightsSurvivingPro"><!--Anchor--></a> &#160; <font style="font-weight: bold;"><u>Accrued
            Rights; Surviving Provisions of the Agreement</u></font>.</font></div>
    <div><font style="font-size: 10pt;">&#160; <br>
      </font> </div>
    <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold; font-size: 10pt;">16.4.1</font><font style="font-size: 10pt;">&#160;&#160; Subject to <u>Section 16.2.1</u><u>,</u> termination or expiration of this Agreement (either in its
        entirety or with respect to one or more countries) for any reason will be without prejudice to any rights that will have accrued to the benefit of any Party prior to such termination or expiration, including any payment obligations accrued as of
        the date of such termination under <u>Article 11</u> hereof, and any and all damages or remedies arising from any breach hereunder. Such termination or expiration will not relieve any Party from obligations which are expressly indicated to survive
        expiration or termination of this Agreement.</font></div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold; font-size: 10pt;">16.4.2</font><font style="font-size: 10pt;">&#160;&#160;&#160; The provisions of <u>Section 2.4.1</u> (with respect to any Eligible Development Expenses incurred
        prior to the effective date of termination), <u>Section 3.4.1</u> (with respect to any Eligible Commercialization Expenses and Eligible Medical Affairs Expenses incurred prior to the effective date of termination), <u>Section 5.3.2</u>, <u>Section


          7.1</u>, <u>Section 7.3</u> (except for the first sentence), <u>Section 8.5</u>, <u>Section 8.7</u> (only in the event of expiration of this Agreement), <u>Section 8.8</u>, <u>Section 8.9</u>, <u>Section 11.5.2</u> ([***] with respect to
        amounts that accrued prior to the effective date of termination), <u>Section 11.5.3</u> (for final accounting), <u>Section 11.7</u> (for final accounting), <u>Section 11.10</u> (with respect to any Other Operating Expenses incurred prior to the
        effective date of termination), <u>Section 11.11.2</u>, <u>Section 11.11.3</u>, <u>Section 11.12</u>, <u>Section 11.13</u>, <u>Section 11.14</u>, <u>Section 11.15</u>, <u>Section 12.1</u>, <u>Section 12.2.1(c)</u>, <u>Section 12.2.2</u>
        (solely with respect to Joint Program Patent Rights), <u>Section 14.1</u> through <u>Section 14.4</u> (for purposes of <u>Article 15</u>), <u>Section 14.5</u>, <u>Section 16.3</u>, and <u>Section 16.4</u> and <u>Article 13</u> (other than <u>Section


          13.5</u>), <u>Article 15</u>, and <u>Article 17</u> (other than <u>Section 17.11</u>) will survive the termination of this Agreement or expiration of this Agreement for any reason, in accordance with their respective terms and conditions, and
        for the duration stated, and where no duration is stated, will survive indefinitely.</font></div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: center; font-weight: bold; font-size: 10pt;">ARTICLE 17</div>
    <div style="text-align: center; font-weight: bold; font-size: 10pt;"><a name="MISCELLANEOUS"><!--Anchor--></a>MISCELLANEOUS</div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; font-size: 10pt;">17.1</font><font style="font-size: 10pt;">&#160;&#160;&#160;&#160; &#160; <font style="font-weight: bold;"><u>Dispute Resolution</u></font>.<a name="DisputeResolution."><!--Anchor--></a></font></div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold; font-size: 10pt;">17.1.1</font><font style="font-size: 10pt;">&#160;&#160; <font style="font-weight: bold;"><u>Resolution by Senior Officers</u></font>. The Parties will seek
        to settle amicably any and all disputes, controversies or claims arising out of or in connection with this Agreement. Any dispute between the Parties will be promptly presented to the Senior Officers, or their respective designees, for resolution.
        Such Senior Officers, or their respective designees, will meet in-person or by teleconference as soon as reasonably possible thereafter, and use their good faith efforts to mutually agree upon the resolution of the dispute, controversy or claim.</font></div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold; font-size: 10pt;">17.1.2</font><font style="font-size: 10pt;">&#160;&#160;&#160; <font style="font-weight: bold;"><u>Request for Arbitration</u></font>. If after negotiating in good
        faith pursuant to <u>Section 17.1.1</u> the Parties fail after good faith discussions undertaken within reasonable promptness, to reach an amicable agreement within [***],<font style="font-weight: bold; font-style: italic;">&#160;</font>then either
        Party may upon written notice to the other submit to binding arbitration pursuant to <u>Section 17.1.3</u>; <font style="font-style: italic;">provided</font> that, except as set forth in <u>Section 6.6.5(g)</u>, any dispute within the JSC&#8217;s
        decision-making authority whether or not resolved by the Senior Officers will not be subject to arbitration. No statements made by either Party during such discussions will be used by the other Party or admissible in arbitration or any other
        subsequent proceeding for resolving the dispute.</font></div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
      <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">87</font></div>
      <div style="page-break-after:always;" id="DSPFPageBreak">
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    </div>
    <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold; font-size: 10pt;">17.1.3</font><font style="font-size: 10pt;">&#160;&#160;&#160; <font style="font-weight: bold;"><u>Arbitration</u></font>.</font></div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: justify; text-indent: 108pt; font-size: 10pt;">(a)&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160; Subject to <u>Section 17.2</u>, any dispute, claim or controversy arising from or related in any way to this Agreement or the interpretation, application, breach,
      termination or validity thereof, including any claim of inducement of this Agreement by fraud or otherwise, not resolved under the provisions of <u>Section 17.1.2</u>, will be resolved by final and binding arbitration conducted in accordance with
      the terms of this <u>Section 17.1.3</u>. The arbitration will be held in New York, New York, USA according to Rules of Arbitration of the ICC. The arbitration will be conducted by a panel of three arbitrators with significant experience in the
      pharmaceutical industry, unless otherwise agreed by the Parties, appointed in accordance with applicable ICC rules. Any arbitration herewith will be conducted in the English language to the maximum extent possible. The arbitrators will render a
      written decision no later than [***] following the selection of the arbitrators, including a basis for any damages awarded and a statement of how the damages were calculated. Any award will be promptly paid in U.S. dollars free of any tax, deduction
      or offset. Each Party agrees to abide by the award rendered in any arbitration conducted pursuant to this <u>Section 17.1.3</u>. With respect to money damages, nothing contained herein will be construed to permit the arbitrator or any court or any
      other forum to award punitive or exemplary damages, except in the case of breach of <u>Article 13</u>. By entering into this agreement to arbitrate, the Parties expressly waive any claim for punitive or exemplary damages, except in the case of
      breach of <u>Article 13</u>. Each Party will pay its legal fees and costs related to the arbitration (including witness and expert fees). Judgment on the award so rendered will be final and may be entered in any court having jurisdiction thereof.</div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: justify; text-indent: 108pt; font-size: 10pt;">(b)&#160; &#160; &#160;&#160; &#160;&#160; EACH PARTY HERETO WAIVES ITS RIGHT TO TRIAL OF ANY ISSUE BY JURY. EACH PARTY HERETO WAIVES ANY CLAIM FOR ATTORNEYS&#8217; FEES AND COSTS AND PREJUDGMENT INTEREST FROM THE
      OTHER.</div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold; font-size: 10pt;">17.1.4</font><font style="font-size: 10pt;">&#160;&#160;&#160; <font style="font-weight: bold;"><u>Court Actions</u></font>. Nothing contained in this Agreement
        will deny either Party the right to seek injunctive or other equitable relief from a court of competent jurisdiction in the context of a<font style="font-style: italic;"> bona fide </font>emergency or prospective irreparable harm, and such an
        action may be filed and maintained notwithstanding any ongoing dispute resolution discussions or arbitration proceeding. In addition, either Party may bring an action in any court of competent jurisdiction to resolve disputes pertaining to the
        validity, construction, scope, enforceability, infringement or other violations of patents or other proprietary or intellectual property rights, and no such claim will be subject to arbitration pursuant to <u>Section 17.1.2</u>.</font></div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; font-size: 10pt;">17.2</font><font style="font-size: 10pt;">&#160;&#160;&#160; <a name="GoverningLawJurisdictionE"><!--Anchor--></a> &#160; <font style="font-weight: bold;"><u>Governing
            Law; Jurisdiction; Equitable Relief; Losses; Remedies</u></font>.</font></div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold; font-size: 10pt;">17.2.1</font><font style="font-size: 10pt;">&#160;&#160;&#160; This Agreement will be governed by and construed and enforced in accordance with the laws of the
        State of New York, USA, without reference to any rules of conflicts of laws. For clarification, subject to <u>Section</u><u> 12.1.2(d)</u>, any dispute relating to the scope, validity, enforceability or infringement of any Patent Rights will be
        governed by and construed and enforced in accordance with the patent laws of the applicable jurisdiction.</font></div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
      <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">88</font></div>
      <div style="page-break-after:always;" id="DSPFPageBreak">
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    </div>
    <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold; font-size: 10pt;">17.2.2</font><font style="font-size: 10pt;">&#160;&#160;&#160; Each Party acknowledges and agrees that the restrictions set forth in <u>Section 5.2</u>, <u>Section


          8.6</u>, <u>Section 9.2</u>, <u>Section 16.3.3</u> and <u>Article 13</u> are reasonable and necessary to protect the legitimate interests of the other Party and that the other Party would not have entered into this Agreement in the absence of
        such restrictions, and that any breach or threatened breach of any of these provisions will result in irreparable injury to the other Party for which there will be no adequate remedy at law. In the event of a breach or threatened breach of <u>Section


          5.2</u>, <u>Section 8.6</u>, <u>Section 9.2</u>, <u>Section 16.3.3</u> or <u>Article 13</u>, each Party will be authorized and entitled to obtain from any court of competent jurisdiction equitable relief, whether preliminary or permanent,
        specific performance and an equitable accounting of all earnings, profits and other benefits arising from such breach, which rights will be cumulative and in addition to any other rights or remedies to which such Party may be entitled in law or
        equity.<font style="font-weight: bold; font-style: italic;">&#160;</font>Each Party agrees to waive any requirement that the other Party (a) post a bond or other security as a condition for obtaining any such relief, and (b) show irreparable harm,
        balancing of harms, consideration of the public interest or inadequacy of monetary damages as a remedy. Nothing in this <u>Section </u><u>17.2.2</u> is intended, or should be construed, to limit a Party&#8217;s rights to equitable relief or any other
        remedy for a breach of any other provision of this Agreement. Except for (i) the offsets and credits explicitly set forth in <u>Section 2.4.1(b)(ii)</u>, <u>Section</u><u> 2.4.1(b)(iii)</u>, <u>Section 2.5.4</u>, and <u>Section </u><u>11.11.3(c)</u>,
        (ii) any amount awarded to be paid by one Party to the other by the panel of arbitrators in a final and binding arbitration proceeding adjudicated under <u>Section 17.1.3</u> and (iii) any offset of undisputed but unpaid amounts under this
        Agreement, neither Party will have the right to set off any amount it is owed or believes it is owed against payments due or payable to the other Party under this Agreement.</font></div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold; font-size: 10pt;">17.2.3</font><font style="font-size: 10pt;">&#160;&#160;&#160; Neither Party will be entitled to recover any Losses relating to any matter arising under one
        provision of this Agreement to the extent that such Party has already recovered Losses with respect to such matter pursuant to other provisions of this Agreement (including recoveries under <u>Section 15.1</u> or <u>Section 15.2</u>).</font></div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold; font-size: 10pt;">17.2.4</font><font style="font-size: 10pt;">&#160;&#160;&#160; Any provisions of this Agreement that describe a payment as non-refundable shall be without prejudice
        to either Party&#8217;s right to bring a claim for breach of this Agreement, misrepresentation or any other claim permissible under applicable Laws, including seeking recovery of payments made and damages for loss.</font></div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; font-size: 10pt;">17.3</font><font style="font-size: 10pt;">&#160;&#160; <a name="AssignmentandSuccessors."><!--Anchor--></a>&#160;&#160;&#160; <font style="font-weight: bold;"><u>Assignment
            and Successors</u></font>. Neither this Agreement nor any obligation of a Party hereunder may be assigned by either Party without the consent of the other, which will not be unreasonably withheld, delayed or conditioned, except that each Party
        may assign this Agreement and the rights, obligations and interests of such Party, in whole or in part, without the other Party&#8217;s consent, to any of its Affiliates, to any purchaser of all or substantially all of its assets to which this Agreement
        or relevant part relates or to any successor corporation resulting from any merger, consolidation, share exchange or other similar transaction; <font style="font-style: italic;">provided</font> that, if a Party transfers or assigns this Agreement
        (or any part hereof) to [***], then such transferring Party (or such Affiliate) (&#8220;<font style="font-weight: bold; font-style: italic;">Transferring Party</font>&#8221;), will [***]. Any purported assignment or transfer made in contravention of this <u>Section


          17.3</u> will be null and void.</font></div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
      <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">89</font></div>
      <div style="page-break-after:always;" id="DSPFPageBreak">
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    </div>
    <div style="text-align: justify; font-size: 10pt;">To the extent the Non-Transferring Party utilizes a [***] in any year, the Non-Transferring Party will [***] to the Transferring Party [***]. To assist the Transferring Party in determining when a
      [***] the Non-Transferring Party pursuant to the foregoing sentence, beginning with the first annual tax return for the year in which the Transferring Party [***] under this <u>Section 17.3</u>, and each year thereafter (including, for clarity, all
      years in which the Non-Transferring Party utilizes [***], the Non-Transferring Party will provide the Transferring Party with the Non-Transferring Party&#8217;s annual tax returns (federal and state) and, in years in which the Non-Transferring Party
      utilizes [***], supporting documentation for such [***].</div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; font-size: 10pt;">17.4</font><font style="font-size: 10pt;">&#160;&#160;&#160;&#160; <a name="PerformancebyAffiliates."><!--Anchor--></a> &#160; <font style="font-weight: bold;"><u>Performance


            by Affiliates</u></font>. Notwithstanding anything to the contrary set forth herein, each Party will have the right to perform any or all of its obligations and exercise any or all of its rights under this Agreement through any of its
        Affiliates. Each Party hereby guarantees the performance by its Affiliates of such Party&#8217;s obligations under this Agreement and will cause its Affiliates to comply with the provisions of this Agreement in connection with such performance.</font></div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; font-size: 10pt;">17.5</font><font style="font-size: 10pt;">&#160;&#160;&#160;&#160;&#160;&#160; <font style="font-weight: bold;"><u>Force Majeure</u></font>.<a name="ForceMajeure."><!--Anchor--></a>
        Neither Party will be held liable or responsible to the other Party nor be deemed to be in default under, or in breach of any provision of, this Agreement for failure or delay in fulfilling or performing any obligation (other than a payment
        obligation) of this Agreement to the extent such failure or delay is due to force majeure. For purposes of this Agreement, &#8220;<font style="font-weight: bold; font-style: italic;">Force Majeure</font>&#8221; is defined as any cause beyond the reasonable
        control of the affected Party and without the fault or negligence of such Party, which may include acts of God; material changes in Law; war; civil commotion; destruction of production facilities or materials by fire, flood, earthquake, explosion
        or storm; labor disturbances; epidemic; pandemic; quarantine; and failure of public utilities or common carriers. The Parties agree the effects of the COVID-19 pandemic that is ongoing as of the Execution Date (including related government orders)
        may be invoked as a Force Majeure for the purposes of this Agreement even though the pandemic is ongoing to the extent those effects are not reasonably foreseeable by the Parties as of the Execution Date. Notwithstanding the foregoing, a Party will
        not be excused from making payments owed hereunder due to any Force Majeure circumstances affecting such Party. In the case of a Force Majeure, the Party affected by such Force Majeure will immediately notify the other Party of such inability and
        of the period for which such inability is expected to continue. The Party giving such notice will thereupon be excused from such of its obligations under this Agreement as it is thereby disabled from performing for so long as it is so disabled for
        up to a maximum of [***], after which time the Parties will promptly meet to discuss in good faith how to best proceed in a manner that maintains and abides by the Agreement. To the extent possible, the Party affected by such Force Majeure will use
        reasonable efforts to minimize the duration of any Force Majeure.</font></div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; font-size: 10pt;">17.6</font><font style="font-size: 10pt;">&#160;&#160;&#160;&#160;&#160;&#160; <font style="font-weight: bold;"><u>Notices</u></font>. Any notice or request required or permitted
        to be given under or in connection with this Agreement will be deemed to have been sufficiently given if in writing and personally delivered or sent by certified mail (return receipt requested) or overnight express courier service (signature
        required), prepaid, to the Party for which such notice is intended, at the address set forth for such Party below:</font></div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
      <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">90</font></div>
      <div style="page-break-after:always;" id="DSPFPageBreak">
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    </div>
    <div style="margin-left: 72pt; font-size: 10pt;">If to AstraZeneca,</div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="margin-left: 72pt; font-size: 10pt;">addressed to:&#160;&#160;&#160;&#160;&#160;&#160;&#160; &#160; &#160; &#160; &#160; &#160; &#160; &#160; AstraZeneca AB</div>
    <div style="margin-left: 180pt; font-size: 10pt;">SE-431 83 M&#246;lndal</div>
    <div style="margin-left: 180pt; font-size: 10pt;">Sweden</div>
    <div style="margin-left: 180pt; font-size: 10pt;">Attention: Legal Department</div>
    <div><font style="font-size: 10pt;"><br>
      </font> </div>
    <div style="margin-left: 72pt; font-size: 10pt;">with a copy to (which shall not constitute notice):</div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="margin-left: 180pt; font-size: 10pt;">AstraZeneca AB</div>
    <div style="margin-left: 180pt; font-size: 10pt;">SE-431 83 M&#246;lndal</div>
    <div style="margin-left: 180pt; font-size: 10pt;">Sweden</div>
    <div style="margin-left: 180pt; font-size: 10pt;">Attention: Alliance and Integration Management</div>
    <div><font style="font-size: 10pt;"><br>
      </font> </div>
    <div style="margin-left: 72pt; font-size: 10pt;">If to Akcea,</div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="margin-left: 72pt; font-size: 10pt;">addressed to:&#160;&#160;&#160;&#160;&#160;&#160;&#160; &#160; &#160; &#160; &#160; &#160; &#160; &#160; Akcea Therapeutics, Inc.</div>
    <div style="text-indent: 108pt; margin-left: 72pt; font-size: 10pt;">c/o Ionis Pharmaceuticals, Inc.</div>
    <div style="margin-left: 180pt; font-size: 10pt;">2855 Gazelle Court</div>
    <div style="margin-left: 180pt; font-size: 10pt;">Carlsbad, CA 92010</div>
    <div style="margin-left: 180pt; font-size: 10pt;">Attention: Chief Executive Officer</div>
    <div style="margin-left: 180pt; font-size: 10pt;">Telephone: [***]</div>
    <div><font style="font-size: 10pt;"><br>
      </font> </div>
    <div style="margin-left: 72pt; font-size: 10pt;">with a copy to (which shall not constitute notice):</div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="margin-left: 180pt; font-size: 10pt;">Akcea Therapeutics, Inc.</div>
    <div style="margin-left: 180pt; font-size: 10pt;">c/o Ionis Pharmaceuticals, Inc.</div>
    <div style="margin-left: 180pt; font-size: 10pt;">2855 Gazelle Court</div>
    <div style="margin-left: 180pt; font-size: 10pt;">Carlsbad, CA 92010</div>
    <div style="margin-left: 180pt; font-size: 10pt;">Attention: General Counsel</div>
    <div style="margin-left: 180pt; font-size: 10pt;">Telephone: [***]</div>
    <div style="margin-left: 180pt; font-size: 10pt;">Email: [***]</div>
    <div><font style="font-size: 10pt;"><br>
      </font> </div>
    <div style="margin-left: 180pt; font-size: 10pt;">Ropes &amp; Gray LLP</div>
    <div style="margin-left: 180pt; font-size: 10pt;">Prudential Tower</div>
    <div style="margin-left: 180pt; font-size: 10pt;">800 Boylston Street</div>
    <div style="margin-left: 180pt; font-size: 10pt;">Boston, Massachusetts 02199</div>
    <div style="margin-left: 180pt; font-size: 10pt;">Attention: Marc Rubenstein</div>
    <div style="margin-left: 180pt; font-size: 10pt;">Telephone: 617-951-7826</div>
    <div style="margin-left: 180pt; font-size: 10pt;">Email: marc.rubenstein@ropesgray.com</div>
    <div><font style="font-size: 10pt;"><br>
      </font> </div>
    <div style="text-align: justify; font-size: 10pt;">or to such other address for such Party as it will have specified by like notice to the other Party, <font style="font-style: italic;">provided </font>that notices of a change of address will be
      effective only upon receipt thereof. If delivered personally, then the date of delivery will be deemed to be the date on which such notice or request was given. If sent by overnight express courier service, then the date of delivery will be deemed to
      be the next Business Day after such notice or request was deposited with such service. If sent by certified mail, then the date of delivery will be deemed to be the third Business Day after such notice or request was deposited with the U.S. Postal
      Service. It is understood and agreed that this Section is not intended to govern the day to day business communications necessary between the parties in performing their duties, in due course, under the terms and conditions of this Agreement.</div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
      <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">91</font></div>
      <div style="page-break-after:always;" id="DSPFPageBreak">
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    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; font-size: 10pt;">17.7</font><font style="font-size: 10pt;">&#160;&#160;&#160;&#160; <a name="ExportClause"><!--Anchor--></a>&#160; &#160; &#160; <font style="font-weight: bold;"><u>Export Clause</u></font>.
        Each Party acknowledges that the Laws of the United States restrict the export and re-export of commodities and technical data of United States origin. Each Party agrees that it will not export or re-export restricted commodities or the technical
        data of the other Party in any form without the appropriate United States and foreign government licenses.</font></div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; font-size: 10pt;">17.8</font><font style="font-size: 10pt;">&#160;&#160;&#160;&#160;&#160; <a name="Waiver."><!--Anchor--></a> &#160; &#160; <font style="font-weight: bold;"><u>Waiver</u></font>.
        Neither Party may waive or release any of its rights or interests in this Agreement except in writing. The failure of either Party to assert a right hereunder or to insist upon compliance with any term or condition of this Agreement will not
        constitute a waiver of that right or excuse a similar subsequent failure to perform any such term or condition. No waiver by either Party of any condition or term in any one or more instances will be construed as a continuing waiver of such
        condition or term or of another condition or term except to the extent set forth in writing.</font></div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; font-size: 10pt;">17.9</font><font style="font-size: 10pt;">&#160;&#160;&#160;&#160;&#160;&#160; <a name="Severability"><!--Anchor--></a>&#160; &#160;&#160; <font style="font-weight: bold;"><u>Severability</u></font>.
        If any provision hereof should be invalid, illegal or unenforceable in any jurisdiction, then the Parties will negotiate in good faith a valid, legal and enforceable substitute provision that most nearly reflects the original intent of the Parties
        and all other provisions hereof will remain in full force and effect in such jurisdiction and will be liberally construed in order to carry out the intentions of the Parties as nearly as may be possible. Such invalidity, illegality or
        unenforceability will not affect the validity, legality or enforceability of such provision in any other jurisdiction.</font></div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; font-size: 10pt;">17.10</font><font style="font-size: 10pt;">&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;<font style="font-weight: bold;"><u>Parent Guaranty</u></font>.<a name="ParentGuaranty."><!--Anchor--></a></font></div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold; font-size: 10pt;">&#160;&#160;&#160;&#160; 17.10.1</font><font style="font-size: 10pt;">&#160;&#160;&#160;&#160;&#160;&#160; Ionis hereby unconditionally, absolutely and irrevocably guarantees, as a primary obligor
        and not merely as surety, the due and punctual payment and performance of all obligations of Akcea under this Agreement (the &#8220;<font style="font-weight: bold; font-style: italic;">Akcea Obligations</font>&#8221;). Ionis agrees that the Akcea Obligations
        may be extended, modified or renewed, in whole or in part, without notice or further assent from it, and that it will remain bound upon its guarantee notwithstanding any extension, modification or renewal of any Akcea Obligation. The obligations of
        Ionis under this <u>Section 17.10</u> shall not be affected by (a) the failure of AstraZeneca to assert any claim or demand or to enforce any right or remedy against Akcea under the provisions of this Agreement or otherwise; or (b) any rescission,
        waiver, amendment or modification of any of the terms or provisions of this Agreement or any other agreement or instrument. Ionis further agrees that its guarantee constitutes a guarantee of payment and performance when due and not of collection
        and waives any right to require that any resort be had by AstraZeneca to Akcea or to any other guarantee for any security held for payment or performance of the Akcea Obligations. This guarantee shall not be subject to any termination for any
        reason.</font></div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold; font-size: 10pt;">&#160;&#160;&#160; 17.10.2</font><font style="font-size: 10pt;">&#160;&#160;&#160;&#160;&#160;&#160;&#160; Ionis and Akcea acknowledge and agree that the Ionis/Akcea Agreement shall be subordinate to
        the provisions of this Agreement, and to the extent any provisions of the Ionis/Akcea Agreement are inconsistent with this Agreement or would impose an additional obligation on, or in any way limit or restrict a right of, AstraZeneca under this
        Agreement, the terms and conditions of this Agreement shall control, and except for its ownership of all right, title and interest in and to the Licensed Technology, solely for the Territory and solely for the benefit of AstraZeneca, Ionis hereby
        waives any and all rights it may have under the Ionis/Akcea Agreement that are inconsistent with this Agreement or that would impose an additional obligation on, or in any way limit or restrict a right of, AstraZeneca under this Agreement. Any
        notice or communication made under this Agreement to or from Akcea shall be deemed to be a notice or communication made to or from Ionis.</font></div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
      <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">92</font></div>
      <div style="page-break-after:always;" id="DSPFPageBreak">
        <hr noshade="noshade" style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;"></div>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; font-size: 10pt;">17.11</font><font style="font-size: 10pt;">&#160;&#160;&#160;&#160; <a name="ChangeofControl."><!--Anchor--></a>&#160;&#160;&#160;&#160; <font style="font-weight: bold;"><u>Change of
            Control</u></font>. If there is a Change of Control of Akcea after the Execution Date, then the following provisions will apply:</font></div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold; font-size: 10pt;">&#160;&#160;&#160; 17.11.1</font><font style="font-size: 10pt;">&#160;&#160;&#160;&#160;&#160;&#160;&#160; Akcea (or its Acquirer) shall provide AstraZeneca with written notice of such Change of
        Control of Akcea within [***] following the signing date and the closing date of such transaction.</font></div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold; font-size: 10pt;">&#160;&#160;&#160; 17.11.2</font><font style="font-size: 10pt;">&#160;&#160;&#160;&#160; If the Acquirer is Developing or Commercializing a product for an Initial Indication or for any
        other Indication for which AstraZeneca is Developing or Commercializing the Licensed Product hereunder, then, upon AstraZeneca&#8217;s request, Akcea and its Acquirer shall establish reasonable procedures, including firewalls between the teams
        responsible for such product and the teams responsible for the Licensed Product (other than members of senior management of the Acquirer responsible for overall product portfolio management), to prevent the use of any Confidential Information of
        AstraZeneca or any Patent Rights or Know-How that are subject to a license grant under this Agreement from being used by the Acquirer or its Affiliates in connection with the Development or Commercialization of such product.</font></div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold; font-size: 10pt;">&#160;&#160;&#160;&#160; 17.11.3</font><font style="font-size: 10pt;">&#160;&#160;&#160;&#160;&#160;&#160; If Akcea has not exercised its Opt-Out Right, then AstraZeneca shall [***] and within [***]
        of the public announcement of the completion of such Change of Control, AstraZeneca shall have the right, by written notice to Akcea, to elect one of the following (and AstraZeneca will be deemed to have elected the effect of clause (a) at the end
        of such [***] period if it does not otherwise notify Akcea during such [***] period): (a) [***], or (b) [***]; <font style="font-style: italic;">provided</font> that, [***].&#160; For clarity, if Akcea [***].</font></div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; font-size: 10pt;">17.12</font><font style="font-size: 10pt;">&#160;&#160;&#160;&#160; <a name="EntireAgreementAmendments"><!--Anchor--></a>&#160;&#160;&#160;&#160; <font style="font-weight: bold;"><u>Entire


            Agreement; Amendments</u></font>. This Agreement (including the attached Appendices, Exhibits and Schedules) sets forth all the covenants, promises, agreements, warranties, representations, conditions and understandings between the Parties
        regarding the subject matter hereof and supersedes and terminates all prior agreements and understanding between the Parties regarding the subject matter hereof. In particular, and without limitation, this Agreement supersedes and replaces any and
        all term sheets relating to the transactions contemplated by this Agreement and exchanged between the Parties prior to the Execution Date. There are no covenants, promises, agreements, warranties, representations, conditions or understandings,
        either oral or written, between the Parties regarding the subject matter hereof other than as set forth herein. No subsequent alteration, amendment, change or addition to this Agreement will be binding upon the Parties unless reduced to writing and
        signed by the respective authorized officers of the Parties.</font></div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; font-size: 10pt;">17.13</font><font style="font-size: 10pt;">&#160;&#160;&#160; <a name="IndependentContractors."><!--Anchor--></a>&#160;&#160;&#160; <font style="font-weight: bold;"><u>Independent


            Contractors</u></font>. Nothing herein will be construed to create any relationship of employer and employee, agent and principal, partnership or joint venture between the Parties. Each Party is an independent contractor with respect to the
        other Party. Neither Party will assume, either directly or indirectly, any liability of or for the other Party. Neither Party will have the authority to bind or obligate the other Party and neither Party will represent that it has such authority.</font></div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
      <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">93</font></div>
      <div style="page-break-after:always;" id="DSPFPageBreak">
        <hr noshade="noshade" style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;"></div>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; font-size: 10pt;">17.14</font><font style="font-size: 10pt;">&#160;&#160;&#160; <a name="HeadingsConstructionInter"><!--Anchor--></a>&#160;&#160;&#160;&#160;&#160; <font style="font-weight: bold;"><u>Headings;


            Construction; Interpretation</u></font>. Headings and any table of contents used herein are for convenience only and will not in any way affect the construction of or be taken into consideration in interpreting this Agreement. The terms and
        conditions of this Agreement represent the results of negotiations between the Parties and their representatives, each of which has been represented by counsel of its own choosing, and neither of which has acted under duress or compulsion, whether
        legal, economic or otherwise. Accordingly, the terms and conditions of this Agreement will be interpreted and construed in accordance with their usual and customary meanings, and each of the Parties hereby waives the application in connection with
        the interpretation and construction of this Agreement of any rule of Law to the effect that ambiguous or conflicting terms or provisions contained in this Agreement will be interpreted or construed against the Party whose attorney prepared the
        executed draft or any earlier draft of this Agreement. Any reference in this Agreement to this &#8220;<font style="font-style: italic;">Agreement</font>&#8221; includes the Schedules and Exhibits hereto, the Development Plan and Budget, the U.S. Medical
        Affairs Plan and Budget, the U.S. Commercialization Plan and Budget and the ROW Commercialization Plan, all of which are incorporated by reference into and constitute a part of this Agreement. Except where explicitly provided, any reference in this
        Agreement to an Article, Section, subsection, paragraph, clause, Schedule or Appendix will be deemed to be a reference to any Article, Section, subsection, paragraph, clause, Schedule or Appendix, of or to, as the case may be, this Agreement.
        Except where the context otherwise requires, (a) any definition of or reference to any agreement, instrument or other document refers to such agreement, instrument other document as from time to time amended, supplemented or otherwise modified
        (subject to any restrictions on such amendments, supplements or modifications set forth herein or therein), (b) any reference to any Law includes all rules and regulations thereunder and any successor Law, in each case as from time to time enacted,
        repealed or amended, (c) the words &#8220;<font style="font-style: italic;">herein</font>,&#8221; &#8220;<font style="font-style: italic;">hereof</font>&#8221; and &#8220;<font style="font-style: italic;">hereunder</font>,&#8221; and words of similar import, refer to this Agreement
        in its entirety and not to any particular provision hereof, (d) the words &#8220;<font style="font-style: italic;">include</font>,&#8221; &#8220;<font style="font-style: italic;">includes</font>,&#8221; &#8220;<font style="font-style: italic;">including</font>&#8221; will be deemed
        to be followed by the phrase &#8220;<font style="font-style: italic;">but not limited to</font>,&#8221; &#8220;<font style="font-style: italic;">without limitation</font>&#8221; or words of similar import, (e) words in the singular or plural form include the plural and
        singular form, respectively, (f) references to any gender refer to each gender, (g) references to a particular Person include such Person&#8217;s successors and assigns to the extent not prohibited by this Agreement, (h) the words &#8220;<font style="font-style: italic;">will</font>&#8221; and &#8220;<font style="font-style: italic;">shall</font>&#8221; shall have the same meaning and shall be understood to be imperative or mandatory in nature, (i) the word &#8220;<font style="font-style: italic;">or</font>&#8221;
        has the inclusive meaning represented by the phrase &#8220;<font style="font-style: italic;">and/or</font>&#8221;, (j) a capitalized term not defined herein but reflecting a different part of speech than a capitalized term which is defined herein will be
        interpreted in a correlative manner, (k) references to a number of days, unless otherwise specified, refers to calendar days, (l) use of the term &#8220;<font style="font-style: italic;">Licensed Compound</font>&#8221; and &#8220;<font style="font-style: italic;">Licensed


          Product</font>&#8221; shall not be deemed to limit any rights of AstraZeneca with respect to all Licensed Compounds and all Licensed Products and (m) the words &#8220;<font style="font-style: italic;">costs</font>&#8221; and &#8220;<font style="font-style: italic;">expenses</font>&#8221;
        shall have the same meaning.</font></div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; font-size: 10pt;">17.15</font><font style="font-size: 10pt;">&#160;&#160;&#160; <a name="FurtherActions."><!--Anchor--></a>&#160;&#160;&#160; <font style="font-weight: bold;"><u>Further Actions</u></font>.
        Each Party will execute, acknowledge and deliver such further instruments, and do all such other acts, as may be necessary or appropriate in order to carry out the expressly stated purposes and the clear intent of this Agreement.</font></div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; font-size: 10pt;">17.16</font><font style="font-size: 10pt;">&#160;&#160;&#160;&#160;&#160; <a name="PartiesinInterest"><!--Anchor--></a>&#160; <font style="font-weight: bold;"><u>Parties in
            Interest</u></font>. All of the terms and provisions of this Agreement will be binding upon, and will inure to the benefit of and be enforceable by the Parties hereto and their respective successors, heirs, administrators and permitted assigns.</font></div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; font-size: 10pt;">17.17</font><font style="font-size: 10pt;">&#160;&#160; <a name="Counterparts."><!--Anchor--></a>&#160;&#160; <font style="font-weight: bold;"><u>Counterparts</u></font>.
        This Agreement may be signed in counterparts, each and every one of which will be deemed an original, notwithstanding variations in format or file designation which may result from the electronic transmission, storage and printing of copies from
        separate computers or printers. Facsimile signatures and signatures transmitted via PDF will be treated as original signatures.</font></div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: center; font-size: 12pt; font-style: italic;"><font style="font-size: 10pt; font-weight: bold;">[</font><font style="font-size: 10pt;">Signature page to follow<font style="font-weight: bold;">]</font></font></div>
    <div style="font-size: 12pt; font-style: italic;"><font style="font-size: 10pt;"><font style="font-weight: bold;"> <br>
        </font></font></div>
    <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
      <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">94</font></div>
      <div style="page-break-after:always;" id="DSPFPageBreak">
        <hr noshade="noshade" style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;"></div>
    </div>
    <div style="text-align: justify; text-indent: 36pt; font-size: 10pt;">IN WITNESS WHEREOF, and intending to be legally bound hereby, the Parties have caused this Agreement to be executed by their duly authorized representatives as of the Execution Date.</div>
    <div style="font-size: 10pt;">&#160;</div>
    <table cellspacing="0" cellpadding="0" border="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; border-collapse: collapse; text-align: left; color: rgb(0, 0, 0);" id="z7bb88336678b45f78e4cde11da18d7c9">

        <tr>
          <td style="width: 50%; vertical-align: top;">&#160;</td>
          <td colspan="3" style="vertical-align: top;">
            <div style="font-weight: bold;">Akcea Therapeutics, Inc.</div>
          </td>
        </tr>
        <tr>
          <td style="width: 50%; vertical-align: top;">&#160;</td>
          <td colspan="3" style="vertical-align: top;">&#160;</td>
        </tr>
        <tr>
          <td style="width: 50%; vertical-align: top; padding-bottom: 2px;">&#160;</td>
          <td style="vertical-align: top; padding-bottom: 2px; width: 3%;" rowspan="1">
            <div>By: <br>
            </div>
          </td>
          <td style="vertical-align: top; border-bottom: 2px solid rgb(0, 0, 0); width: 37%;" rowspan="1">/s/ Brett Monia</td>
          <td style="vertical-align: top; width: 10%; padding-bottom: 2px;" rowspan="1">&#160;</td>
        </tr>
        <tr>
          <td style="width: 50%; vertical-align: top;">&#160;</td>
          <td style="width: 3%; vertical-align: top;"><br>
          </td>
          <td style="vertical-align: top;" colspan="2">
            <div>
              <div>Name:Brett Monia</div>
            </div>
          </td>
        </tr>
        <tr>
          <td style="width: 50%; vertical-align: top;">&#160;</td>
          <td style="width: 3%; vertical-align: top;"><br>
          </td>
          <td style="vertical-align: top;" colspan="2">
            <div>
              <div>Title:President</div>
            </div>
          </td>
        </tr>
        <tr>
          <td style="width: 50%; vertical-align: top;">&#160;</td>
          <td style="width: 3%; vertical-align: top;">&#160;</td>
          <td style="vertical-align: top;" colspan="2">&#160;</td>
        </tr>
        <tr>
          <td style="width: 50%; vertical-align: top;">&#160;</td>
          <td colspan="3" style="vertical-align: top;">
            <div style="font-weight: bold;">AstraZeneca AB (publ)</div>
          </td>
        </tr>
        <tr>
          <td rowspan="1" style="width: 50%; vertical-align: top;">&#160;</td>
          <td rowspan="1" colspan="3" style="vertical-align: top;">&#160;</td>
        </tr>
        <tr>
          <td style="width: 50%; vertical-align: top; padding-bottom: 2px;">&#160;</td>
          <td style="vertical-align: top; padding-bottom: 2px; width: 3%;" rowspan="1">
            <div>By: <br>
            </div>
          </td>
          <td style="vertical-align: top; border-bottom: 2px solid rgb(0, 0, 0); width: 37%;" rowspan="1">/s/ Elisabeth Bj&#1255;rk</td>
          <td style="vertical-align: top; width: 10%; padding-bottom: 2px;" rowspan="1">&#160;</td>
        </tr>
        <tr>
          <td style="width: 50%; vertical-align: top;">&#160;</td>
          <td style="width: 3%; vertical-align: top;"><br>
          </td>
          <td style="vertical-align: top;" colspan="2">
            <div>
              <div>Name:&#160;&#160;&#160;&#160; Elisabeth Bj&#246;rk</div>
            </div>
          </td>
        </tr>
        <tr>
          <td style="width: 50%; vertical-align: top;">&#160;</td>
          <td style="width: 3%; vertical-align: top;"><br>
          </td>
          <td style="vertical-align: top;" colspan="2">
            <div>
              <div>Title:&#160;&#160;&#160;&#160;&#160;&#160; Senior Vice President, Late CVRM</div>
            </div>
          </td>
        </tr>

    </table>
    <div><font style="font-size: 10pt;"><br>
      </font> </div>
    <div style="font-size: 10pt;">With respect to&#160;<u>Article 14</u>&#160;and <u>Section 17.10</u> only:</div>
    <div><font style="font-size: 10pt;"><br>
      </font> </div>
    <table cellspacing="0" cellpadding="0" border="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; border-collapse: collapse; text-align: left; color: #000000;" id="z2b32904934304311ba9fc074f112d799">

        <tr>
          <td style="width: 50%; vertical-align: top;">&#160;</td>
          <td colspan="3" style="vertical-align: top;">
            <div style="font-weight: bold;">Ionis Pharmaceuticals, Inc.</div>
          </td>
        </tr>
        <tr>
          <td style="width: 50%; vertical-align: top;">&#160;</td>
          <td style="width: 3%; vertical-align: top;">&#160;</td>
          <td style="vertical-align: top;" colspan="2">&#160;</td>
        </tr>
        <tr>
          <td style="width: 50%; vertical-align: top; padding-bottom: 2px;">&#160;</td>
          <td style="width: 3%; vertical-align: top; padding-bottom: 2px;">
            <div>By:</div>
          </td>
          <td style="width: 37%; vertical-align: top; border-bottom: 2px solid black;">
            <div>/s/ Brett Monia</div>
          </td>
          <td style="width: 10%; vertical-align: top; padding-bottom: 2px;">&#160;</td>
        </tr>
        <tr>
          <td style="width: 50%; vertical-align: top;">&#160;</td>
          <td style="width: 3%; vertical-align: top;">&#160;</td>
          <td style="vertical-align: top;" colspan="2">
            <div>Name: Brett Monia</div>
          </td>
        </tr>
        <tr>
          <td style="width: 50%; vertical-align: top;">&#160;</td>
          <td style="width: 3%; vertical-align: top;">&#160;</td>
          <td style="vertical-align: top;" colspan="2">
            <div>Title: Chief Executive Officer</div>
          </td>
        </tr>

    </table>
    <div> <br>
    </div>
    <div>
      <div style="text-align: center; font-family: 'Times New Roman',Times,serif; font-size: 10pt; font-style: italic;">[Signature Page to Collaboration and License Agreement]</div>
    </div>
    <div> <br>
    </div>
    <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
      <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">95</font></div>
      <div style="page-break-after:always;" id="DSPFPageBreak">
        <hr noshade="noshade" style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;"></div>
    </div>
    <div style="text-align: center; font-weight: bold; font-size: 10pt;"><u>Appendix 1</u></div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: center; font-weight: bold; font-size: 10pt;">Definitions</div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: justify; font-size: 10pt;">For purposes of this Agreement, the following terms will have the meanings set forth below:</div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; font-size: 10pt;">1.1</font><font style="font-size: 10pt;">&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#8220;<font style="font-weight: bold; font-style: italic;">Accounting Standards</font>&#8221; means, with
        respect to a Party, IFRS or GAAP, as applicable, as generally and consistently applied throughout a Party&#8217;s organization.</font></div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; font-size: 10pt;">1.2</font><font style="font-size: 10pt;">&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#8220;<font style="font-weight: bold; font-style: italic;">Acquirer</font>&#8221; has the meaning set forth
        in the definition of &#8220;<font style="font-style: italic;">Change of Control</font>&#8221;.</font></div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; font-size: 10pt;">1.3</font><font style="font-size: 10pt;">&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#8220;<font style="font-weight: bold; font-style: italic;">Additional Core IP</font>&#8221; means Third Party
        intellectual property that is necessary to Exploit the Licensed Compound as it is being clinically Developed on the Execution Date and relates generally to the same class of oligonucleotides as eplontersen, including [***] Conjugate Technology.</font></div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; font-size: 10pt;">1.4</font><font style="font-size: 10pt;">&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#8220;<font style="font-weight: bold; font-style: italic;">Additional Development</font>&#8221; has the
        meaning set forth in <u>Section 2.5.1</u>.</font></div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; font-size: 10pt;">1.5</font><font style="font-size: 10pt;">&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#8220;<font style="font-weight: bold; font-style: italic;">Additional Development Proposal</font>&#8221; has
        the meaning set forth in <u>Section 2.5.1</u>.</font></div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; font-size: 10pt;">1.6</font><font style="font-size: 10pt;">&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#8220;<font style="font-weight: bold; font-style: italic;">Affiliate</font>&#8221; means any Person that,
        directly or indirectly through one or more intermediaries, controls, is controlled by or is under common control with a Party to this Agreement at the applicable time. A Person will be deemed to &#8220;<font style="font-style: italic;">control</font>&#8221;
        another Person if it (a) owns, directly or indirectly, beneficially or legally, at least 50% of the outstanding voting securities or capital stock (or such lesser percentage which is the maximum allowed to be owned by a foreign corporation in a
        particular jurisdiction) of such other Person, or has other comparable ownership interest with respect to any Person other than a corporation; or (b) has the power, whether pursuant to contract, ownership of securities or otherwise, to direct the
        management and policies of such other Person. For clarity, Ionis is an Affiliate of Akcea.</font></div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; font-size: 10pt;">1.7</font><font style="font-size: 10pt;">&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#8220;<font style="font-weight: bold; font-style: italic;">Agreement</font>&#8221; has the meaning set forth
        in the Preamble of this Agreement.</font></div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; font-size: 10pt;">1.8</font><font style="font-size: 10pt;">&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#8220;<font style="font-weight: bold; font-style: italic;">Akcea</font>&#8221; has the meaning set forth in
        the Preamble of this Agreement.</font></div>
    <div style="font-size: 10pt;">&#160;</div>
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        Compound or the Licensed Product, regardless of sequence or chemical modification; <font style="font-style: italic;">except</font> Akcea Manufacturing Patent Rights do not include Patent Rights specifically directed to oligonucleotide compounds
        that specifically modulate expression of TTR via the binding, partially or wholly, of such compound to RNA that encodes TTR (which Patent Rights will be Akcea Product-Specific Patent Rights). Akcea Manufacturing Patent Rights includes Akcea
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    <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; font-size: 10pt;">1.20</font><font style="font-size: 10pt;">&#160;&#160;&#160;&#160;&#160;&#160;&#160; &#8220;<font style="font-weight: bold; font-style: italic;">Akcea Patent Rights</font>&#8221; means,
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    <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; font-size: 10pt;">1.21</font><font style="font-size: 10pt;">&#160;&#160;&#160;&#160;&#160;&#160;&#160; &#8220;<font style="font-weight: bold; font-style: italic;">Akcea Product-Specific IP</font>&#8221; means the
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      <div style="page-break-after:always;" id="DSPFPageBreak">
        <hr noshade="noshade" style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;"></div>
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        all Know-How, other than Joint Know-How, Controlled by Akcea or its Affiliates on the Execution Date or at any time prior to the end of the Term necessary or reasonably useful to Exploit the Licensed Compound or the Licensed Product, in each case,
        that specifically relates to (a) the composition of matter of the Licensed Compound or the Licensed Product, or (b) methods of using the Licensed Compound or the Licensed Product as a prophylactic, therapeutic or diagnostic; <font style="font-style: italic;">provided, however</font>, Know-How Controlled by Akcea or any of its Affiliates to the extent (i) consisting of subject matter applicable to oligonucleotide compounds or products in general, or (ii) relating to an
        oligonucleotide compound that does not specifically modulate expression of TTR via the binding, partially or wholly, of such compound to RNA that encodes TTR, will not be considered Akcea Product-Specific Know-How. Know-How that would otherwise
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        Product, or (b) methods of using a Licensed Compound or a Licensed Product as a prophylactic, therapeutic or diagnostic; <font style="font-style: italic;">except</font> for those Patent Rights set forth on <u>Schedule </u><u>1.11</u>, which
        scheduled Patent Rights will be considered Akcea Core Technology Patent Rights. The Akcea Product-Specific Patent Rights as of the Execution Date are set forth on <u>Schedule 1.23</u> attached hereto; provided that, the Patent Rights set forth on
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    <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; font-size: 10pt;">1.24</font><font style="font-size: 10pt;">&#160;&#160;&#160;&#160;&#160;&#160;&#160; &#8220;<font style="font-weight: bold; font-style: italic;">Akcea Program Technology</font>&#8221; has the
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    <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; font-size: 10pt;">1.25</font><font style="font-size: 10pt;">&#160;&#160;&#160;&#160;&#160;&#160;&#160; &#8220;<font style="font-weight: bold; font-style: italic;">Alliance Manager</font>&#8221; has the meaning set
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    <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; font-size: 10pt;">1.26</font><font style="font-size: 10pt;">&#160;&#160;&#160;&#160;&#160;&#160;&#160; &#8220;<font style="font-weight: bold; font-style: italic;">Allowable Overruns</font>&#8221; means, on an
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        U.S. Medical Affairs Plan and Budget, or U.S. Commercialization Plan and Budget, as applicable; <font style="font-style: italic;">provided </font>that such amount is not attributable to (i) the breach of this Agreement by the incurring Party or
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        pharmaceutical ingredient manufactured in accordance with cGMP (unless expressly stated otherwise) for a Licensed Product. The quantity of API will be the as-is gross mass of the API after lyophilization (<font style="font-style: italic;">i.e.</font>,
        including such amounts of water, impurities, salt, heavy, metals, etc. within the limits set forth in the API specifications) and before release, retention, stability or characterization samples are removed (if needed).</font></div>
    <div style="font-size: 10pt;">&#160;</div>
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      <div style="page-break-after:always;" id="DSPFPageBreak">
        <hr noshade="noshade" style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;"></div>
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    <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; font-size: 10pt;">1.31</font><font style="font-size: 10pt;">&#160;&#160;&#160;&#160;&#160;&#160; &#8220;<font style="font-weight: bold; font-style: italic;">ASO</font>&#8221; means a single-stranded or
        double-stranded oligonucleotide compound, or analog, variant, mimic, or mimetic thereof, having a sequence that is between six and one hundred nucleotides long and is designed to hybridize to a nucleic acid transcript via the binding, partially or
        wholly, of such compound to such nucleic acid transcript.</font></div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; font-size: 10pt;">1.32</font><font style="font-size: 10pt;">&#160;&#160;&#160;&#160;&#160;&#160;&#160; &#8220;<font style="font-weight: bold; font-style: italic;">AstraZeneca</font>&#8221; has the meaning set forth
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    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; font-size: 10pt;">1.33</font><font style="font-size: 10pt;">&#160;&#160;&#160;&#160;&#160;&#160; &#8220;<font style="font-weight: bold; font-style: italic;">AstraZeneca Indemnified Parties</font>&#8221; has
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    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; font-size: 10pt;">1.34</font><font style="font-size: 10pt;">&#160;&#160;&#160;&#160;&#160;&#160;&#160; &#8220;<font style="font-weight: bold; font-style: italic;">AstraZeneca IP</font>&#8221; means, collectively,
        (a) the AstraZeneca Know-How, (b) the AstraZeneca Patent Rights and (c) AstraZeneca&#8217;s interest in the Joint Program Technology.</font></div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; font-size: 10pt;">1.35</font><font style="font-size: 10pt;">&#160;&#160;&#160;&#160;&#160;&#160; &#8220;<font style="font-weight: bold; font-style: italic;">AstraZeneca Know-How</font>&#8221; means all
        Know-How, other than Joint Know-How, Controlled by AstraZeneca on the Execution Date or at any time prior to the end of the Term that is necessary to perform Akcea&#8217;s U.S. Development Activities, Global Development Activities or Co-Commercialization
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    <div style="font-size: 10pt;">&#160;</div>
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    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; font-size: 10pt;">1.37</font><font style="font-size: 10pt;">&#160;&#160;&#160;&#160;&#160;&#160;&#160; &#8220;<font style="font-weight: bold; font-style: italic;">AstraZeneca Manufacturing Improvements</font>&#8221;
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        Co-Commercialization and Medical Affairs Activities, in each case, as set forth in the Development Plan and Budget, U.S. Commercialization Plan and Budget or U.S. Medical Affairs Plan and Budget, as applicable.</font></div>
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    <div style="font-size: 10pt;">&#160;</div>
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    <div style="font-size: 10pt;">&#160;</div>
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    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; font-size: 10pt;">1.42</font><font style="font-size: 10pt;">&#160;&#160;&#160;&#160;&#160;&#160; &#8220;<font style="font-weight: bold; font-style: italic;">AstraZeneca Reversion Know-How</font>&#8221; means
        all Know-How, other than Joint Know-How, Controlled by AstraZeneca as of the effective date of termination that is necessary or that is actually being used as of the effective date of termination to Exploit the Licensed Compound or the Licensed
        Product in the applicable Terminated Territory as such Licensed Product is being clinically Developed or Commercialized by AstraZeneca or its Affiliates in the applicable Terminated Territory as of the effective date of termination, but excluding
        any Know-How that is (a) related to [***], or (b) (i) related to [***], or (ii) [***] as of the effective date of termination to Exploit the Licensed Product as it is being Commercialized by AstraZeneca or its Affiliates in the applicable
        Terminated Territory as of the effective date of termination.</font></div>
    <div style="font-size: 10pt;">&#160;</div>
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      <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">99</font></div>
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        or the Licensed Product in the applicable Terminated Territory as such Licensed Product is being clinically Developed or Commercialized by AstraZeneca or its Affiliates in the applicable Terminated Territory as of the effective date of termination,
        but excluding any Patent Right that (a) [***], or (b) (i) claims [***], or (ii) [***] as of the effective date of termination to Exploit the Licensed Product as it is being Commercialized by AstraZeneca or its Affiliates in the applicable
        Terminated Territory as of the effective date of termination.</font></div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; font-size: 10pt;">1.44</font><font style="font-size: 10pt;">&#160;&#160;&#160;&#160;&#160;&#160; &#8220;<font style="font-weight: bold; font-style: italic;">AstraZeneca Third Party Product-Specific
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    <div style="font-size: 10pt;">&#160;</div>
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        <u>Section </u><u>11.11.3(d)</u>.</font></div>
    <div style="font-size: 10pt;">&#160;</div>
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        forth in <u>Section</u><u>&#160;</u><u>8.3.2</u>.</font></div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; font-size: 10pt;">1.47</font><font style="font-size: 10pt;">&#160;&#160;&#160;&#160;&#160;&#160;&#160; &#8220;<font style="font-weight: bold; font-style: italic;">Breaching Party</font>&#8221; has the meaning set
        forth in <u>Section 16.2.1(a)</u>.</font></div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; font-size: 10pt;">1.48</font><font style="font-size: 10pt;">&#160;&#160;&#160;&#160;&#160;&#160; &#8220;<font style="font-weight: bold; font-style: italic;">Business Day</font>&#8221; means any day, other than
        Saturday, Sunday, or any statutory holiday or bank holiday in the United States or London, England.</font></div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; font-size: 10pt;">1.49</font><font style="font-size: 10pt;">&#160;&#160;&#160;&#160;&#160; &#8220;<font style="font-weight: bold; font-style: italic;">Calendar Quarter</font>&#8221; means a period of
        three consecutive months corresponding to the Calendar Year commencing on January 1, April 1, July 1 and October 1, except that the first Calendar Quarter of the Term shall commence on the Closing Date and end on the day immediately prior to the
        first to occur of January 1, April 1, July 1 or October 1 after the Closing Date and the last Calendar Quarter shall end on the last day of the Term.</font></div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; font-size: 10pt;">1.50</font><font style="font-size: 10pt;">&#160;&#160;&#160;&#160;&#160;&#160; &#8220;<font style="font-weight: bold; font-style: italic;">Calendar Year</font>&#8221; means a period of 12
        consecutive months corresponding to the Calendar Year commencing on the first day of January, except that the first Calendar Year of the Term shall commence on the Closing Date and end on December 31 of the year in which the Closing Date occurs and
        the last Calendar Year of the Term shall commence on January 1 of the year in which the Term ends and end on the last day of the Term.</font></div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; font-size: 10pt;">1.51</font><font style="font-size: 10pt;">&#160;&#160;&#160;&#160;&#160;&#160; &#8220;<font style="font-weight: bold; font-style: italic;">Change of Control</font>&#8221; means, with respect
        to a Party (a) the acquisition of beneficial ownership, directly or indirectly, by any Third Party (or group of Third Parties) of securities or other voting interest of such Party (or any controlling Affiliate of such Party) representing 50% or
        more of the combined voting power of such Party&#8217;s (or any controlling Affiliate of such Party&#8217;s) then outstanding securities or other voting interests, (b) any merger, reorganization, consolidation or business combination involving such Party (or
        any controlling Affiliate of such Party) with a Third Party that results in the holders of beneficial ownership (other than by virtue of obtaining irrevocable proxies) of the voting securities or other voting interests of such Party (or any
        controlling Affiliate of such Party) immediately prior to such merger, reorganization, consolidation or business combination ceasing to hold beneficial ownership of more than 50% of the combined voting power of the surviving entity (or any
        controlling Affiliate of such Party) immediately after such merger, reorganization, consolidation or business combination, or (c) any sale, lease, exchange, contribution or other transfer to a Third Party (in one transaction or a series of related
        transactions) of all or substantially all of the assets of such Party (or any controlling Affiliate of such Party) to which this Agreement relates. The acquiring or combining Third Party in any of clause (a), (b) or (c), is referred to herein as
        the &#8220;<font style="font-weight: bold; font-style: italic;">Acquirer</font>&#8221;.</font></div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
      <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">100</font></div>
      <div style="page-break-after:always;" id="DSPFPageBreak">
        <hr noshade="noshade" style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;"></div>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; font-size: 10pt;">1.52</font><font style="font-size: 10pt;">&#160;&#160;&#160;&#160;&#160;&#160; &#8220;<font style="font-weight: bold; font-style: italic;">Clinical Trial</font>&#8221; means any human
        clinical trial for a product, including (a) a Phase 1 Clinical Trial, Phase 2 Clinical Trial, or Phase 3 Clinical Trial, and (b) any human clinical trial in any country after Regulatory Approval, including (i) clinical trials conducted voluntarily
        after Regulatory Approval for enhancing marketing or scientific knowledge of an approved Indication, (ii) trials conducted after Regulatory Approval due to a request or requirement of a Regulatory Authority or as a condition of a previously granted
        Regulatory Approval, and (iii) any REMS/RMP related study after Regulatory Approval.</font></div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; font-size: 10pt;">1.53</font><font style="font-size: 10pt;">&#160;&#160;&#160;&#160;&#160;&#160;&#160; &#8220;<font style="font-weight: bold; font-style: italic;">Closing</font>&#8221; has the meaning set forth in
        <u>Section 10.1</u>.</font></div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; font-size: 10pt;">1.54</font><font style="font-size: 10pt;">&#160;&#160;&#160;&#160;&#160;&#160;&#160; &#8220;<font style="font-weight: bold; font-style: italic;">Closing</font>&#160;<font style="font-weight: bold; font-style: italic;">Date</font>&#8221; has the meaning set forth in <u>Section 10.1</u>.</font></div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; font-size: 10pt;">1.55</font><font style="font-size: 10pt;">&#160;&#160;&#160;&#160;&#160;&#160;&#160; &#8220;<font style="font-weight: bold; font-style: italic;">CM</font>&#8221; means transthyretin&#8209;mediated
        amyloid cardiomyopathy. For the avoidance of doubt, CM includes cardiomyopathy of wild-type or hereditary transthyretin-mediated amyloidosis.</font></div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; font-size: 10pt;">1.56</font><font style="font-size: 10pt;">&#160;&#160;&#160;&#160;&#160;&#160;&#160; &#8220;<font style="font-weight: bold; font-style: italic;">CMO</font>&#8221; means a Third Party primarily
        engaged in the business of providing contract manufacturing or manufacturing services.</font></div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; font-size: 10pt;">1.57</font><font style="font-size: 10pt;">&#160;&#160;&#160;&#160;&#160;&#160;&#160; &#8220;<font style="font-weight: bold; font-style: italic;">Co-Commercialization and Medical Affairs
          Activities</font>&#8221; has the meaning set forth in <u>Section 3.2.2</u>.</font></div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; font-size: 10pt;">1.58</font><font style="font-size: 10pt;">&#160;&#160;&#160;&#160;&#160;&#160; &#8220;<font style="font-weight: bold; font-style: italic; color: rgb(0, 0, 0);">COGS</font><font style="color: rgb(0, 0, 0);">&#8221; means, with respect to a Licensed Product, the standard cost of such Licensed Product calculated as the fully absorbed cost of the Manufacturing Party incurred in the Manufacture of that Licensed Product ready for
          delivery from such Party, as calculated in a manner consistent with the methodology and internal accounting policies employed by such Party for other products, excluding, unless and until the Opt-Out Date (if any), any costs or expenses included
          as Eligible Expenses other than COGS.</font></font></div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; font-size: 10pt;">1.59</font><font style="font-size: 10pt;">&#160;&#160;&#160;&#160;&#160;&#160;&#160; &#8220;[***]&#8221;<font style="color: rgb(0, 0, 0);"> has the meaning set forth in <u>Section 11.5.2</u>.</font></font></div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; font-size: 10pt;">1.60</font><font style="font-size: 10pt;">&#160;&#160;&#160;&#160;&#160;&#160;&#160; &#8220;[***]&#8221; means [***].</font></div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; font-size: 10pt;">1.61</font><font style="font-size: 10pt;">&#160;&#160;&#160;&#160;&#160;&#160; &#8220;<font style="font-weight: bold; font-style: italic;">Commercialization</font>&#8221; and &#8220;<font style="font-weight: bold; font-style: italic;">Commercialize</font>&#8221; means any and all activities undertaken relating to the marketing, obtaining Pricing and Reimbursement Approvals, post-approval commitments, other phase IV studies, promotion
        (including advertising or detailing), or any other offering for sale or any sale of a product, including any distribution, importation, exportation or transport of a product for sales purposes. &#8220;<font style="font-weight: bold; font-style: italic;">Commercialization</font>&#8221;
        will not include Development or Manufacturing.</font></div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
      <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">101</font></div>
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        <hr noshade="noshade" style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;"></div>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; font-size: 10pt;">1.62</font><font style="font-size: 10pt;">&#160;&#160;&#160;&#160;&#160;&#160;&#160; &#8220;<font style="font-weight: bold; font-style: italic;">Commercialization and Medical Affairs Cost
          Share Notice</font>&#8221; has the meaning set forth in <u>Section 3.4.1(b)(i)</u>.</font></div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; font-size: 10pt;">1.63</font><font style="font-size: 10pt;">&#160;&#160;&#160;&#160;&#160;&#160;&#160; &#8220;<font style="font-weight: bold; font-style: italic;">Commercially Reasonable Efforts</font>&#8221;
        means:</font></div>
    <div style="font-size: 10pt;">&#160;</div>
    <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;" class="DSPFListTable" id="z1cd52efcf3ad4930a4ce489ce3c1894c">

        <tr>
          <td style="width: 73pt;"><br>
          </td>
          <td style="width: 36pt; vertical-align: top;">(a)</td>
          <td style="width: auto; vertical-align: top; text-align: justify;">
            <div>with respect to AstraZeneca, efforts to achieve an objective under this Agreement, including Development and Commercialization objectives, that are not less than the [***], to other compounds and products of similar commercial potential
              and in a similar commercial space at a similar stage in its lifecycle, taking into consideration relative safety and efficacy, product profile, the competitiveness of the marketplace, market potential, the relative profitability of the
              product (including pricing and reimbursement status) and other relevant factors, including technical, legal, scientific and medical factors, and</div>
          </td>
        </tr>

    </table>
    <div style="font-size: 10pt;">&#160;</div>
    <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;" class="DSPFListTable" id="z16beaea14d4d44b4bab0ccabd7bd025e">

        <tr>
          <td style="width: 73pt;"><br>
          </td>
          <td style="width: 36pt; vertical-align: top;">(b)</td>
          <td style="width: auto; vertical-align: top; text-align: justify;">
            <div>with respect to Akcea, efforts to achieve an objective under this Agreement, including Development and Commercialization objectives, that are not less than the [***] to other compounds and products of similar commercial potential and in a
              similar commercial space at a similar stage in its lifecycle, taking into consideration relative safety and efficacy, product profile, the competitiveness of the marketplace, market potential, the relative profitability of the product
              (including pricing and reimbursement status) and other relevant factors, including technical, legal, scientific and medical factors.</div>
          </td>
        </tr>

    </table>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: justify; margin-left: 72pt; font-size: 10pt;">With respect to an activity that is subcontracted by either AstraZeneca or Akcea, &#8220;Commercially Reasonable Efforts&#8221; means the exercise of such care and the dedication of such efforts
      with respect to: the selection of a subcontractor, the entry into the subcontract with such subcontractor, and the management of such subcontract (including, if applicable, the enforcement thereof), as are commercially reasonable. &#8220;Commercially
      Reasonable Efforts&#8221; will be determined on a country-by-country basis in the relevant countries, and activities that are or are not conducted in one country or factors that stem from one country, in each case, that have an effect on achieving the
      relevant objective in another country will be considered in determining whether Commercially Reasonable Efforts have been applied in such other country.</div>
    <div style="margin-left: 9pt; font-size: 10pt;">&#160;</div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; font-size: 10pt;">1.64</font><font style="font-size: 10pt;">&#160;&#160;&#160;&#160;&#160;&#160;&#160; &#8220;<font style="font-weight: bold; font-style: italic;">Competitive Infringement</font>&#8221;<font style="font-weight: bold;">&#160;</font>has the meaning set forth in <u>Section 12.4</u>.</font></div>
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    <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; font-size: 10pt;">1.65</font><font style="font-size: 10pt;">&#160;&#160;&#160;&#160;&#160;&#160;&#160; &#8220;<font style="font-weight: bold; font-style: italic;">Competitive Oligo</font>&#8221; means a
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    <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; font-size: 10pt;">1.66</font><font style="font-size: 10pt;">&#160;&#160;&#160;&#160;&#160;&#160; &#8220;<font style="font-weight: bold; font-style: italic;">Complete,</font>&#8221; &#8220;<font style="font-weight: bold; font-style: italic;">Completed</font>,&#8221; or &#8220;<font style="font-weight: bold; font-style: italic;">Completion</font>&#8221; means, with respect to a Clinical Trial, the point in time at which database lock for such trial has occurred and the
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    <div style="font-size: 10pt;">&#160;</div>
    <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
      <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">102</font></div>
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        <hr noshade="noshade" style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;"></div>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; font-size: 10pt;">1.67</font><font style="font-size: 10pt;">&#160;&#160;&#160;&#160;&#160;&#160;&#160; &#8220;<font style="font-weight: bold; font-style: italic;">Compulsory Sublicensee</font>&#8221; has the
        meaning set forth in <u>Section 11.6.2(c)</u>.</font></div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; font-size: 10pt;">1.68</font><font style="font-size: 10pt;">&#160;&#160;&#160;&#160;&#160;&#160;&#160; &#8220;<font style="font-weight: bold; font-style: italic;">Confidential Information</font>&#8221; has the
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    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; font-size: 10pt;">1.69</font><font style="font-size: 10pt;">&#160;&#160;&#160;&#160;&#160;&#160; &#8220;<font style="font-weight: bold; font-style: italic;">Conjugate Technology</font>&#8221; means chemistry
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        receptor (ASGP-R) and enhancing the targeting or uptake of antisense drugs to the liver.</font></div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; font-size: 10pt;">1.70</font><font style="font-size: 10pt;">&#160;&#160;&#160;&#160;&#160;&#160;&#160; &#8220;<font style="font-weight: bold; font-style: italic;">Continuing Party</font>&#8221; has the meaning set
        forth in <u>Section 12.2.1(c)</u>.</font></div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; font-size: 10pt;">1.71</font><font style="font-size: 10pt;">&#160;&#160;&#160;&#160;&#160;&#160; &#8220;<font style="font-weight: bold; font-style: italic;">Control</font>&#8221; or &#8220;<font style="font-weight: bold; font-style: italic;">Controlled</font>&#8221; means, with respect to a Party and any intellectual property right or other intangible property, the possession by such Party of the ability to grant a license or sublicense hereunder without
        violating the terms of any agreement with any Third Party. Notwithstanding anything in this Agreement to the contrary, a Party will be deemed to not Control any intellectual property that is owned or controlled by an Acquirer or such Acquirer&#8217;s
        Affiliates (other than the Change of Control Party and any Affiliate of such Party prior to the Change of Control and any successor entity to the Change of Control Party or any such Affiliates thereof (each, a &#8220;<font style="font-weight: bold; font-style: italic;">Party Affiliate</font>&#8221;)), (a) prior to the closing of such Change of Control, except to the extent that any such intellectual property (i) was developed prior to such Change of Control through the use of any intellectual
        property of a Party Affiliate or any Confidential Information of the other Party or (ii) is used by or on behalf of such Party or any of its Affiliates in performing its obligations under this Agreement, or (b) after such Change of Control, to the
        extent that such intellectual property (i) is developed or conceived by such Third Party or its Affiliates (other than a Party Affiliate) after such Change of Control without using or incorporating any intellectual property of a Party Affiliate or
        any Confidential Information of the other Party, (ii) is not used by or on behalf of such Party or any of its Affiliates in performing its obligations under this Agreement, and (iii) is not incorporated into any Licensed Compound or Licensed
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    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; font-size: 10pt;">1.72</font><font style="font-size: 10pt;">&#160;&#160;&#160;&#160;&#160;&#160;&#160; &#8220;<font style="font-weight: bold; font-style: italic;">Cost Sharing Cap</font>&#8221; has the meaning set
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    <div style="font-size: 10pt;">&#160;</div>
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        Patent Right the act of making, using, or selling of such Licensed Product by such Person would infringe a Valid Claim included in such Patent Right, or in the case of a Patent Right that is a patent application, would infringe a Valid Claim in
        such patent application if it were to issue as a patent.</font></div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; font-size: 10pt;">1.74</font><font style="font-size: 10pt;">&#160;&#160;&#160;&#160;&#160;&#160;&#160; &#8220;<font style="font-weight: bold; font-style: italic;">CSO</font>&#8221; means a Third Party primarily
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    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; font-size: 10pt;">1.75</font><font style="font-size: 10pt;">&#160;&#160;&#160;&#160;&#160;&#160;&#160; &#8220;<font style="font-weight: bold; font-style: italic;">Cure Period</font>&#8221; has the meaning set forth
        in <u>Section</u><u> 16.2.1(a)</u>.</font></div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; font-size: 10pt;">1.76</font><font style="font-size: 10pt;">&#160;&#160;&#160;&#160;&#160;&#160;&#160; <font style="color: rgb(0, 0, 0);">&#8220;</font><font style="font-weight: bold; font-style: italic; color: rgb(0, 0, 0);">Current Year Percentage Cap</font><font style="color: rgb(0, 0, 0);">&#8221; means </font>[***]<font style="color: rgb(0, 0, 0);">%.</font></font></div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
      <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">103</font></div>
      <div style="page-break-after:always;" id="DSPFPageBreak">
        <hr noshade="noshade" style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;"></div>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; font-size: 10pt;">1.77</font><font style="font-size: 10pt;">&#160;&#160;&#160;&#160;&#160;&#160;&#160; &#8220;<font style="font-weight: bold; font-style: italic;">Declining Party</font>&#8221; has the meaning set
        forth in <u>Section 12.2.1(c)</u>.</font></div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; font-size: 10pt;">1.78</font><font style="font-size: 10pt;">&#160;&#160;&#160;&#160;&#160;&#160;&#160; &#8220;<font style="font-weight: bold; font-style: italic;">Default Notice</font>&#8221; has the meaning set
        forth in <u>Section 16.2.1(a)</u>.</font></div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; font-size: 10pt;">1.79</font><font style="font-size: 10pt;">&#160;&#160;&#160;&#160;&#160;&#160; &#8220;<font style="font-weight: bold; font-style: italic;">Develop</font>&#8221; or &#8220;<font style="font-weight: bold; font-style: italic;">Development</font>&#8221; means research, including pre-clinical and clinical research and development activities, including drug metabolism and pharmacokinetics, translational research, toxicology, pharmacology toxicology
        studies, statistical analysis and report writing, formulation development and optimization, Clinical Trials, regulatory affairs (including preparation for a Regulatory Approval Application submission and other submission-related activities),
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    <div style="font-size: 10pt;">&#160;</div>
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    <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; font-size: 10pt;">1.82</font><font style="font-size: 10pt;">&#160;&#160;&#160;&#160;&#160;&#160;&#160; &#8220;<font style="font-weight: bold; font-style: italic;">Device</font>&#8221; has the meaning set forth in
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    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; font-size: 10pt;">1.83</font><font style="font-size: 10pt;">&#160;&#160;&#160;&#160;&#160;&#160;&#160; &#8220;<font style="font-weight: bold; font-style: italic;">Disclosing Party</font>&#8221; has the meaning set
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    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; font-size: 10pt;">1.84</font><font style="font-size: 10pt;">&#160;&#160;&#160;&#160;&#160;&#160;&#160; &#8220;<font style="font-weight: bold; font-style: italic;">Dollars</font>&#8221; or &#8220;<font style="font-weight: bold; font-style: italic;">$</font>&#8221; means the legal tender of the United States.</font></div>
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    <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; font-size: 10pt;">1.85</font><font style="font-size: 10pt;">&#160;&#160;&#160;&#160;&#160;&#160; &#8220;<font style="font-weight: bold; font-style: italic;">Eligible Commercialization Expenses</font>&#8221;
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        <tr>
          <td style="width: 72pt;"><br>
          </td>
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            <div>[***];</div>
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        </tr>

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    <div style="font-size: 10pt;">&#160;</div>
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        <tr>
          <td style="width: 72pt;"><br>
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    <div style="font-size: 10pt;">&#160;</div>
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        <tr>
          <td style="width: 72pt;"><br>
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    <div style="font-size: 10pt;">&#160;</div>
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            <div>[***];</div>
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    <div style="font-size: 10pt;">&#160;</div>
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        <tr>
          <td style="width: 72pt;"><br>
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            <div>[***];</div>
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    <div style="font-size: 10pt;">&#160;</div>
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        <tr>
          <td style="width: 72pt;"><br>
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            <div>[***]; and</div>
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      <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">104</font></div>
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            <div>any other categories of expenses expressly identified in the U.S. Commercialization Plan and Budget (<font style="font-style: italic;">provided</font> that, in the event of a conflict regarding a category of expenses to be included in the
              U.S. Commercialization Plan and Budget and any provision of this Agreement that specifies that such category of expenses will be treated in a different manner (including, for example, by treating such category of expenses as included in
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    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; font-size: 10pt;">1.86</font><font style="font-size: 10pt;">&#160;&#160;&#160;&#160;&#160;&#160; &#8220;<font style="font-weight: bold; font-style: italic;">Eligible Development Expenses</font>&#8221; means
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        Affiliates before the Closing Date) that are, unless specifically stated otherwise, reasonably allocable to Development of the Licensed Product (including Manufacturing in support thereof) after the Closing Date and, except with respect to <u>Section


          3.6.2(a)(i)</u>, prior to the Opt-Out Date, in each case, to the extent such activities are in furtherance of the objectives set forth in the Development Plan and Budget and such costs are consistent with the Development Plan and Budget, <font style="font-style: italic;">plus</font> Allowable Overruns, but expressly excluding Non-Reimbursable Expenses.&#160; Subject to the foregoing, Eligible Development Expenses includes:</font></div>
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          <td style="width: 72pt;"><br>
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            <div>[***];</div>
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        </tr>

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    <div style="font-size: 10pt;">&#160;</div>
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        <tr>
          <td style="width: 72pt;"><br>
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            <div>[***];</div>
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        </tr>

    </table>
    <div style="font-size: 10pt;">&#160;</div>
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        <tr>
          <td style="width: 72pt;"><br>
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            <div>[***];</div>
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        </tr>

    </table>
    <div style="font-size: 10pt;">&#160;</div>
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        <tr>
          <td style="width: 72pt;"><br>
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            <div>[***];</div>
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    </table>
    <div style="font-size: 10pt;">&#160;</div>
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        <tr>
          <td style="width: 72pt;"><br>
          </td>
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            <div>[***];</div>
          </td>
        </tr>

    </table>
    <div style="font-size: 10pt;">&#160;</div>
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        <tr>
          <td style="width: 72pt;"><br>
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            <div>[***]; and</div>
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    </table>
    <div style="font-size: 10pt;">&#160;</div>
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        <tr>
          <td style="width: 72pt;"><br>
          </td>
          <td style="width: 45pt; vertical-align: top;">(g)</td>
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            <div>any other categories of expenses expressly identified in the Development Plan and Budget <font style="font-style: italic;">(provided</font> that, in the event of a conflict regarding a category of expenses to be included in the
              Development Plan and Budget and any provision of this Agreement that specifies that such category of expenses will be treated in a different manner (including, for example, by treating such category of expenses as included in Eligible
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    <div style="font-size: 10pt;">&#160;</div>
    <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
      <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">105</font></div>
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    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; font-size: 10pt;">1.87</font><font style="font-size: 10pt;">&#160;&#160;&#160;&#160;&#160;&#160;&#160; &#8220;<font style="font-weight: bold; font-style: italic;">Eligible Expenses</font>&#8221; means Eligible
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    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; font-size: 10pt;">1.88</font><font style="font-size: 10pt;">&#160;&#160;&#160;&#160;&#160;&#160;&#160; &#8220;<font style="font-weight: bold; font-style: italic;">Eligible Medical Affairs Expenses</font>&#8221;
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    <div style="font-size: 10pt;">&#160;</div>
    <div>
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            <td style="align: left; vertical-align: top; width: auto;">
              <div style="text-align: justify;">[***];</div>
            </td>
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      </table>
    </div>
    <div style="font-size: 10pt;">&#160;</div>
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        <tr>
          <td style="width: 72pt;"><br>
          </td>
          <td style="width: 45pt; vertical-align: top;">(b)</td>
          <td style="width: auto; vertical-align: top; text-align: justify;">
            <div>[***];</div>
          </td>
        </tr>

    </table>
    <div style="font-size: 10pt;">&#160;</div>
    <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;" class="DSPFListTable" id="z613603c37e6a46938d558a864a562f75">

        <tr>
          <td style="width: 72pt;"><br>
          </td>
          <td style="width: 45pt; vertical-align: top;">(c)</td>
          <td style="width: auto; vertical-align: top; text-align: justify;">
            <div>[***];</div>
          </td>
        </tr>

    </table>
    <div style="font-size: 10pt;">&#160;</div>
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        <tr>
          <td style="width: 72pt;"><br>
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          <td style="width: 45pt; vertical-align: top;">(d)</td>
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            <div>[***];</div>
          </td>
        </tr>

    </table>
    <div style="font-size: 10pt;">&#160;</div>
    <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;" class="DSPFListTable" id="z43c52ab5a2784ebda1340525e897510a">

        <tr>
          <td style="width: 72pt;"><br>
          </td>
          <td style="width: 45pt; vertical-align: top;">(e)</td>
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            <div>[***]; and</div>
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        </tr>

    </table>
    <div style="font-size: 10pt;">&#160;</div>
    <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;" class="DSPFListTable" id="z90da4eadc5ab411f8780a4bfbb2ca3a5">

        <tr>
          <td style="width: 72pt;"><br>
          </td>
          <td style="width: 45pt; vertical-align: top;">(f)</td>
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            <div>any other categories of expenses expressly identified in the U.S. Medical Affairs Plan and Budget (<font style="font-style: italic;">provided</font> that, in the event of a conflict regarding a category of expenses to be included in the
              U.S. Medical Affairs Plan and Budget and any provision of this Agreement that specifies that such category of expenses will be treated in a different manner (including, for example, by treating such category of expenses as included in
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        </tr>

    </table>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
      <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">106</font></div>
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    </div>
    <div style="text-align: justify; margin-left: 108pt; font-size: 10pt;">If any FTE Cost, Out-of-Pocket Cost, or other cost or expense is included in more than one category of Eligible Medical Affairs Expenses set forth above, then such cost or expense
      will only be counted once (<font style="font-style: italic;">i.e.</font>, as an Eligible Medical Affairs Expenses with respect to only one such category). No expense included as an Eligible Medical Affairs Expense will also be included as an Eligible
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    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; font-size: 10pt;">1.89</font><font style="font-size: 10pt;">&#160;&#160;&#160;&#160;&#160;&#160;&#160; &#8220;<font style="font-weight: bold; font-style: italic;">EMA</font>&#8221; means the European Medicines
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    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; font-size: 10pt;">1.90</font><font style="font-size: 10pt;">&#160;&#160;&#160;&#160;&#160;&#160;&#160; &#8220;<font style="font-weight: bold; font-style: italic;">EU</font>&#8221; means the member countries of the
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    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; font-size: 10pt;">1.91</font><font style="font-size: 10pt;">&#160;&#160;&#160;&#160;&#160;&#160;&#160; &#8220;<font style="font-weight: bold; font-style: italic;">Exchange Rate</font>&#8221; has the meaning set
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    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; font-size: 10pt;">1.92</font><font style="font-size: 10pt;">&#160;&#160;&#160;&#160;&#160;&#160;&#160; &#8220;<font style="font-weight: bold; font-style: italic;">Exclusivity Period</font>&#8221; has the meaning
        set forth in <u>Section 9.2</u>.</font></div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; font-size: 10pt;">1.93</font><font style="font-size: 10pt;">&#160;&#160;&#160;&#160;&#160;&#160;&#160; &#8220;<font style="font-weight: bold; font-style: italic;">Execution Date</font>&#8221; has the meaning set
        forth in the Preamble of this Agreement.</font></div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; font-size: 10pt;">1.94</font><font style="font-size: 10pt;">&#160;&#160;&#160;&#160;&#160;&#160;&#160; &#8220;<font style="font-weight: bold; font-style: italic;">Existing In-License Agreements</font>&#8221; means
        those Akcea in-license agreements set forth on <u>Schedule </u><u>1.94</u> attached hereto.</font></div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; font-size: 10pt;">1.95</font><font style="font-size: 10pt;">&#160;&#160;&#160;&#160;&#160;&#160;&#160; &#8220;<font style="font-weight: bold; font-style: italic;">Exploit</font>&#8221; or &#8220;<font style="font-weight: bold; font-style: italic;">Exploitation</font>&#8221; means to make, have made, export, have exported, import, have imported, use, have used, sell, have sold, offer for sale, Develop, have Developed, Manufacture, have Manufactured, Commercialize, have
        Commercialized and otherwise exploit and have exploited.</font></div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; font-size: 10pt;">1.96</font><font style="font-size: 10pt;">&#160;&#160;&#160;&#160;&#160;&#160;&#160; &#8220;<font style="font-weight: bold; font-style: italic;">FDA</font>&#8221; means the U.S. Food and Drug
        Administration, and any successor entity thereto.</font></div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; font-size: 10pt;">1.97</font><font style="font-size: 10pt;">&#160;&#160;&#160;&#160;&#160;&#160;&#160; &#8220;<font style="font-weight: bold; font-style: italic;">Field</font>&#8221; means all human and non-human
        diagnostic, prophylactic and therapeutic uses.</font></div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; font-size: 10pt;">1.98</font><font style="font-size: 10pt;">&#160;&#160;&#160;&#160;&#160;&#160; &#8220;<font style="font-weight: bold; font-style: italic;">First Commercial Sale</font>&#8221; means the first
        sale of the Licensed Product by AstraZeneca, its Affiliate or Sublicensee to a Third Party in a particular country in the Territory after Regulatory Approval (other than Pricing and Reimbursement Approvals) of such Licensed Product has been
        obtained in such country.</font></div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; font-size: 10pt;">1.99</font><font style="font-size: 10pt;">&#160;&#160;&#160;&#160;&#160;&#160;&#160; &#8220;<font style="font-weight: bold; font-style: italic;">First Opt-Out Period</font>&#8221; has the meaning
        set forth in <u>Section 3.6.1</u>.</font></div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; font-size: 10pt;">1.100</font><font style="font-size: 10pt;">&#160;&#160;&#160;&#160;&#160; &#8220;<font style="font-weight: bold; font-style: italic;">Force Majeure</font>&#8221; has the meaning set
        forth in <u>Section 17.5</u>.</font></div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; font-size: 10pt;">1.101</font><font style="font-size: 10pt;">&#160;&#160;&#160;&#160;&#160; &#8220;<font style="font-weight: bold; font-style: italic;">FTE</font>&#8221; means the efforts of one or more
        employees of a Party (or its Affiliate) equivalent to the efforts of one full-time employee for one year, or in the case of less than a full-time dedicated person, a full-time equivalent person-year, in each case, based upon a total of 1,710 hours
        per year of work; <font style="font-style: italic;">provided</font> that any such employee who devotes fewer than 1,710 hours per year under this Agreement shall be treated as an FTE on a <font style="font-style: italic;">pro rata </font>basis
        based on the number of hours worked under this Agreement (based on such Party&#8217;s internal tracking processes) divided by 1,710.</font></div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
      <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">107</font></div>
      <div style="page-break-after:always;" id="DSPFPageBreak">
        <hr noshade="noshade" style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;"></div>
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    <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; font-size: 10pt;">1.102</font><font style="font-size: 10pt;">&#160;&#160;&#160;&#160;&#160; &#8220;<font style="font-weight: bold; font-style: italic;">FTE Costs</font>&#8221; means the product of the
        number of FTEs and the FTE Rate.</font></div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; font-size: 10pt;">1.103</font><font style="font-size: 10pt;">&#160;&#160;&#160;&#160; &#8220;<font style="font-weight: bold; font-style: italic;">FTE Rate</font>&#8221; means [***] per FTE for the
        period commencing on the Closing Date and ending December 31, 2022. On January 1, 2023 and on January 1st of each subsequent Calendar Year, the foregoing rate will be adjusted for the Calendar Year then commencing by the [***]; <font style="font-style: italic;">provided</font>, <font style="font-style: italic;">however</font>, that in no event will such adjustment result in an FTE Rate less than [***]. As used in this <u>Section </u><u>1.103</u>, [***].</font></div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; font-size: 10pt;">1.104</font><font style="font-size: 10pt;">&#160;&#160;&#160;&#160; &#8220;<font style="font-weight: bold; font-style: italic;">Future In-License Agreement</font>&#8221; means any
        agreement between Akcea or its Affiliate, on the one hand, and a Third Party, on the other hand, that is entered into after the Execution Date and pursuant to which Akcea acquires Control of any Licensed Technology.</font></div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; font-size: 10pt;">1.105</font><font style="font-size: 10pt;">&#160;&#160;&#160;&#160;&#160; &#8220;<font style="font-weight: bold; font-style: italic;">GAAP</font>&#8221; means United States generally
        accepted accounting principles consistently applied.</font></div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; font-size: 10pt;">1.106</font><font style="font-size: 10pt;">&#160;&#160;&#160;&#160;&#160; &#8220;<font style="font-weight: bold; font-style: italic;">Generic Intrusion</font>&#8221; means, with respect
        to a Licensed Product in a particular country in the Territory (the &#8220;<font style="font-weight: bold; font-style: italic;">Reference Product</font>&#8221;), when the Generic Products have, in the aggregate, achieved more than [***]% of the market share in
        such country by unit volume (based on data provided by <font style="color: rgb(0, 0, 0);">IQVIA</font> or another reliable Third Party data source mutually agreed by the Parties) of combined unit sales of the Reference Product and all Generic
        Products.</font></div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; font-size: 10pt;">1.107</font><font style="font-size: 10pt;">&#160;&#160;&#160;&#160;&#160; &#8220;<font style="font-weight: bold; font-style: italic;">Generic Product</font>&#8221; means, with respect to
        the Reference Product in a particular country in the Territory, any pharmaceutical product sold by a Third Party that is not authorized by AstraZeneca (other than through a Settlement Sublicense) that:</font></div>
    <div style="font-size: 10pt;">&#160;</div>
    <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;" class="DSPFListTable" id="z838d40ea1e6349b6ad3b981f14459e30">

        <tr>
          <td style="width: 72pt;"><br>
          </td>
          <td style="width: 45pt; vertical-align: top;">(a)</td>
          <td style="width: auto; vertical-align: top; text-align: justify;">
            <div>(i) contains the same active pharmaceutical ingredient as the Reference Product, and (ii) is approved in reliance, in whole or in part, on a prior Regulatory Approval of the Reference Product (or data submitted in support of such
              Regulatory Approval); or</div>
          </td>
        </tr>

    </table>
    <div style="font-size: 10pt;">&#160;</div>
    <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;" class="DSPFListTable" id="zb2028fb92a0c46228c9e37288cc775b3">

        <tr>
          <td style="width: 72pt;"><br>
          </td>
          <td style="width: 45pt; vertical-align: top;">(b)</td>
          <td style="width: auto; vertical-align: top; text-align: justify;">
            <div>(i) is approved in reliance, in whole or in part, on a prior Regulatory Approval of the Reference Product (or data submitted in support of such Regulatory Approval) and (ii) is determined by the applicable Regulatory Authority to be
              substitutable for the Reference Product.</div>
          </td>
        </tr>

    </table>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; font-size: 10pt;">1.108</font><font style="font-size: 10pt;">&#160;&#160;&#160;&#160;&#160; &#8220;<font style="font-weight: bold; font-style: italic;">Global Development Activities</font>&#8221; has the
        meaning set forth in <u>Section 2.4.1</u>.</font></div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; font-size: 10pt;">1.109</font><font style="font-size: 10pt;">&#160;&#160;&#160;&#160; &#8220;<font style="font-weight: bold; font-style: italic;">Good Clinical Practices</font>&#8221; or &#8220;<font style="font-weight: bold; font-style: italic;">cGCP</font>&#8221; means the then-current standards, practices, procedures and regulatory requirements promulgated or endorsed by the FDA and its applicable foreign counterparts, including the guidelines
        adopted by the ICH, titled &#8220;<font style="font-style: italic;">Guidance for Industry E6 Good Clinical Practice: Consolidated Guidance</font>&#8221;.</font></div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; font-size: 10pt;">1.110</font><font style="font-size: 10pt;">&#160;&#160;&#160;&#160; &#8220;<font style="font-weight: bold; font-style: italic;">Good Laboratory Practices</font>&#8221; or &#8220;<font style="font-weight: bold; font-style: italic;">cGLP</font>&#8221; means the then-current good laboratory practice standards promulgated or endorsed by the FDA, as defined in U.S. 21 C.F.R. Part 58, and such comparable regulatory standards in those
        applicable jurisdictions outside of the United States.</font></div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
      <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">108</font></div>
      <div style="page-break-after:always;" id="DSPFPageBreak">
        <hr noshade="noshade" style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;"></div>
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    <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; font-size: 10pt;">1.111</font><font style="font-size: 10pt;">&#160;&#160;&#160;&#160;&#160; &#8220;<font style="font-weight: bold; font-style: italic;">Good Manufacturing Practices</font>&#8221; or &#8220;<font style="font-weight: bold; font-style: italic;">cGMP</font>&#8221; means the then-current good manufacturing practices and standards promulgated or endorsed by the FDA, as provided for in the Current Good Manufacturing Practice Regulations of the U.S.
        Code of Federal Regulations Title 21 (21 C.F.R. &#167;&#167;210 and 211), and such comparable regulatory standards in those applicable jurisdictions outside of the United States, including the guidelines adopted by the ICH, titled, &#8220;<font style="font-style: italic;">Good Manufacturing Practice Guide for Active Ingredients, Q7</font>&#8221;.</font></div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; font-size: 10pt;">1.112</font><font style="font-size: 10pt;">&#160;&#160;&#160;&#160; &#8220;<font style="font-weight: bold; font-style: italic;">Government Official</font>&#8221; means: (a) any
        elected or appointed government official (<font style="font-style: italic;">e.g.</font>, a member of a ministry of health), (b) any employee or person acting for or on behalf of a government official, agency, or enterprise performing a governmental
        function, (c) any political party officer, employee, or person acting for or on behalf of a political party or candidate for public office, (d) an employee or person acting for or on behalf of a public international organization, or (e) any person
        otherwise categorized as a government official under local Law. As used herein, &#8220;<font style="font-style: italic;">government</font>&#8221; is meant to include all levels and subdivisions of non-U.S. governments (<font style="font-style: italic;">i.e.</font>,
        local, regional, or national and administrative, legislative, or executive).</font></div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; font-size: 10pt;">1.113</font><font style="font-size: 10pt;">&#160;&#160;&#160;&#160;&#160; &#8220;<font style="font-weight: bold; font-style: italic;">Governmental Authority</font>&#8221; means any
        court, agency, department, authority or other instrumentality of any national, state, county, city or other political subdivision.</font></div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; font-size: 10pt;">1.114</font><font style="font-size: 10pt;">&#160;&#160;&#160;&#160;&#160; &#8220;<font style="font-weight: bold; font-style: italic;">HSR</font>&#160;<font style="font-weight: bold; font-style: italic;">Act</font>&#8221; means the Hart-Scott-Rodino Antitrust Improvements Act of 1976, as amended, and the rules and regulations promulgated thereunder.</font></div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; font-size: 10pt;">1.115</font><font style="font-size: 10pt;">&#160;&#160;&#160;&#160;&#160; &#8220;<font style="font-weight: bold; font-style: italic;">HSR Clearance</font>&#8221; has the meaning set
        forth in <u>Section</u><u> 10.1</u>.</font></div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; font-size: 10pt;">1.116</font><font style="font-size: 10pt;">&#160;&#160;&#160;&#160;&#160; &#8220;<font style="font-weight: bold; font-style: italic;">ICH</font>&#8221; means the International Council
        for Harmonization.</font></div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; font-size: 10pt;">1.117</font><font style="font-size: 10pt;">&#160;&#160;&#160;&#160; &#8220;<font style="font-weight: bold; font-style: italic;">IFRS</font>&#8221; means international financial
        reporting standards, consistently applied.</font></div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; font-size: 10pt;">1.118</font><font style="font-size: 10pt;">&#160;&#160;&#160;&#160;&#160; &#8220;<font style="font-weight: bold; font-style: italic;">In-License Agreement</font>&#8221; means (a) any
        Existing In-License Agreement, and (b) any Future In-License Agreement, in each case of (a) and (b), as amended from time to time.</font></div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; font-size: 10pt;">1.119</font><font style="font-size: 10pt;">&#160;&#160;&#160;&#160;&#160; &#8220;<font style="font-weight: bold; font-style: italic;">Inbound Licensor</font>&#8221; means any Third Party
        licensor under any of the In-License Agreements.</font></div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; font-size: 10pt;">1.120</font><font style="font-size: 10pt;">&#160;&#160;&#160;&#160;&#160; &#8220;<font style="font-weight: bold; font-style: italic;">Included FTE Costs and Expenses</font>&#8221; means
        the sum of (a) [***], (b) [***] and (c) [***], in each case ((a), (b) and (c)), (i) [***], and (ii) except as may be specifically agreed otherwise as an item included in the budget in the then-current Development Plan and Budget, U.S.
        Commercialization Plan and Budget or U.S. Medical Affairs Plan and Budget, as applicable.</font></div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; font-size: 10pt;">1.121</font><font style="font-size: 10pt;">&#160;&#160;&#160;&#160; &#8220;<font style="font-weight: bold; font-style: italic;">IND</font>&#8221; means an investigational new drug
        application submitted to the FDA pursuant to Part 312 of Title 21 of the U.S. Code of Federal Regulations, including any amendments thereto. References herein to IND will include, to the extent applicable, any comparable filing(s) outside the U.S.
        for the investigation of any product in any other country or group of countries.</font></div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
      <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">109</font></div>
      <div style="page-break-after:always;" id="DSPFPageBreak">
        <hr noshade="noshade" style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;"></div>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; font-size: 10pt;">1.122</font><font style="font-size: 10pt;">&#160;&#160;&#160;&#160;&#160; &#8220;<font style="font-weight: bold; font-style: italic;">Indemnification Claim Notice</font>&#8221; has the
        meaning set forth in <u>Section </u><u>15.4.1</u>.</font></div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; font-size: 10pt;">1.123</font><font style="font-size: 10pt;">&#160;&#160;&#160;&#160;&#160; &#8220;<font style="font-weight: bold; font-style: italic;">Indemnified Party</font>&#8221; has the meaning set
        forth in <u>Section </u><u>15.4.1</u>.</font></div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; font-size: 10pt;">1.124</font><font style="font-size: 10pt;">&#160;&#160;&#160;&#160; &#8220;<font style="font-weight: bold; font-style: italic;">Indication</font>&#8221; means a primary sickness or
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        market and sell the Licensed Product for such disease, and will include sub-types of the same disease and pediatric populations of the same disease (<font style="font-style: italic;">i.e.</font>, such sub-types and pediatric populations shall be
        part of the same Indication and shall not be treated as a separate Indication).</font></div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; font-size: 10pt;">1.125</font><font style="font-size: 10pt;">&#160;&#160;&#160;&#160;&#160; &#8220;<font style="font-weight: bold; font-style: italic;">Indirect Taxes</font>&#8221; means value added
        taxes, sales taxes, consumption taxes and other similar taxes required by applicable Law to be disclosed on the invoice.</font></div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; font-size: 10pt;">1.126</font><font style="font-size: 10pt;">&#160;&#160;&#160;&#160;&#160; &#8220;<font style="font-weight: bold; font-style: italic;">Initial Indication</font>&#8221; means, with respect
        to the Licensed Product, each of (a) PN and (b) CM.</font></div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; font-size: 10pt;">1.127</font><font style="font-size: 10pt;">&#160;&#160;&#160;&#160; &#8220;<font style="font-weight: bold; font-style: italic;">Inotersen</font>&#8221; means the compound having the
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        and T have the same nucleobase structure and the choice for the symbol depends on whether the sugar is 2&#8242;-deoxy-D-ribose or D-ribose. Each of the 19 internucleoside linkages is a phosphorothioate linkage. Inotersen does not include any product
        containing Conjugate Technology.</font></div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; font-size: 10pt;">1.128</font><font style="font-size: 10pt;">&#160;&#160;&#160;&#160; &#8220;<font style="font-weight: bold; font-style: italic;">Inotersen Product</font>&#8221; means any
        pharmaceutical preparation that (a) contains Inotersen as an active pharmaceutical ingredient and (b) does not contain any other ASO that is designed to bind to the RNA of TTR and reduce or block the production of the TTR protein.</font></div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; font-size: 10pt;">1.129</font><font style="font-size: 10pt;">&#160;&#160;&#160;&#160; &#8220;<font style="font-weight: bold; font-style: italic;">Interim U.S. Commercialization Plan and Budget</font>&#8221;
        has the meaning set forth in <u>Section 3.2.1(a)</u>.</font></div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; font-size: 10pt;">1.130</font><font style="font-size: 10pt;">&#160;&#160;&#160;&#160;&#160; &#8220;<font style="font-weight: bold; font-style: italic;">Interim U.S. Medical Affairs Plan and Budget</font>&#8221;
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    <div style="font-size: 10pt;">&#160;</div>
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        applicable rules, regulations, guidelines, or other requirements of the Regulatory Authorities that may be in effect from time to time.</font></div>
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    <div style="font-size: 10pt;">&#160;</div>
    <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;" class="DSPFListTable" id="z76efcc61aad14e3fa6232ee3b4e543bd">

        <tr>
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            <div>normal and customary trade, quantity or prompt settlement discounts (including initial launch stocking discounts, chargebacks and allowances) actually allowed, <font style="font-style: italic;">provided </font>that such discounts are not
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    <div style="font-size: 10pt;">&#160;</div>
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            <div>amounts repaid or credited by reason of rejection, returns or recalls of goods, rebates or bona fide price reductions determined by AstraZeneca, its Affiliates or its or their Sublicensees in good faith;</div>
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        </tr>

    </table>
    <div style="font-size: 10pt;">&#160;</div>
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        <tr>
          <td style="width: 72pt;"><br>
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          <td style="width: 45pt; vertical-align: top;">(c)</td>
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            <div>rebates and similar payments made with respect to sales paid for by any Governmental Authority such as, by way of illustration and not in limitation of the Parties&#8217; rights hereunder, Federal or state Medicaid, Medicare or similar state
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        </tr>

    </table>
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          <td style="width: 72pt;"><br>
          </td>
          <td style="width: 45pt; vertical-align: top;">(d)</td>
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            <div>any invoiced amounts that are not collected by AstraZeneca, its Affiliates or its or their Sublicensees, including bad debts;</div>
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        </tr>

    </table>
    <div style="font-size: 10pt;">&#160;</div>
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        <tr>
          <td style="width: 72pt;"><br>
          </td>
          <td style="width: 45pt; vertical-align: top;">(e)</td>
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            <div>excise taxes, value added taxes, sales taxes, consumption taxes and other similar taxes (excluding any income, franchise or withholding taxes), customs duties, customs levies and import fees imposed on the sale, importation, use or
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        </tr>

    </table>
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            <div>the portion of administrative fees paid during the relevant time period to group purchasing organizations or pharmaceutical benefit managers relating to the Licensed Product;</div>
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        </tr>

    </table>
    <div style="font-size: 10pt;">&#160;</div>
    <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;" class="DSPFListTable" id="zee6e34d1a09545aeb596771a14b06441">

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          <td style="width: 72pt;"><br>
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            <div>service fees payable under any wholesaler agreement, distribution services agreement, inventory management agreement or other similar agreement;</div>
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        </tr>

    </table>
    <div style="font-size: 10pt;">&#160;</div>
    <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;" class="DSPFListTable" id="z89d1599e5931431b854f5ee32a58d6fb">

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          <td style="width: 72pt;"><br>
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          <td style="width: 45pt; vertical-align: top;">(h)</td>
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            <div>any other similar and customary deductions (including co-pay cards) that are consistent with the United States generally accepted accounting principles or, in the case of non-United States sales, other applicable accounting standards;</div>
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        </tr>

    </table>
    <div style="font-size: 10pt;">&#160;</div>
    <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;" class="DSPFListTable" id="zcc58724165c14addb1e32a11cf949d3e">

        <tr>
          <td style="width: 72pt;"><br>
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          <td style="width: 45pt; vertical-align: top;">(i)</td>
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            <div>an allowance for transportation costs, distribution expenses, special packaging and related insurance charges equal to three percent (3%) of the amount arrived at after application of the deductions under clauses (a) to (h) above; and</div>
          </td>
        </tr>

    </table>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
      <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">113</font></div>
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        <tr>
          <td style="width: 72pt;"><br>
          </td>
          <td style="width: 45pt; vertical-align: top;">(j)</td>
          <td style="width: auto; vertical-align: top; text-align: justify;">
            <div>the actual cost paid by AstraZeneca, its Affiliates or its or their Sublicensees for each unit of a Device.</div>
          </td>
        </tr>

    </table>
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    <div style="text-align: justify; margin-left: 72pt; font-size: 10pt;">Net Sales (including any deductions) will be calculated using AstraZeneca&#8217;s internal audited systems used to report such sales as adjusted for any of the items above not taken into
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        <tr>
          <td style="width: 72pt;"><br>
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            <div>the upfront fees payable by AstraZeneca to Akcea pursuant to <u>Section 11.1</u>;</div>
          </td>
        </tr>

    </table>
    <div style="font-size: 10pt;">&#160;</div>
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        <tr>
          <td style="width: 72pt;"><br>
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            <div>the milestone payments payable by AstraZeneca to Akcea pursuant to <u>Section 11.2</u> and <u>Section 11.3</u>;</div>
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        <tr>
          <td style="width: 72pt;"><br>
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            <div>any royalties payable by AstraZeneca to Akcea pursuant to <u>Section 11.5</u> and <u>Section 11.6</u>;</div>
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        </tr>

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        <tr>
          <td style="width: 72pt;"><br>
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            <div>expenses associated with stock-based compensation expenses; and</div>
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        </tr>

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        <tr>
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        <tr>
          <td style="width: 36pt;"><br>
          </td>
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            <div>[***];</div>
          </td>
        </tr>

    </table>
    <div style="font-size: 10pt;">&#160;</div>
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        <tr>
          <td style="width: 36pt;"><br>
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            <div>[***];</div>
          </td>
        </tr>

    </table>
    <div style="font-size: 10pt;">&#160;</div>
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        <tr>
          <td style="width: 36pt;"><br>
          </td>
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            <div>[***];</div>
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        </tr>

    </table>
    <div style="font-size: 10pt;">&#160;</div>
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        <tr>
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          </td>
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            <div>[***];</div>
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        </tr>

    </table>
    <div style="font-size: 10pt;">&#160;</div>
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            <div>[***];</div>
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        </tr>

    </table>
    <div style="font-size: 10pt;">&#160;</div>
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            <div>[***];</div>
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        </tr>

    </table>
    <div style="font-size: 10pt;">&#160;</div>
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        </tr>

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    <div style="font-size: 10pt;">&#160;</div>
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        <tr>
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            <div>other expenses incurred by or on behalf of a Party or its Affiliates in connection with the Exploitation of such Licensed Product approved by the JSC as Other Operating Expenses.</div>
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    <div style="text-align: justify; margin-left: 72pt; font-size: 10pt;">No expense included as an Eligible Development Expense, an Eligible Commercialization Expense or an Eligible Medical Affairs Expense will also be included as an Other Operating
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    <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; font-size: 10pt;">1.167</font><font style="font-size: 10pt;">&#160;&#160;&#160;&#160;&#160; &#8220;<font style="font-weight: bold; font-style: italic;">Other Operating Expenses Cost Share Notice</font>&#8221;
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    <div style="font-size: 10pt;">&#160;</div>
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        forth in <u>Section </u><u>16.2.3</u>.</font></div>
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        Licensed Product, or (ii) methods of using a Licensed Compound or a Licensed Product as a prophylactic, therapeutic or diagnostic, or (b) in challenging any Patent Right Controlled by Third Parties to obtain freedom to operate for a Licensed
        Product, in each case ((a) and (b)), with respect to the U.S.</font></div>
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        continuations-in-part of and similar applications claiming priority to any of the foregoing, and (c) all patents and similar government-issued rights protecting inventions issuing on any of the foregoing applications, together with all
        patents-of-additions, registrations, reissues, renewals, re-examinations, confirmations, supplementary protection certificates, and extensions or restorations mechanisms, including patent term adjustments, pediatric exclusivity, Patent Term
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        Product-Specific Patent Rights or the Akcea Product-Specific Know-How) to enable such Third Party to manufacture or formulate oligonucleotides generally (and not specific to TTR), where (i) such Third Party is primarily engaged in providing
        contract manufacturing or services and is not engaged in drug discovery, development or commercialization of therapeutics in any material respect; and (ii) Akcea and its Affiliates do not assist such Third Party, or grant rights to such Third
        Party, to identify, discover or make an antisense oligonucleotide designed to bind to TTR; and (b) material transfer, collaboration, or sponsored research agreements with academic collaborators or non-profit institutions solely to conduct
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    <div style="font-size: 10pt;">&#160;</div>
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        intended use, (ii) define warnings, precautions and adverse reactions that are associated with the product in the dosage range to be prescribed, and (iii) support Regulatory Approval for such product, or (b) such other Clinical Trial designated as
        a Phase 3 Clinical Trial in the Development Plan and Budget, the protocol for such trial, or on clinicaltrials.gov (or foreign equivalent).</font></div>
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    <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; font-size: 10pt;">1.184</font><font style="font-size: 10pt;">&#160;&#160;&#160;&#160; &#8220;<font style="font-weight: bold; font-style: italic;">Pricing and Reimbursement Approval</font>&#8221;
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        pharmaceutical product, in each case, in a country in the Territory where Governmental Authorities or Regulatory Authorities approve or determine pricing for pharmaceutical products for reimbursement or otherwise.</font></div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; font-size: 10pt;">1.185</font><font style="font-size: 10pt;">&#160;&#160;&#160;&#160;&#160; &#8220;<font style="font-weight: bold; font-style: italic;">Prior Agreements</font>&#8221; means the agreements
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    <div style="font-size: 10pt;">&#160;</div>
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        <hr noshade="noshade" style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;"></div>
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        requests for patent term adjustments and Patent Term Extensions with respect to such Patent Right, together with the initiation or defense of interferences, the initiation or defense of oppositions and other similar proceedings with respect to the
        particular Patent Right, and any appeals therefrom. For clarification, &#8220;<font style="font-weight: bold; font-style: italic;">Prosecution and Maintenance</font>&#8221; or &#8220;<font style="font-weight: bold; font-style: italic;">Prosecute and Maintain</font>&#8221;
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    <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; font-size: 10pt;">1.188</font><font style="font-size: 10pt;">&#160;&#160;&#160;&#160;&#160; &#8220;<font style="font-weight: bold; font-style: italic;">PTC Agreement</font>&#8221; means the Collaboration
        and License Agreement dated August 1, 2018, by and between PTC and Akcea.</font></div>
    <div style="font-size: 10pt;">&#160;</div>
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        the Caribbean, using the United Nations M49 standard definition for that region, but excluding the following countries and territories: Anguilla, Aruba, Bahamas, Barbados, Bonaire, Sint Eustatius and Saba, British Virgin Islands, Cayman Islands,
        Cura&#231;ao, Guadeloupe, Martinique, Montserrat, Puerto Rico, Saint Barth&#233;lemy, Saint Martin (French Part), Sint Maarten (Dutch part), Turks and Caicos Islands, United States Virgin Islands, Bouvet Island, Falkland Islands (Malvinas), French Guiana,
        South Georgia and the South Sandwich Islands.</font></div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; font-size: 10pt;">1.190</font><font style="font-size: 10pt;">&#160;&#160;&#160;&#160;&#160; &#8220;<font style="font-weight: bold; font-style: italic;">PTC Territory License Date</font>&#8221; has the
        meaning set forth in <u>Section 8.1.1</u>.</font></div>
    <div style="font-size: 10pt;">&#160;</div>
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        forth in <u>Section 13.1</u>.</font></div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; font-size: 10pt;">1.192</font><font style="font-size: 10pt;">&#160;&#160;&#160;&#160;&#160; &#8220;<font style="font-weight: bold; font-style: italic;">Reference Calendar Year</font>&#8221; has the
        meaning set forth in <u>Section 3.2.3(b)</u>.</font></div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; font-size: 10pt;">1.193</font><font style="font-size: 10pt;">&#160;&#160;&#160;&#160;&#160; &#8220;<font style="font-weight: bold; font-style: italic;">Reference Product</font>&#8221; has the meaning set
        forth in the definition of &#8220;<font style="font-style: italic;">Generic Intrusion</font>&#8221;.</font></div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; font-size: 10pt;">1.194</font><font style="font-size: 10pt;">&#160;&#160;&#160;&#160;&#160; &#8220;<font style="font-weight: bold; font-style: italic;">Regulatory Approval</font>&#8221; means, with
        respect to a country or other jurisdiction in the Territory, the approval of the applicable Regulatory Authority necessary for the marketing and sale of a product in such country or other jurisdiction, including, where applicable, (a) Pricing and
        Reimbursement Approvals in such country or other jurisdiction and (b) the expansion or modification of the label for additional Indications or uses, but excluding any Emergency Use Approval pursuant to Section 564 of the United States Federal Food,
        Drug and Cosmetic Act, as amended, and any similar approval in a country other than the U.S.</font></div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; font-size: 10pt;">1.195</font><font style="font-size: 10pt;">&#160;&#160;&#160;&#160;&#160; &#8220;<font style="font-weight: bold; font-style: italic;">Regulatory Approval Application</font>&#8221; means
        (a) an NDA, (b) an MAA or (c) any other application to seek Regulatory Approval of a product in any country in the Territory, as defined in applicable Laws and filed with the relevant Regulatory Authorities of such country.</font></div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; font-size: 10pt;">1.196</font><font style="font-size: 10pt;">&#160;&#160;&#160;&#160; &#8220;<font style="font-weight: bold; font-style: italic;">Regulatory Authority</font>&#8221; means the FDA in
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    <div style="font-size: 10pt;">&#160;</div>
    <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
      <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">118</font></div>
      <div style="page-break-after:always;" id="DSPFPageBreak">
        <hr noshade="noshade" style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;"></div>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; font-size: 10pt;">1.197</font><font style="font-size: 10pt;">&#160;&#160;&#160;&#160;&#160; &#8220;<font style="font-weight: bold; font-style: italic;">Regulatory Exclusivity Period</font>&#8221; means,
        with respect to each Licensed Product in any country in the Territory, a period of exclusivity (other than Patent Right exclusivity) granted or afforded by applicable Law or by a Regulatory Authority in such country that confers exclusive marketing
        rights with respect to such Licensed Product for all approved Indications in such country, such as new chemical entity exclusivity, orphan drug exclusivity, non-patent related pediatric exclusivity or any other applicable marketing exclusivity,
        including any such periods listed in the FDA&#8217;s Orange Book or any such periods under national implementations in the EU of Article 10 of Directive 2001/83/ED, Article 14(11) of Parliament and Council Regulation (EC) No. 726/2004, Parliament and
        Council Regulation (ED) No. 141/2000 on orphan medicines, Parliament and Council Regulation (ED) No. 1901/2006 on medicinal products for pediatric use and all international equivalents of any of the foregoing.</font></div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; font-size: 10pt;">1.198</font><font style="font-size: 10pt;">&#160;&#160;&#160; &#8220;<font style="font-weight: bold; font-style: italic;">Regulatory Filing</font>&#8221; means, with respect to
        a product, any documentation comprising or relating to or supporting any filing or application with any Regulatory Authority with respect to such product, or its use or potential use, including any document submitted to any Regulatory Authority,
        including any IND, any drug master files, any Regulatory Approval Application and any correspondence with any Regulatory Authority with respect to such product (including minutes of any meetings, telephone conferences or discussions with any
        Regulatory Authority).</font></div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; font-size: 10pt;">1.199</font><font style="font-size: 10pt;">&#160;&#160;&#160;&#160;&#160; &#8220;<font style="font-weight: bold; font-style: italic;">Regulatory Owner</font>&#8221; has the meaning set
        forth in <u>Section 4.3.1</u>.</font></div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; font-size: 10pt;">1.200</font><font style="font-size: 10pt;">&#160;&#160;&#160;&#160;&#160; &#8220;<font style="font-weight: bold; font-style: italic;">Regulatory Strategy</font>&#8221; has the meaning
        set forth in <u>Section </u><u>4.1</u>.</font></div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; font-size: 10pt;">1.201</font><font style="font-size: 10pt;">&#160;&#160;&#160;&#160;&#160; &#8220;<font style="font-weight: bold; font-style: italic;">Regulatory Working Group</font>&#8221; or &#8220;<font style="font-weight: bold; font-style: italic;">RWG</font>&#8221; has the meaning set forth in <u>Section 6.5.1</u>.</font></div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; font-size: 10pt;">1.202</font><font style="font-size: 10pt;">&#160;&#160;&#160;&#160;&#160; &#8220;<font style="font-weight: bold; font-style: italic;">Reversion License</font>&#8221;<font style="font-weight: bold;">&#160;</font>has the meaning set forth in <u>Section</u><u> 16.3.1(b)(i)</u>.</font></div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; font-size: 10pt;">1.203</font><font style="font-size: 10pt;">&#160;&#160;&#160;&#160;&#160; &#8220;<font style="font-weight: bold; font-style: italic;">Right of First Negotiation</font>&#8221;<font style="font-weight: bold;">&#160;</font>has the meaning set forth in <u>Section 9.1</u>.</font></div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; font-size: 10pt;">1.204</font><font style="font-size: 10pt;">&#160;&#160;&#160;&#160;&#160; &#8220;<font style="font-weight: bold; font-style: italic;">ROW Commercialization Plan</font>&#8221; has the
        meaning set forth in <u>Section 3.3</u>.</font></div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; font-size: 10pt;">1.205</font><font style="font-size: 10pt;">&#160;&#160;&#160;&#160;&#160; &#8220;<font style="font-weight: bold; font-style: italic;">ROW Development Activities</font>&#8221; has the
        meaning set forth in <u>Section 2.2.2</u>.</font></div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; font-size: 10pt;">1.206</font><font style="font-size: 10pt;">&#160;&#160;&#160;&#160;&#160; &#8220;<font style="font-weight: bold; font-style: italic;">ROW Net Sales</font>&#8221; has the meaning set
        forth in <u>Section</u><u> 11.6.1</u>.</font></div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; font-size: 10pt;">1.207</font><font style="font-size: 10pt;">&#160;&#160;&#160;&#160;&#160; &#8220;<font style="font-weight: bold; font-style: italic;">ROW Royalties</font>&#8221; has the meaning set
        forth in <u>Section 11.6.1</u>.</font></div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; font-size: 10pt;">1.208</font><font style="font-size: 10pt;">&#160;&#160;&#160;&#160;&#160; &#8220;<font style="font-weight: bold; font-style: italic;">ROW Royalty Rates</font>&#8221; has the meaning set
        forth in <u>Section 11.6.1</u>.</font></div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; font-size: 10pt;">1.209</font><font style="font-size: 10pt;">&#160;&#160;&#160;&#160;&#160; &#8220;<font style="font-weight: bold; font-style: italic;">ROW Territory</font>&#8221; means the Territory
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    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; font-size: 10pt;">1.210</font><font style="font-size: 10pt;">&#160;&#160;&#160;&#160; <font style="font-style: italic;">&#8220;</font><font style="font-weight: bold; font-style: italic;">Royalties</font>&#8221;
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    <div style="font-size: 10pt;">&#160;</div>
    <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
      <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">119</font></div>
      <div style="page-break-after:always;" id="DSPFPageBreak">
        <hr noshade="noshade" style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;"></div>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; font-size: 10pt;">1.211</font><font style="font-size: 10pt;">&#160;&#160;&#160;&#160;&#160; &#8220;<font style="font-weight: bold; font-style: italic;">Royalty Term</font><font style="font-style: italic;">&#8221; </font>means, with respect to each Licensed Product in each country in the Territory, the period commencing on the First Commercial Sale of such Licensed Product in such country and expiring upon the latest of (a) [***], (b) [***],
        (c) [***], and (d) the [***] anniversary of the First Commercial Sale of such Licensed Product in such country.</font></div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; font-size: 10pt;">1.212</font><font style="font-size: 10pt;">&#160;&#160;&#160;&#160;&#160; &#8220;<font style="font-weight: bold; font-style: italic;">SDEA</font>&#8221; has the meaning set forth in <u>Section


          4.6.2</u>.</font></div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; font-size: 10pt;">1.213</font><font style="font-size: 10pt;">&#160;&#160;&#160;&#160;&#160; &#8220;<font style="font-weight: bold; font-style: italic;">Second Opt-Out Period</font>&#8221; has the meaning
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    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; font-size: 10pt;">1.214</font><font style="font-size: 10pt;">&#160;&#160;&#160;&#160;&#160; &#8220;<font style="font-weight: bold; font-style: italic;">Securities Acts</font>&#8221; means the Securities
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    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; font-size: 10pt;">1.215</font><font style="font-size: 10pt;">&#160;&#160;&#160;&#160; &#8220;<font style="font-weight: bold; font-style: italic;">Senior Officers</font>&#8221; means the President of
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        Senior Vice President level or above who have the authority to decide the applicable matter.</font></div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; font-size: 10pt;">1.216</font><font style="font-size: 10pt;">&#160;&#160;&#160;&#160; &#8220;<font style="font-weight: bold; font-style: italic;">Settlement Sublicense</font>&#8221; means a
        sublicense to a Third Party granted by AstraZeneca under its licenses set forth in <u>Section 8.1</u> to settle or avoid litigation related to (a) the alleged infringement by a Licensed Compound or Licensed Product or the Exploitation thereof of
        any Patent Rights or other intellectual property of a Third Party or (b) the alleged non-infringement, invalidity or unenforceability of any Patent Rights claiming a Licensed Compound or Licensed Product or Exploitation thereof; <font style="font-style: italic;">provided</font> that any payments received from a Third Party under a Settlement Sublicense as consideration for the Settlement Sublicense will be shared as provided in <u>Section 12.4.4</u>.</font></div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; font-size: 10pt;">1.217</font><font style="font-size: 10pt;">&#160;&#160;&#160;&#160;&#160; &#8220;[***]&#8221; means, with respect to [***]; <font style="font-style: italic;">provided</font> that <font style="color: rgb(0, 0, 0);">if</font> [***], then [***]:</font></div>
    <div style="font-size: 10pt;">&#160;</div>
    <table cellspacing="0" cellpadding="0" border="0" align="center" style="border-collapse: collapse; width: 80%; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; text-align: left;" id="zaefea6cb680e45c3baa81c066b96875f">

        <tr>
          <td style="width: 40%; vertical-align: top; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0);">
            <div style="text-align: center; font-weight: bold;">Reference Calendar Year</div>
          </td>
          <td style="width: 40%; vertical-align: top; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0);">
            <div style="text-align: center;">[***]<font style="font-weight: bold;"> for such Reference Calendar Year</font></div>
          </td>
        </tr>
        <tr>
          <td style="width: 40%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">2022</div>
          </td>
          <td style="width: 40%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]%</div>
          </td>
        </tr>
        <tr>
          <td style="width: 40%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">2023</div>
          </td>
          <td style="width: 40%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]%</div>
          </td>
        </tr>
        <tr>
          <td style="width: 40%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">2024</div>
          </td>
          <td style="width: 40%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]%</div>
          </td>
        </tr>
        <tr>
          <td style="width: 40%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">2025</div>
          </td>
          <td style="width: 40%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]%</div>
          </td>
        </tr>
        <tr>
          <td style="width: 40%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">2026</div>
          </td>
          <td style="width: 40%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]%</div>
          </td>
        </tr>
        <tr>
          <td style="width: 40%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">2027</div>
          </td>
          <td style="width: 40%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]%</div>
          </td>
        </tr>
        <tr>
          <td style="width: 40%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">2028</div>
          </td>
          <td style="width: 40%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]%</div>
          </td>
        </tr>
        <tr>
          <td style="width: 40%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">2029 and each Calendar Year thereafter</div>
          </td>
          <td style="width: 40%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]%</div>
          </td>
        </tr>

    </table>
    <div><font style="font-size: 10pt;"><br>
      </font> </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; font-size: 10pt;">1.218</font><font style="font-size: 10pt;">&#160;&#160;&#160;&#160;&#160; &#8220;<font style="font-weight: bold; font-style: italic;">Statement of Interest</font>&#8221; has the meaning
        set forth in <u>Section 9.1</u>.</font></div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
      <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">120</font></div>
      <div style="page-break-after:always;" id="DSPFPageBreak">
        <hr noshade="noshade" style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;"></div>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; font-size: 10pt;">1.219</font><font style="font-size: 10pt;">&#160;&#160;&#160;&#160;&#160; &#8220;<font style="font-weight: bold; font-style: italic;">Subcommittee</font>&#8221; has the meaning set forth
        in <u>Section</u><u> 6.2</u>.</font></div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; font-size: 10pt;">1.220</font><font style="font-size: 10pt;">&#160;&#160;&#160;&#160;&#160; &#8220;<font style="font-weight: bold; font-style: italic;">Sublicense</font>&#8221; has the meaning set forth
        in <u>Section </u><u>8.4</u>.</font></div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; font-size: 10pt;">1.221</font><font style="font-size: 10pt;">&#160;&#160;&#160;&#160;&#160; &#8220;<font style="font-weight: bold; font-style: italic;">Sublicensee</font>&#8221; means a Third Party to
        whom AstraZeneca or its Affiliates has granted a Sublicense under any Licensed Technology in accordance with the terms and conditions of this Agreement. For clarity, Akcea and its Affiliates are not Sublicensees of AstraZeneca.</font></div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; font-size: 10pt;">1.222</font><font style="font-size: 10pt;">&#160;&#160;&#160;&#160;&#160; &#8220;<font style="font-weight: bold; font-style: italic;">Supply Agreement</font>&#8221; means any agreement
        between AstraZeneca and a Third Party for the supply of the Licensed Compound or Licensed Product to AstraZeneca, but solely to the extent that any such agreement is solely and exclusively related to the Licensed Product and not any other
        AstraZeneca product.</font></div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; font-size: 10pt;">1.223</font><font style="font-size: 10pt;">&#160;&#160;&#160;&#160;&#160; &#8220;<font style="font-weight: bold; font-style: italic;">Term</font>&#8221; has the meaning set forth in <u>Section


          16.1</u>.</font></div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; font-size: 10pt;">1.224</font><font style="font-size: 10pt;">&#160;&#160;&#160;&#160;&#160; &#8220;<font style="font-weight: bold; font-style: italic;">Terminated</font><font style="font-style: italic;">&#160;</font><font style="font-weight: bold; font-style: italic;">Territory</font>&#8221; means, with respect to a Licensed Product, any country or jurisdiction for which this Agreement is terminated with respect to such Licensed Product, or the
        Territory if this Agreement is terminated in its entirety with respect to such Licensed Product.</font></div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; font-size: 10pt;">1.225</font><font style="font-size: 10pt;">&#160;&#160;&#160;&#160;&#160; &#8220;<font style="font-weight: bold; font-style: italic;">Territory</font>&#8221; means all countries of the
        world other than (a) the Terminated Territory and (b) the PTC Territory unless and until the PTC Territory License Date. For clarity, from and after the PTC Territory License Date, the &#8220;Territory&#8221; shall include the PTC Territory.</font></div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; font-size: 10pt;">1.226</font><font style="font-size: 10pt;">&#160;&#160;&#160;&#160;&#160; &#8220;<font style="font-weight: bold; font-style: italic;">Third Party</font>&#8221; means any Person that is
        neither a Party nor an Affiliate of a Party.</font></div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; font-size: 10pt;">1.227</font><font style="font-size: 10pt;">&#160;&#160;&#160;&#160;&#160; &#8220;<font style="font-weight: bold; font-style: italic;">Third Party Claims</font>&#8221; has the meaning set
        forth in <u>Section </u><u>15.1</u>.</font></div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; font-size: 10pt;">1.228</font><font style="font-size: 10pt;">&#160;&#160;&#160;&#160;&#160; &#8220;<font style="font-weight: bold; font-style: italic;">Third Party Payments</font>&#8221; has the meaning
        set forth in <u>Section</u><u> 11.6.2(d)</u>.</font></div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; font-size: 10pt;">1.229</font><font style="font-size: 10pt;">&#160;&#160;&#160;&#160; &#8220;<font style="font-weight: bold; font-style: italic;">Trademark</font>&#8221; means any word, name, symbol,
        color, shape, designation or any combination thereof, including any trademarks, service marks, certification marks, trade dress, internet domain names, trade names, identifying symbols, designs, product names, company names, slogans, logos or
        insignia, that functions as an identifier of source, origin or quality, whether registered or unregistered, and all common law rights, applications and registrations therefor, and all goodwill associated therewith, and all domain names, URLs or
        social media tags, handles and other identifiers containing such marks.</font></div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; font-size: 10pt;">1.230</font><font style="font-size: 10pt;">&#160;&#160;&#160;&#160;&#160; &#8220;<font style="font-weight: bold; font-style: italic;">Transferring Party</font>&#8221; has the meaning set
        forth in <u>Section 17.3</u>.</font></div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; font-size: 10pt;">1.231</font><font style="font-size: 10pt;">&#160;&#160;&#160;&#160;&#160; &#8220;<font style="font-weight: bold; font-style: italic;">Transition Period</font>&#8221; has the meaning set
        forth in <u>Section 16.3.3(a)(iii)</u>.</font></div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; font-size: 10pt;">1.232</font><font style="font-size: 10pt;">&#160;&#160;&#160;&#160;&#160; &#8220;<font style="font-weight: bold; font-style: italic;">Transition Plan</font>&#8221; has the meaning set
        forth in <u>Section 16.3.3(a)(i)</u>.</font></div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; font-size: 10pt;">1.233</font><font style="font-size: 10pt;">&#160;&#160;&#160;&#160;&#160; &#8220;<font style="font-weight: bold; font-style: italic;">Transition Services</font>&#8221; has the meaning
        set forth in <u>Section 16.3.3(a)(i)</u>.</font></div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; font-size: 10pt;">1.234</font><font style="font-size: 10pt;">&#160;&#160;&#160;&#160;&#160; &#8220;<font style="font-weight: bold; font-style: italic;">TTR</font>&#8221; means the human gene transthyretin
        (NCBI Accession No. NM_000371; Gen ID: 7276), or any alternative splice variants, mutants, polymorphisms and fragments thereof.</font></div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
      <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">121</font></div>
      <div style="page-break-after:always;" id="DSPFPageBreak">
        <hr noshade="noshade" style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;"></div>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; font-size: 10pt;">1.235</font><font style="font-size: 10pt;">&#160;&#160;&#160;&#160;&#160; &#8220;<font style="font-weight: bold; font-style: italic;">United States</font>&#8221; or &#8220;<font style="font-weight: bold; font-style: italic;">U.S.</font>&#8221; means the United States of America and all of its territories and possessions.</font></div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; font-size: 10pt;">1.236</font><font style="font-size: 10pt;">&#160;&#160;&#160;&#160;&#160; &#8220;<font style="font-weight: bold; font-style: italic;">U.S. Commercialization Plan and Budget</font>&#8221;
        has the meaning set forth in <u>Section 3.2.1</u>.</font></div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; font-size: 10pt;">1.237</font><font style="font-size: 10pt;">&#160;&#160;&#160;&#160;&#160; &#8220;<font style="font-weight: bold; font-style: italic;">U.S. Development Activities</font>&#8221; has the
        meaning set forth in <u>Section </u><u>2.4.1</u>.</font></div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; font-size: 10pt;">1.238</font><font style="font-size: 10pt;">&#160;&#160;&#160;&#160;&#160; &#8220;<font style="font-weight: bold; font-style: italic;">U.S. Medical Affairs Plan and Budget</font>&#8221;
        has the meaning set forth in <u>Section 3.2.2</u>.</font></div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; font-size: 10pt;">1.239</font><font style="font-size: 10pt;">&#160;&#160;&#160;&#160;&#160; &#8220;<font style="font-weight: bold; font-style: italic;">U.S. Royalties</font>&#8221; has the meaning set
        forth in <u>Section 11.5.1</u>.</font></div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; font-size: 10pt;">1.240</font><font style="font-size: 10pt;">&#160;&#160;&#160;&#160;&#160; &#8220;<font style="font-weight: bold; font-style: italic;">U.S. Royalty Rates</font>&#8221; has the meaning set
        forth in <u>Section 11.5.1</u>.</font></div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; font-size: 10pt;">1.241</font><font style="font-size: 10pt;">&#160;&#160;&#160;&#160; &#8220;<font style="font-weight: bold; font-style: italic;">Valid Claim</font>&#8221; means a claim (a) of any
        issued, unexpired United States or foreign Patent Right, which will not, in the country of issuance, have been donated to the public, disclaimed, nor held invalid or unenforceable by a court of competent jurisdiction in an unappealed or
        unappealable decision, or (b) of any United States or foreign patent application within a Patent Right, which will not, in the country in question, have been cancelled, withdrawn, abandoned nor been pending for more than seven years, not including
        in calculating such seven-year period of time in which such application is in interference or opposition or similar proceedings or time in which a decision of an examiner is being appealed. Notwithstanding the foregoing, on a country-by-country
        basis, a patent application pending for more than seven years will not be considered to have any Valid Claim for purposes of this Agreement unless and until a patent meeting the criteria set forth in clause (a) above with respect to such
        application issues.</font></div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
      <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">122</font></div>
      <div style="page-break-after:always;" id="DSPFPageBreak">
        <hr noshade="noshade" style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;"></div>
    </div>
    <div style="text-align: center; font-weight: bold; font-size: 10pt;"><u>Schedule 1.11</u></div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: center; text-indent: -36pt; margin-left: 36pt; font-weight: bold; font-size: 10pt;">Akcea Core Technology Patent Rights</div>
    <div style="font-size: 10pt;">&#160;</div>
    <table cellspacing="0" cellpadding="0" border="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; border-collapse: collapse; text-align: left; color: #000000;" id="z7b36289ca3bc48919723ab6e2667621a">

        <tr>
          <td style="width: 16.9%; vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0) rgb(0, 0, 0) rgb(0, 0, 0) rgb(0, 0, 0);">
            <div style="text-align: center; font-weight: bold;">Akcea Docket </div>
            <div style="text-align: center; font-weight: bold;">Number</div>
          </td>
          <td style="width: 12.67%; vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0) rgb(0, 0, 0) rgb(0, 0, 0);">
            <div style="text-align: center; font-weight: bold;">Country</div>
          </td>
          <td style="width: 10.4%; vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0) rgb(0, 0, 0) rgb(0, 0, 0);">
            <div style="text-align: center; font-weight: bold;">Status</div>
          </td>
          <td style="width: 17.24%; vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0);">
            <div style="text-align: center; font-weight: bold;">Patent/</div>
            <div style="text-align: center; font-weight: bold;">Application No.</div>
          </td>
          <td style="width: 11.64%; vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0) rgb(0, 0, 0) rgb(0, 0, 0);">
            <div style="text-align: center; font-weight: bold;">Filing Date</div>
          </td>
          <td style="width: 11.31%; vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0) rgb(0, 0, 0) rgb(0, 0, 0);">
            <div style="text-align: center; font-weight: bold;">Grant Date</div>
          </td>
          <td style="width: 19.83%; vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0) rgb(0, 0, 0) rgb(0, 0, 0) rgb(0, 0, 0);">
            <div style="text-align: center; font-weight: bold;">Title</div>
          </td>
        </tr>
        <tr>
          <td style="width: 16.9%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 12.67%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 10.4%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 17.24%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.64%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.31%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 19.83%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
        </tr>
        <tr>
          <td style="width: 16.9%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 12.67%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 10.4%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 17.24%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.64%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.31%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 19.83%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
        </tr>
        <tr>
          <td style="width: 16.9%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 12.67%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 10.4%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 17.24%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.64%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.31%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 19.83%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
        </tr>
        <tr>
          <td style="width: 16.9%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 12.67%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 10.4%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 17.24%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.64%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.31%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 19.83%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
        </tr>
        <tr>
          <td style="width: 16.9%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 12.67%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 10.4%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 17.24%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 11.64%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.31%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 19.83%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
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        <tr>
          <td style="width: 16.9%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 12.67%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 10.4%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 17.24%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.64%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.31%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
          <td style="width: 19.83%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
        </tr>
        <tr>
          <td style="width: 16.9%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 12.67%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 10.4%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 17.24%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.64%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.31%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 19.83%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
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        <tr>
          <td style="width: 16.9%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 12.67%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 10.4%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 17.24%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 11.64%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.31%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
          <td style="width: 19.83%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
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        <tr>
          <td style="width: 16.9%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 12.67%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 10.4%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 17.24%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 11.64%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 11.31%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 19.83%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
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        <tr>
          <td style="width: 16.9%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 12.67%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 10.4%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 17.24%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 11.64%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 11.31%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
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            <div style="text-align: center;">[***]</div>
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          <td style="width: 16.9%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 12.67%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
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            <div style="text-align: center;">[***]</div>
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            <div style="text-align: center;">[***]</div>
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          <td style="width: 11.64%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 19.83%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
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        <tr>
          <td style="width: 16.9%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 12.67%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
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            <div style="text-align: center;">[***]</div>
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          <td style="width: 17.24%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 11.64%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
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          <td style="width: 16.9%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 12.67%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
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            <div style="text-align: center;">[***]</div>
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          <td style="width: 17.24%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 11.64%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 11.31%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 19.83%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
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        <tr>
          <td style="width: 16.9%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
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          <td style="width: 16.9%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
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            <div style="text-align: center;">[***]</div>
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            <div style="text-align: center;">[***]</div>
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            <div style="text-align: center;">[***]</div>
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          <td style="width: 19.83%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
        </tr>
        <tr>
          <td style="width: 16.9%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 12.67%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 10.4%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 17.24%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.64%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.31%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
          <td style="width: 19.83%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
        </tr>
        <tr>
          <td style="width: 16.9%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 12.67%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 10.4%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 17.24%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.64%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.31%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 19.83%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
        </tr>
        <tr>
          <td style="width: 16.9%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 12.67%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 10.4%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 17.24%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.64%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.31%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
          <td style="width: 19.83%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
        </tr>
        <tr>
          <td style="width: 16.9%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 12.67%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 10.4%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 17.24%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.64%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.31%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 19.83%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
        </tr>
        <tr>
          <td style="width: 16.9%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 12.67%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 10.4%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 17.24%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.64%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.31%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 19.83%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
        </tr>
        <tr>
          <td style="width: 16.9%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 12.67%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 10.4%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 17.24%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.64%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.31%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 19.83%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
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        <tr>
          <td style="width: 16.9%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 12.67%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 10.4%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 17.24%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.64%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.31%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
          <td style="width: 19.83%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
        </tr>
        <tr>
          <td style="width: 16.9%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 12.67%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 10.4%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 17.24%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.64%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.31%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 19.83%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
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        <tr>
          <td style="width: 16.9%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 12.67%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 10.4%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 17.24%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 11.64%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 11.31%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
          <td style="width: 19.83%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
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        <tr>
          <td style="width: 16.9%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 12.67%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 10.4%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 17.24%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 11.64%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 11.31%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 19.83%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
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        </tr>
        <tr>
          <td style="width: 16.9%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 12.67%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 10.4%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 17.24%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 11.64%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 11.31%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
          <td style="width: 19.83%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
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        <tr>
          <td style="width: 16.9%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 12.67%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 10.4%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 17.24%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 11.64%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 11.31%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 19.83%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
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        </tr>
        <tr>
          <td style="width: 16.9%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 12.67%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 10.4%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 17.24%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.64%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.31%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
          <td style="width: 19.83%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
        </tr>
        <tr>
          <td style="width: 16.9%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 12.67%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 10.4%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 17.24%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.64%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.31%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 19.83%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
        </tr>
        <tr>
          <td style="width: 16.9%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 12.67%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 10.4%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 17.24%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.64%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.31%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
          <td style="width: 19.83%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
        </tr>
        <tr>
          <td style="width: 16.9%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 12.67%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 10.4%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 17.24%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.64%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.31%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 19.83%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
        </tr>
        <tr>
          <td style="width: 16.9%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 12.67%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 10.4%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 17.24%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.64%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.31%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
          <td style="width: 19.83%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
        </tr>
        <tr>
          <td style="width: 16.9%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 12.67%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 10.4%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 17.24%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.64%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.31%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 19.83%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
        </tr>
        <tr>
          <td style="width: 16.9%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 12.67%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 10.4%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 17.24%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.64%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.31%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
          <td style="width: 19.83%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
        </tr>
        <tr>
          <td style="width: 16.9%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 12.67%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 10.4%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 17.24%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.64%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.31%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 19.83%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
        </tr>
        <tr>
          <td style="width: 16.9%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 12.67%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 10.4%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 17.24%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.64%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.31%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
          <td style="width: 19.83%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
        </tr>
        <tr>
          <td style="width: 16.9%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 12.67%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 10.4%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 17.24%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.64%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.31%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 19.83%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
        </tr>
        <tr>
          <td style="width: 16.9%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 12.67%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 10.4%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 17.24%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.64%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.31%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
          <td style="width: 19.83%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
        </tr>
        <tr>
          <td style="width: 16.9%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 12.67%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 10.4%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 17.24%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.64%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.31%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 19.83%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
        </tr>

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    <div><font style="font-size: 10pt;"><br>
      </font> </div>
    <table cellspacing="0" cellpadding="0" border="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; border-collapse: collapse; text-align: left; color: #000000;" id="z14e2f58c7e534da79b39b48859bdf0f2">

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            <div style="text-align: center; font-weight: bold;">Akcea Docket</div>
            <div style="text-align: center; font-weight: bold;"> Number</div>
          </td>
          <td style="width: 12.67%; vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0) rgb(0, 0, 0) rgb(0, 0, 0);" rowspan="1">
            <div style="text-align: center; font-weight: bold;">Country</div>
          </td>
          <td style="width: 10.4%; vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0) rgb(0, 0, 0) rgb(0, 0, 0);" rowspan="1">
            <div style="text-align: center; font-weight: bold;">Status</div>
          </td>
          <td style="width: 17.24%; vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0) rgb(0, 0, 0) rgb(0, 0, 0);" rowspan="1">
            <div style="text-align: center; font-weight: bold;">Patent/</div>
            <div style="text-align: center; font-weight: bold;">Application No.</div>
          </td>
          <td style="width: 11.64%; vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0) rgb(0, 0, 0) rgb(0, 0, 0);" rowspan="1">
            <div style="text-align: center; font-weight: bold;">Filing Date</div>
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            <div style="text-align: center; font-weight: bold;">Grant Date</div>
          </td>
          <td style="width: 19.83%; vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); font-weight: bold; text-align: center;" rowspan="1">Title</td>
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          </td>
        </tr>
        <tr>
          <td style="width: 16.9%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 12.67%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 10.4%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 17.24%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.64%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.31%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 19.83%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
        </tr>
        <tr>
          <td style="width: 16.9%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 12.67%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 10.4%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 17.24%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.64%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.31%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 19.83%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
        </tr>
        <tr>
          <td style="width: 16.9%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 12.67%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 10.4%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 17.24%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.64%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.31%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 19.83%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
        </tr>
        <tr>
          <td style="width: 16.9%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 12.67%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 10.4%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 17.24%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.64%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.31%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 19.83%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
        </tr>
        <tr>
          <td style="width: 16.9%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 12.67%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 10.4%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 17.24%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.64%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.31%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 19.83%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
        </tr>
        <tr>
          <td style="width: 16.9%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 12.67%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 10.4%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 17.24%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.64%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.31%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 19.83%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
        </tr>
        <tr>
          <td style="width: 16.9%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 12.67%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 10.4%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 17.24%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.64%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.31%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 19.83%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
        </tr>
        <tr>
          <td style="width: 16.9%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 12.67%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 10.4%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 17.24%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.64%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.31%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 19.83%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
        </tr>
        <tr>
          <td style="width: 16.9%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 12.67%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 10.4%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 17.24%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.64%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.31%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 19.83%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
        </tr>
        <tr>
          <td style="width: 16.9%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 12.67%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 10.4%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 17.24%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.64%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.31%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 19.83%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
        </tr>
        <tr>
          <td style="width: 16.9%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 12.67%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 10.4%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 17.24%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.64%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.31%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 19.83%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
        </tr>
        <tr>
          <td style="width: 16.9%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 12.67%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 10.4%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 17.24%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.64%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.31%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 19.83%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
        </tr>
        <tr>
          <td style="width: 16.9%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 12.67%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 10.4%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 17.24%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.64%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.31%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 19.83%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
        </tr>
        <tr>
          <td style="width: 16.9%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 12.67%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 10.4%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 17.24%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.64%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.31%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 19.83%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
        </tr>
        <tr>
          <td style="width: 16.9%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 12.67%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 10.4%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 17.24%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.64%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.31%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 19.83%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
        </tr>
        <tr>
          <td style="width: 16.9%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 12.67%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 10.4%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 17.24%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.64%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.31%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 19.83%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
        </tr>
        <tr>
          <td style="width: 16.9%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 12.67%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 10.4%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 17.24%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.64%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.31%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 19.83%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
        </tr>
        <tr>
          <td style="width: 16.9%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 12.67%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 10.4%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 17.24%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.64%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.31%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 19.83%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
        </tr>
        <tr>
          <td style="width: 16.9%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 12.67%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 10.4%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 17.24%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.64%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.31%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 19.83%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
        </tr>
        <tr>
          <td style="width: 16.9%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 12.67%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 10.4%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 17.24%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.64%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.31%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 19.83%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
        </tr>
        <tr>
          <td style="width: 16.9%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 12.67%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 10.4%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 17.24%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.64%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.31%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 19.83%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
        </tr>
        <tr>
          <td style="width: 16.9%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 12.67%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 10.4%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 17.24%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.64%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.31%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 19.83%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
        </tr>
        <tr>
          <td style="width: 16.9%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 12.67%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 10.4%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 17.24%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.64%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.31%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 19.83%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
        </tr>
        <tr>
          <td style="width: 16.9%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 12.67%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 10.4%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 17.24%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.64%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.31%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 19.83%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
        </tr>
        <tr>
          <td style="width: 16.9%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 12.67%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 10.4%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 17.24%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.64%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.31%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 19.83%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
        </tr>
        <tr>
          <td style="width: 16.9%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 12.67%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 10.4%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 17.24%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.64%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.31%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 19.83%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
        </tr>
        <tr>
          <td style="width: 16.9%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 12.67%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 10.4%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 17.24%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.64%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.31%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 19.83%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
        </tr>
        <tr>
          <td style="width: 16.9%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 12.67%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 10.4%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 17.24%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.64%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.31%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 19.83%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
        </tr>
        <tr>
          <td style="width: 16.9%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 12.67%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 10.4%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 17.24%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.64%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.31%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 19.83%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
        </tr>
        <tr>
          <td style="width: 16.9%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 12.67%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 10.4%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 17.24%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.64%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.31%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 19.83%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
        </tr>
        <tr>
          <td style="width: 16.9%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 12.67%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 10.4%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 17.24%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.64%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.31%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 19.83%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
        </tr>
        <tr>
          <td style="width: 16.9%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 12.67%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 10.4%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 17.24%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.64%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.31%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 19.83%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
        </tr>
        <tr>
          <td style="width: 16.9%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 12.67%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 10.4%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 17.24%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.64%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.31%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 19.83%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
        </tr>

    </table>
    <div><font style="font-size: 10pt;"><br>
      </font> </div>
    <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
      <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">124</font></div>
      <div style="page-break-after:always;" id="DSPFPageBreak">
        <hr noshade="noshade" style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;"></div>
    </div>
    <table cellspacing="0" cellpadding="0" border="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; border-collapse: collapse; text-align: left; color: #000000;" id="z8a7c4af457164a03a81ad1ceeaad8534">

        <tr>
          <td style="width: 16.9%; vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0) rgb(0, 0, 0) rgb(0, 0, 0) rgb(0, 0, 0);" rowspan="1">
            <div style="text-align: center; font-weight: bold;">Akcea Docket</div>
            <div style="text-align: center; font-weight: bold;"> Number</div>
          </td>
          <td style="width: 12.67%; vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0) rgb(0, 0, 0) rgb(0, 0, 0);" rowspan="1">
            <div style="text-align: center; font-weight: bold;">Country</div>
          </td>
          <td style="width: 10.4%; vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0) rgb(0, 0, 0) rgb(0, 0, 0);" rowspan="1">
            <div style="text-align: center; font-weight: bold;">Status</div>
          </td>
          <td style="width: 17.24%; vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0) rgb(0, 0, 0) rgb(0, 0, 0);" rowspan="1">
            <div style="text-align: center; font-weight: bold;">Patent/</div>
            <div style="text-align: center; font-weight: bold;">Application No.</div>
          </td>
          <td style="width: 11.64%; vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0) rgb(0, 0, 0) rgb(0, 0, 0);" rowspan="1">
            <div style="text-align: center; font-weight: bold;">Filing Date</div>
          </td>
          <td style="width: 11.31%; vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0) rgb(0, 0, 0) rgb(0, 0, 0);" rowspan="1">
            <div style="text-align: center; font-weight: bold;">Grant Date</div>
          </td>
          <td style="width: 19.83%; vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); font-weight: bold; text-align: center;" rowspan="1">Title</td>
        </tr>
        <tr>
          <td style="width: 16.9%; vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 12.67%; vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 10.4%; vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 17.24%; vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.64%; vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.31%; vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 19.83%; vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
        </tr>
        <tr>
          <td style="width: 16.9%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 12.67%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 10.4%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 17.24%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.64%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.31%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 19.83%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
        </tr>
        <tr>
          <td style="width: 16.9%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 12.67%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 10.4%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 17.24%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.64%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.31%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 19.83%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
        </tr>
        <tr>
          <td style="width: 16.9%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 12.67%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 10.4%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 17.24%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.64%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.31%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 19.83%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
        </tr>
        <tr>
          <td style="width: 16.9%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 12.67%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 10.4%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 17.24%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.64%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.31%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 19.83%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
        </tr>
        <tr>
          <td style="width: 16.9%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 12.67%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 10.4%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 17.24%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.64%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.31%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 19.83%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
        </tr>
        <tr>
          <td style="width: 16.9%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 12.67%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 10.4%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 17.24%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.64%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.31%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 19.83%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
        </tr>
        <tr>
          <td style="width: 16.9%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 12.67%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 10.4%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 17.24%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 11.64%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.31%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 19.83%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
        </tr>
        <tr>
          <td style="width: 16.9%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 12.67%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 10.4%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 17.24%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.64%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.31%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 19.83%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
        </tr>
        <tr>
          <td style="width: 16.9%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 12.67%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 10.4%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 17.24%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.64%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.31%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 19.83%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
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        </tr>
        <tr>
          <td style="width: 16.9%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 12.67%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 10.4%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 17.24%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.64%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.31%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 19.83%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
        </tr>
        <tr>
          <td style="width: 16.9%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 12.67%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 10.4%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 17.24%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 11.64%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 11.31%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 19.83%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
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        <tr>
          <td style="width: 16.9%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
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            <div style="text-align: center;">[***]</div>
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          <td style="width: 10.4%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 17.24%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 11.64%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
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            <div style="text-align: center;">[***]</div>
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            <div style="text-align: center;">[***]</div>
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        <tr>
          <td style="width: 16.9%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
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            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 10.4%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 17.24%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.64%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.31%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
          <td style="width: 19.83%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
        </tr>
        <tr>
          <td style="width: 16.9%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 12.67%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 10.4%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 17.24%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.64%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.31%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 19.83%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
        </tr>
        <tr>
          <td style="width: 16.9%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 12.67%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 10.4%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 17.24%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.64%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.31%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 19.83%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
        </tr>
        <tr>
          <td style="width: 16.9%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 12.67%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 10.4%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 17.24%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 11.64%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
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            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 19.83%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
        </tr>
        <tr>
          <td style="width: 16.9%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 12.67%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 10.4%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 17.24%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.64%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.31%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 19.83%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
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        <tr>
          <td style="width: 16.9%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 12.67%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 10.4%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 17.24%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.64%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.31%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 19.83%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
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        <tr>
          <td style="width: 16.9%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 12.67%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 10.4%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 17.24%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.64%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.31%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
          <td style="width: 19.83%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
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        <tr>
          <td style="width: 16.9%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 12.67%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 10.4%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 17.24%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 11.64%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 19.83%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
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        <tr>
          <td style="width: 16.9%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 12.67%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 10.4%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 17.24%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 11.64%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
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            <div style="text-align: center;">[***]</div>
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        <tr>
          <td style="width: 16.9%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 12.67%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 10.4%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 17.24%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 11.64%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 11.31%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 19.83%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
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        <tr>
          <td style="width: 16.9%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 12.67%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 10.4%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 17.24%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 11.64%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 19.83%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
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        <tr>
          <td style="width: 16.9%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 12.67%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 10.4%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 17.24%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 11.64%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 11.31%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 19.83%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
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        <tr>
          <td style="width: 16.9%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 12.67%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
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          <td style="width: 10.4%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 17.24%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.64%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.31%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
          <td style="width: 19.83%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
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        <tr>
          <td style="width: 16.9%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 12.67%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 10.4%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 17.24%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.64%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.31%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 19.83%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
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        <tr>
          <td style="width: 16.9%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 12.67%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 10.4%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 17.24%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.64%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.31%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
          <td style="width: 19.83%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
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        <tr>
          <td style="width: 16.9%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 12.67%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 10.4%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 17.24%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.64%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.31%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 19.83%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
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        <tr>
          <td style="width: 16.9%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 12.67%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 10.4%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 17.24%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.64%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.31%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
          <td style="width: 19.83%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
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        <tr>
          <td style="width: 16.9%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 12.67%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 10.4%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 17.24%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.64%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.31%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 19.83%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
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        <tr>
          <td style="width: 16.9%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 12.67%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 10.4%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 17.24%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 11.64%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 11.31%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 19.83%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
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        <tr>
          <td style="width: 16.9%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 12.67%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 10.4%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 17.24%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 11.64%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 11.31%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 19.83%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
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        <tr>
          <td style="width: 16.9%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
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            <div style="text-align: center;">[***]</div>
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          <td style="width: 10.4%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 17.24%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 11.64%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
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        <tr>
          <td style="width: 16.9%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 12.67%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
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            <div style="text-align: center;">[***]</div>
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          <td style="width: 17.24%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 11.64%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 11.31%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 19.83%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
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        <tr>
          <td style="width: 16.9%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 12.67%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
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          <td style="width: 10.4%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
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          <td style="width: 17.24%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
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            <div style="text-align: center;">[***]</div>
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        <tr>
          <td style="width: 16.9%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
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            <div style="text-align: center;">[***]</div>
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            <div style="text-align: center;">[***]</div>
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            <div style="text-align: center;">[***]</div>
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            <div style="text-align: center;">[***]</div>
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          <td style="width: 11.31%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">&#160;</td>
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            <div style="text-align: center;">[***]</div>
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        <tr>
          <td style="width: 16.9%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
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            <div style="text-align: center;">[***]</div>
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            <div style="text-align: center;">[***]</div>
          </td>
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        <tr>
          <td style="width: 16.9%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 12.67%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 10.4%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 17.24%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.64%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.31%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">&#160;</td>
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            <div style="text-align: center;">[***]</div>
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          <td style="width: 16.9%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
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          <td style="width: 10.4%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
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            <div style="text-align: center;">[***]</div>
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          <td style="width: 11.64%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 11.31%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
          <td style="width: 19.83%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
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            <div style="text-align: center;">[***]</div>
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            <div style="text-align: center;">[***]</div>
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            <div style="text-align: center;">[***]</div>
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        <tr>
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            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.64%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.31%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 19.83%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
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        <tr>
          <td style="width: 16.9%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 12.67%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 10.4%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 17.24%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 11.64%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.31%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
          <td style="width: 19.83%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
        </tr>
        <tr>
          <td style="width: 16.9%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 12.67%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 10.4%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 17.24%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.64%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.31%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 19.83%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
        </tr>
        <tr>
          <td style="width: 16.9%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 12.67%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 10.4%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 17.24%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 11.64%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.31%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
          <td style="width: 19.83%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
        </tr>
        <tr>
          <td style="width: 16.9%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 12.67%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 10.4%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 17.24%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 11.64%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.31%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 19.83%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
        </tr>
        <tr>
          <td style="width: 16.9%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 12.67%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 10.4%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 17.24%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.64%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.31%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
          <td style="width: 19.83%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
        </tr>
        <tr>
          <td style="width: 16.9%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 12.67%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 10.4%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 17.24%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.64%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.31%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 19.83%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
        </tr>
        <tr>
          <td style="width: 16.9%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 12.67%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 10.4%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 17.24%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.64%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.31%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
          <td style="width: 19.83%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
        </tr>

    </table>
    <div> <font style="font-size: 10pt;"><br>
      </font> </div>
    <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
      <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">126</font></div>
      <div style="page-break-after:always;" id="DSPFPageBreak">
        <hr noshade="noshade" style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;"></div>
    </div>
    <div style="text-align: center; font-weight: bold; font-size: 10pt;"><u>Schedule 1.18</u></div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: center; font-weight: bold; font-size: 10pt;">Akcea Manufacturing Patent Rights</div>
    <div style="font-size: 10pt;">&#160;</div>
    <table cellspacing="0" cellpadding="0" border="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; border-collapse: collapse; text-align: left; color: #000000;" id="zd3c5e576802f4653a08925c7c2ece91c">

        <tr>
          <td style="width: 13.84%; vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0) rgb(0, 0, 0) rgb(0, 0, 0) rgb(0, 0, 0);">
            <div style="text-align: center; text-indent: -36pt; margin-left: 36pt; font-weight: bold;">Technology</div>
          </td>
          <td style="width: 16.36%; vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0) rgb(0, 0, 0) rgb(0, 0, 0);">
            <div style="text-align: center; font-weight: bold;">Akcea Docket </div>
            <div style="text-align: center; font-weight: bold;">Number</div>
          </td>
          <td style="width: 10%; vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0) rgb(0, 0, 0) rgb(0, 0, 0);">
            <div style="text-align: center; font-weight: bold;">Status</div>
          </td>
          <td style="width: 14.05%; vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0) rgb(0, 0, 0) rgb(0, 0, 0);">
            <div style="text-align: center; font-weight: bold;">Country/Treaty</div>
          </td>
          <td style="width: 14.97%; vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0);">
            <div style="text-align: center; font-weight: bold;">Application/Pate</div>
            <div style="text-align: center; font-weight: bold;">nt</div>
            <div style="text-align: center; font-weight: bold;">Number</div>
          </td>
          <td style="width: 11.36%; vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0) rgb(0, 0, 0) rgb(0, 0, 0);">
            <div style="text-align: center; font-weight: bold;">Filing Date</div>
          </td>
          <td style="width: 20%; vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0) rgb(0, 0, 0) rgb(0, 0, 0) rgb(0, 0, 0);">
            <div style="text-align: center; font-weight: bold;">Title</div>
          </td>
        </tr>
        <tr>
          <td style="width: 13.84%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center; font-weight: bold;">[***]</div>
          </td>
          <td style="width: 16.36%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center; font-weight: bold;">[***]</div>
          </td>
          <td style="width: 10%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center; font-weight: bold;">[***]</div>
          </td>
          <td style="width: 14.05%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center; font-weight: bold;">[***]</div>
          </td>
          <td style="width: 14.97%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center; font-weight: bold;">[***]</div>
          </td>
          <td style="width: 11.36%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center; font-weight: bold;">[***]</div>
          </td>
          <td style="width: 20%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center; font-weight: bold;">[***]</div>
          </td>
        </tr>
        <tr>
          <td style="width: 13.84%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center; font-weight: bold;">[***]</div>
          </td>
          <td style="width: 16.36%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center; font-weight: bold;">[***]</div>
          </td>
          <td style="width: 10%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center; font-weight: bold;">[***]</div>
          </td>
          <td style="width: 14.05%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center; font-weight: bold;">[***]</div>
          </td>
          <td style="width: 14.97%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center; font-weight: bold;">[***]</div>
          </td>
          <td style="width: 11.36%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center; font-weight: bold;">[***]</div>
          </td>
          <td style="width: 20%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center; font-weight: bold;">[***]</div>
          </td>
        </tr>
        <tr>
          <td style="width: 13.84%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 16.36%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 10%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 14.05%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 14.97%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.36%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 20%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
        </tr>
        <tr>
          <td style="width: 13.84%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
          <td style="width: 16.36%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 10%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 14.05%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 14.97%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.36%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 20%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
        </tr>
        <tr>
          <td style="width: 13.84%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 16.36%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 10%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 14.05%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 14.97%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.36%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 20%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
        </tr>
        <tr>
          <td style="width: 13.84%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
          <td style="width: 16.36%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 10%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 14.05%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 14.97%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.36%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 20%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
        </tr>
        <tr>
          <td style="width: 13.84%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 16.36%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 10%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 14.05%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 14.97%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.36%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 20%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
        </tr>
        <tr>
          <td style="width: 13.84%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center; font-weight: bold;">[***]</div>
          </td>
          <td style="width: 16.36%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center; font-weight: bold;">[***]</div>
          </td>
          <td style="width: 10%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center; font-weight: bold;">[***]</div>
          </td>
          <td style="width: 14.05%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center; font-weight: bold;">[***]</div>
          </td>
          <td style="width: 14.97%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center; font-weight: bold;">[***]</div>
          </td>
          <td style="width: 11.36%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center; font-weight: bold;">[***]</div>
          </td>
          <td style="width: 20%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center; font-weight: bold;">[***]</div>
          </td>
        </tr>
        <tr>
          <td style="width: 13.84%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 16.36%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 10%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 14.05%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 14.97%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.36%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 20%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
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        <tr>
          <td style="width: 13.84%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
          <td style="width: 16.36%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 10%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 14.05%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 14.97%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.36%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 20%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
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        <tr>
          <td style="width: 13.84%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 16.36%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 10%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 14.05%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 14.97%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 11.36%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 20%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
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        <tr>
          <td style="width: 13.84%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
          <td style="width: 16.36%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 10%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 14.05%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 14.97%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 11.36%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 20%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 13.84%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 16.36%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 10%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 14.05%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 14.97%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 11.36%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 20%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
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        <tr>
          <td style="width: 13.84%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
          <td style="width: 16.36%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 10%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 14.05%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 14.97%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 11.36%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 20%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
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        <tr>
          <td style="width: 13.84%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center; font-weight: bold;">[***]</div>
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          <td style="width: 16.36%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center; font-weight: bold;">[***]</div>
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          <td style="width: 10%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center; font-weight: bold;">[***]</div>
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          <td style="width: 14.05%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center; font-weight: bold;">[***]</div>
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          <td style="width: 14.97%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center; font-weight: bold;">[***]</div>
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          <td style="width: 11.36%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center; font-weight: bold;">[***]</div>
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          <td style="width: 20%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center; font-weight: bold;">[***]</div>
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        </tr>
        <tr>
          <td style="width: 13.84%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
          <td style="width: 16.36%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 10%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 14.05%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 14.97%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.36%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 20%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
        </tr>
        <tr>
          <td style="width: 13.84%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 16.36%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 10%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 14.05%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 14.97%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.36%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 20%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
        </tr>
        <tr>
          <td style="width: 13.84%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
          <td style="width: 16.36%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 10%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 14.05%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 14.97%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.36%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 20%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
        </tr>
        <tr>
          <td style="width: 13.84%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 16.36%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 10%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 14.05%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 14.97%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.36%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 20%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
        </tr>
        <tr>
          <td style="width: 13.84%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
          <td style="width: 16.36%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 10%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 14.05%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 14.97%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.36%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 20%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
        </tr>

    </table>
    <div> <font style="font-size: 10pt;"><br>
      </font> </div>
    <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
      <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">127</font></div>
      <div style="page-break-after:always;" id="DSPFPageBreak">
        <hr noshade="noshade" style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;"></div>
    </div>
    <div style="text-align: center; font-weight: bold; font-size: 10pt;"><u>Schedule 1.23</u></div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: center; font-weight: bold; font-size: 10pt;">Akcea Product-Specific Patent Rights</div>
    <div style="font-size: 10pt;">&#160;</div>
    <table cellspacing="0" cellpadding="0" border="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; border-collapse: collapse; text-align: left; color: #000000;" id="zc0fef831b967454b95faf13a363d6b60">

        <tr>
          <td style="width: 13.84%; vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0) rgb(0, 0, 0) rgb(0, 0, 0) rgb(0, 0, 0);">
            <div style="text-align: center; font-weight: bold;">Akcea Docket Number</div>
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          <td style="width: 16.36%; vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0) rgb(0, 0, 0) rgb(0, 0, 0);">
            <div style="text-align: center; font-weight: bold;">Country</div>
          </td>
          <td style="width: 10%; vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0) rgb(0, 0, 0) rgb(0, 0, 0);">
            <div style="text-align: center; font-weight: bold;">Status</div>
          </td>
          <td style="width: 14.05%; vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0);">
            <div style="text-align: center; font-weight: bold;">Patent/</div>
            <div style="text-align: center; font-weight: bold;">Application No.</div>
          </td>
          <td style="width: 14.97%; vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0) rgb(0, 0, 0) rgb(0, 0, 0);">
            <div style="text-align: center; font-weight: bold;">Filing Date</div>
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          <td style="width: 11.36%; vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0) rgb(0, 0, 0) rgb(0, 0, 0);">
            <div style="text-align: center; font-weight: bold;">Grant Date</div>
          </td>
          <td style="width: 20%; vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0) rgb(0, 0, 0) rgb(0, 0, 0) rgb(0, 0, 0);">
            <div style="text-align: center; font-weight: bold;">Title</div>
          </td>
        </tr>
        <tr>
          <td style="width: 13.84%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 16.36%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 10%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 14.05%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 14.97%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.36%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 20%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
        </tr>
        <tr>
          <td style="width: 13.84%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 16.36%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 10%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 14.05%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 14.97%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.36%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
          <td style="width: 20%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
        </tr>
        <tr>
          <td style="width: 13.84%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 16.36%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 10%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 14.05%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 14.97%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.36%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 20%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
        </tr>
        <tr>
          <td style="width: 13.84%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 16.36%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 10%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 14.05%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 14.97%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.36%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 20%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
        </tr>
        <tr>
          <td style="width: 13.84%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 16.36%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 10%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 14.05%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 14.97%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.36%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 20%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
        </tr>
        <tr>
          <td style="width: 13.84%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 16.36%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 10%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 14.05%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 14.97%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.36%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 20%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
        </tr>
        <tr>
          <td style="width: 13.84%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 16.36%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 10%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 14.05%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 14.97%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.36%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 20%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
        </tr>
        <tr>
          <td style="width: 13.84%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 16.36%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 10%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 14.05%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 14.97%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.36%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 20%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
        </tr>
        <tr>
          <td style="width: 13.84%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 16.36%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 10%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 14.05%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 14.97%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.36%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 20%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
        </tr>
        <tr>
          <td style="width: 13.84%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 16.36%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 10%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 14.05%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 14.97%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.36%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 20%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
        </tr>
        <tr>
          <td style="width: 13.84%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 16.36%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 10%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 14.05%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 14.97%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.36%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 20%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
        </tr>
        <tr>
          <td style="width: 13.84%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 16.36%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 10%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 14.05%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 14.97%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.36%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 20%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
        </tr>
        <tr>
          <td style="width: 13.84%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 16.36%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 10%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 14.05%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 14.97%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.36%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 20%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
        </tr>
        <tr>
          <td style="width: 13.84%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 16.36%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 10%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 14.05%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 14.97%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.36%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 20%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
        </tr>
        <tr>
          <td style="width: 13.84%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 16.36%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 10%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 14.05%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 14.97%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.36%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 20%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
        </tr>
        <tr>
          <td style="width: 13.84%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 16.36%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 10%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 14.05%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 14.97%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.36%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 20%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
        </tr>
        <tr>
          <td style="width: 13.84%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 16.36%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 10%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 14.05%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 14.97%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.36%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 20%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
        </tr>
        <tr>
          <td style="width: 13.84%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 16.36%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 10%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 14.05%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
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            <div style="text-align: center;">[***]</div>
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            <div style="text-align: center;">[***]</div>
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          <td style="width: 20%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
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        <tr>
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            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 16.36%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 10%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 14.05%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 14.97%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.36%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 20%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
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        <tr>
          <td style="width: 13.84%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 16.36%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 10%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 14.05%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
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            <div style="text-align: center;">[***]</div>
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          <td style="width: 11.36%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 20%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
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        <tr>
          <td style="width: 13.84%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 16.36%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 10%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 14.05%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 14.97%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 11.36%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 20%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
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        <tr>
          <td style="width: 13.84%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 16.36%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 10%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 14.05%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 14.97%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 11.36%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
          <td style="width: 20%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
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        <tr>
          <td style="width: 13.84%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 16.36%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 10%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 14.05%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 14.97%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 11.36%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 20%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 13.84%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
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            <div style="text-align: center;">[***]</div>
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          <td style="width: 10%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 14.05%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 14.97%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 11.36%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
          <td style="width: 20%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 13.84%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 16.36%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 10%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 14.05%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 14.97%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 11.36%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 20%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 13.84%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
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            <div style="text-align: center;">[***]</div>
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          <td style="width: 10%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
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            <div style="text-align: center;">[***]</div>
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            <div style="text-align: center;">[***]</div>
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            <div style="text-align: center;">[***]</div>
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            <div style="text-align: center;">[***]</div>
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            <div style="text-align: center;">[***]</div>
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            <div style="text-align: center;">[***]</div>
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            <div style="text-align: center;">[***]</div>
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          <td style="width: 11.36%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 20%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 13.84%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
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            <div style="text-align: center;">[***]</div>
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            <div style="text-align: center;">[***]</div>
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          <td style="width: 11.36%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
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            <div style="text-align: center;">[***]</div>
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            <div style="text-align: center;">[***]</div>
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            <div style="text-align: center;">[***]</div>
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            <div style="text-align: center;">[***]</div>
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            <div style="text-align: center;">[***]</div>
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            <div style="text-align: center;">[***]</div>
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            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 20%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
        </tr>
        <tr>
          <td style="width: 13.84%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 16.36%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 10%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 14.05%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 14.97%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.36%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 20%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
        </tr>
        <tr>
          <td style="width: 13.84%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 16.36%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 10%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 14.05%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 14.97%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.36%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 20%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
        </tr>
        <tr>
          <td style="width: 13.84%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 16.36%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 10%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 14.05%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 14.97%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.36%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 20%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
        </tr>
        <tr>
          <td style="width: 13.84%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 16.36%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 10%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 14.05%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 14.97%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.36%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 20%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
        </tr>
        <tr>
          <td style="width: 13.84%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 16.36%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 10%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 14.05%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 14.97%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.36%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 20%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
        </tr>
        <tr>
          <td style="width: 13.84%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 16.36%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 10%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 14.05%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 14.97%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.36%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 20%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
        </tr>
        <tr>
          <td style="width: 13.84%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 16.36%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 10%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 14.05%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 14.97%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.36%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 20%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
        </tr>
        <tr>
          <td style="width: 13.84%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 16.36%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 10%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 14.05%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 14.97%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.36%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 20%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
        </tr>

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    <div><font style="font-size: 10pt;"><br>
      </font> </div>
    <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
      <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">128</font></div>
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        <tr>
          <td style="width: 13.84%; vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0) rgb(0, 0, 0) rgb(0, 0, 0) rgb(0, 0, 0);" rowspan="1">
            <div style="text-align: center; font-weight: bold;">Akcea Docket Number</div>
          </td>
          <td style="width: 16.36%; vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); font-weight: bold; text-align: center;" rowspan="1">Country</td>
          <td style="width: 10%; vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0) rgb(0, 0, 0) rgb(0, 0, 0);" rowspan="1">
            <div style="text-align: center; font-weight: bold;">Status</div>
          </td>
          <td style="width: 14.05%; vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0) rgb(0, 0, 0) rgb(0, 0, 0);" rowspan="1">
            <div style="text-align: center; font-weight: bold;">Patent/</div>
            <div style="text-align: center; font-weight: bold;">Application No.</div>
          </td>
          <td style="width: 14.97%; vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0) rgb(0, 0, 0) rgb(0, 0, 0);" rowspan="1">
            <div style="text-align: center; font-weight: bold;">Filing Date</div>
          </td>
          <td style="width: 11.36%; vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0) rgb(0, 0, 0) rgb(0, 0, 0);" rowspan="1">
            <div style="text-align: center; font-weight: bold;">Grant Date</div>
          </td>
          <td style="width: 20%; vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); font-weight: bold; text-align: center;" rowspan="1">Title</td>
        </tr>
        <tr>
          <td style="width: 13.84%; vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 16.36%; vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 10%; vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 14.05%; vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 14.97%; vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.36%; vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 20%; vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
        </tr>
        <tr>
          <td style="width: 13.84%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 16.36%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 10%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 14.05%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 14.97%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.36%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
          <td style="width: 20%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
        </tr>
        <tr>
          <td style="width: 13.84%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 16.36%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 10%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 14.05%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 14.97%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.36%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 20%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
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        <tr>
          <td style="width: 13.84%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 16.36%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 10%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
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            <div style="text-align: center;">[***]</div>
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            <div style="text-align: center;">[***]</div>
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          <td style="width: 11.36%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 20%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
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        <tr>
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            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 16.36%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 10%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 14.05%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 14.97%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 11.36%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 20%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
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        <tr>
          <td style="width: 13.84%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 16.36%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 10%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 14.05%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 14.97%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 11.36%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 20%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
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        <tr>
          <td style="width: 13.84%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 16.36%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 10%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 14.05%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 14.97%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.36%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 20%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
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        <tr>
          <td style="width: 13.84%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 16.36%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 10%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 14.05%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 14.97%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 11.36%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
          <td style="width: 20%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 13.84%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 16.36%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 10%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 14.05%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 14.97%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 11.36%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 20%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
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        <tr>
          <td style="width: 13.84%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 16.36%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 10%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 14.05%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 14.97%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 11.36%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 20%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
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            <div style="text-align: center;">[***]</div>
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          <td style="width: 16.36%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 10%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
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            <div style="text-align: center;">[***]</div>
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            <div style="text-align: center;">[***]</div>
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          <td style="width: 11.36%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 20%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
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            <div style="text-align: center;">[***]</div>
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            <div style="text-align: center;">[***]</div>
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          <td style="width: 10%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
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            <div style="text-align: center;">[***]</div>
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            <div style="text-align: center;">[***]</div>
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            <div style="text-align: center;">[***]</div>
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            <div style="text-align: center;">[***]</div>
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            <div style="text-align: center;">[***]</div>
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            <div style="text-align: center;">[***]</div>
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            <div style="text-align: center;">[***]</div>
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            <div style="text-align: center;">[***]</div>
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            <div style="text-align: center;">[***]</div>
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          <td style="width: 20%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 11.36%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
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            <div style="text-align: center;">[***]</div>
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            <div style="text-align: center;">[***]</div>
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            <div style="text-align: center;">[***]</div>
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            <div style="text-align: center;">[***]</div>
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            <div style="text-align: center;">[***]</div>
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          <td style="width: 11.36%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
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            <div style="text-align: center;">[***]</div>
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        <tr>
          <td style="width: 13.84%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 16.36%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 10%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 14.05%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 14.97%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.36%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
          <td style="width: 20%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
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        <tr>
          <td style="width: 13.84%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 16.36%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 10%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 14.05%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 14.97%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 11.36%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 20%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
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        <tr>
          <td style="width: 13.84%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 16.36%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 10%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 14.05%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 14.97%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 11.36%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
          <td style="width: 20%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
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        <tr>
          <td style="width: 13.84%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 16.36%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 10%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 14.05%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 14.97%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 11.36%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 20%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
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        <tr>
          <td style="width: 13.84%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 16.36%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 10%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 14.05%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 14.97%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 11.36%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
          <td style="width: 20%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 13.84%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 16.36%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 10%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
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            <div style="text-align: center;">[***]</div>
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          <td style="width: 14.97%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 11.36%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 20%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 13.84%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 16.36%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 10%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
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            <div style="text-align: center;">[***]</div>
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            <div style="text-align: center;">[***]</div>
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            <div style="text-align: center;">[***]</div>
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            <div style="text-align: center;">[***]</div>
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            <div style="text-align: center;">[***]</div>
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          <td style="width: 10%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
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            <div style="text-align: center;">[***]</div>
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            <div style="text-align: center;">[***]</div>
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          <td style="width: 20%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
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            <div style="text-align: center;">[***]</div>
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            <div style="text-align: center;">[***]</div>
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            <div style="text-align: center;">[***]</div>
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            <div style="text-align: center;">[***]</div>
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            <div style="text-align: center;">[***]</div>
          </td>
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        <tr>
          <td style="width: 13.84%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 16.36%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 10%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 14.05%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 14.97%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 11.36%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
          <td style="width: 20%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 13.84%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 16.36%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 10%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 14.05%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 14.97%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 11.36%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 20%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
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        <tr>
          <td style="width: 13.84%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 16.36%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 10%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 14.05%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 14.97%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 11.36%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
          <td style="width: 20%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
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        <tr>
          <td style="width: 13.84%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 16.36%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 10%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 14.05%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 14.97%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
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          <td style="width: 11.36%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 20%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
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              <div>1.</div>
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              <div>[***]</div>
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    <div style="font-size: 10pt;">&#160;</div>
    <div>
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              <div>2.</div>
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              <div>Development, Commercialization and License Agreement between Akcea Therapeutics, Inc. and Ionis Pharmaceuticals, Inc. dated March 14, 2018 (subject to that certain Letter Agreement by and among between AstraZeneca AB, Akcea Therapeutics,
                Inc. and Ionis Pharmaceuticals, Inc., dated as of the Execution Date)</div>
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    <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
      <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">130</font></div>
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        <hr noshade="noshade" style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;"></div>
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    <div style="text-align: center; font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>Schedule</u></font><font style="font-size: 10pt;"><u>&#160;</u></font><font style="font-size: 10pt; font-weight: bold;"><u>1.185</u></font></div>
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    <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;" class="DSPFListTable" id="z1d9898038af049b4823ec567b72d1484">

        <tr>
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            <div>[***]</div>
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    <div style="font-size: 10pt;">&#160;</div>
    <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;" class="DSPFListTable" id="z28eeda37402349a89929605db6dfcc90">

        <tr>
          <td style="width: 18pt;"><br>
          </td>
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          <td style="width: auto; vertical-align: top;">
            <div>Development, Commercialization and License Agreement between Akcea Therapeutics, Inc. and Ionis Pharmaceuticals, Inc. dated March 14, 2018 (subject to that certain Letter Agreement by and among between AstraZeneca AB, Akcea Therapeutics,
              Inc. and Ionis Pharmaceuticals, Inc., dated as of the Execution Date)</div>
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    <div style="font-size: 10pt;">&#160;</div>
    <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;" class="DSPFListTable" id="z7b3545ecb9b74d81a0ff60646e677654">

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            <div>[***]</div>
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    <div style="font-size: 10pt;">&#160;</div>
    <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
      <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">131</font></div>
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        <hr noshade="noshade" style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;"></div>
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    <div style="text-align: center; font-weight: bold; font-size: 10pt;"><u>Schedule 2.2.1</u></div>
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    <div style="text-align: center; font-weight: bold; font-size: 10pt;">Initial Development Plan and Budget</div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: center; font-weight: bold; font-size: 10pt;">[***]</div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: center; font-weight: bold; font-size: 10pt;">ION-682884 (Eplontersen)</div>
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    <div style="text-align: center; color: rgb(0, 0, 0); font-weight: bold; font-size: 10pt;">December 6, 2021</div>
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      </font> </div>
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    <div style="font-size: 10pt;"> <br>
    </div>
    <div style="font-size: 10pt; text-align: center;">[***] </div>
    <div style="font-size: 10pt;"> <br>
    </div>
    <div style="text-align: center;"><font style="font-size: 10pt;"> </font>
      <hr noshade="noshade" align="left" style="height: 2px; width: 25%; color: #000000; background-color: #000000; text-align: left; margin-left: 0px; margin-right: auto; border: none;"></div>
    <div style="font-size: 10pt;"><sup style="vertical-align: text-top; line-height: 1; font-size: smaller;">1</sup> To be updated after the Closing Date and approved by the Joint Steering Committee</div>
    <div style="font-size: 10pt;"> <br>
    </div>
    <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
      <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">132</font></div>
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    <div style="font-size: 10pt;">&#160;</div>
    <div style="font-size: 10pt;">[***]</div>
    <div style="font-size: 10pt;">&#160;</div>
    <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;" class="DSPFListTable" id="zcffe2527a5ce498cba67bcbf8612f6e5">

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            <div style="font-weight: bold;">Key program goals to the end of Phase 3</div>
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    <div style="margin-left: 49.5pt; font-size: 10pt;">[***]</div>
    <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
      <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">133</font></div>
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        <hr noshade="noshade" style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;"></div>
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    <div style="font-size: 10pt;">&#160;</div>
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            <div style="font-weight: bold;">Toxicology and Pharmacokinetic Studies</div>
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    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-indent: -54pt; margin-left: 54pt; font-weight: bold; font-size: 10pt;">2.1.1.Toxicology and PK Summary</div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="font-size: 10pt;">[***]</div>
    <div style="font-size: 10pt;">&#160;</div>
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    <div style="font-size: 10pt;">&#160;</div>
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        <tr>
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            <div style="font-weight: bold;">Study Type and Duration</div>
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          <td style="width: 1%; vertical-align: top; border-top: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); border-left: 2px solid rgb(0, 0, 0);" colspan="1">&#160;</td>
          <td style="width: 21.63%; vertical-align: top; border-top: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="font-weight: bold;">Species and Strain</div>
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          <td style="width: 1%; vertical-align: top; border-top: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); border-left: 2px solid rgb(0, 0, 0);" colspan="1">&#160;</td>
          <td style="width: 9.42%; vertical-align: top; border-top: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="font-weight: bold;">Route</div>
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          <td style="width: 1%; vertical-align: top; border-top: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); border-left: 2px solid rgb(0, 0, 0);" colspan="1">&#160;</td>
          <td style="width: 29%; vertical-align: top; border-top: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="font-weight: bold;">Dose and Regimen</div>
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            <div style="text-align: center; font-weight: bold;">GLP</div>
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            <div style="font-weight: bold;">Repeated-Dose Toxicity</div>
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          <td style="width: 1%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);" colspan="1">&#160;</td>
          <td style="width: 27%; vertical-align: top; border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div>[***]</div>
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          <td style="width: 1%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);" colspan="1">&#160;</td>
          <td style="width: 21.63%; vertical-align: top; border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div>[***]</div>
          </td>
          <td style="width: 1%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);" colspan="1">&#160;</td>
          <td style="width: 9.42%; vertical-align: top; border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div>[***]</div>
          </td>
          <td style="width: 1%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255); border-top: 2px solid rgb(0, 0, 0);" colspan="1">&#160;</td>
          <td style="width: 29%; vertical-align: top; border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255); border-top: 2px solid rgb(0, 0, 0);">
            <div>[***]</div>
          </td>
          <td style="width: 8.75%; vertical-align: top; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0) rgb(0, 0, 0) rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
        </tr>
        <tr>
          <td style="width: 1%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);" colspan="1">&#160;</td>
          <td style="width: 27%; vertical-align: top; border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div>[***]</div>
          </td>
          <td style="width: 1%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);" colspan="1">&#160;</td>
          <td style="width: 21.63%; vertical-align: top; border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div>[***]</div>
          </td>
          <td style="width: 1%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);" colspan="1">&#160;</td>
          <td style="width: 9.42%; vertical-align: top; border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div>[***]</div>
          </td>
          <td style="width: 1%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);" colspan="1">&#160;</td>
          <td style="width: 29%; vertical-align: top; border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div>[***]</div>
          </td>
          <td style="width: 8.75%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
        </tr>
        <tr>
          <td style="width: 1%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);" colspan="1">&#160;</td>
          <td style="width: 27%; vertical-align: top; border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div>[***]</div>
          </td>
          <td style="width: 1%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);" colspan="1">&#160;</td>
          <td style="width: 21.63%; vertical-align: top; border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div>[***]</div>
          </td>
          <td style="width: 1%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);" colspan="1">&#160;</td>
          <td style="width: 9.42%; vertical-align: top; border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div>[***]</div>
          </td>
          <td style="width: 1%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);" colspan="1">&#160;</td>
          <td style="width: 29%; vertical-align: top; border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div>[***]</div>
          </td>
          <td style="width: 8.75%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
        </tr>
        <tr>
          <td style="width: 1%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);" colspan="1">&#160;</td>
          <td style="width: 27%; vertical-align: top; border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div>[***]</div>
          </td>
          <td style="width: 1%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);" colspan="1">&#160;</td>
          <td style="width: 21.63%; vertical-align: top; border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div>[***]</div>
          </td>
          <td style="width: 1%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);" colspan="1">&#160;</td>
          <td style="width: 9.42%; vertical-align: top; border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div>[***]</div>
          </td>
          <td style="width: 1%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);" colspan="1">&#160;</td>
          <td style="width: 29%; vertical-align: top; border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div>[***]</div>
          </td>
          <td style="width: 8.75%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
        </tr>
        <tr>
          <td colspan="1" style="width: 1%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
          <td colspan="5" style="vertical-align: top; border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="font-weight: bold;">Genotoxicity</div>
          </td>
        </tr>
        <tr>
          <td style="width: 1%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);" colspan="1">&#160;</td>
          <td style="width: 27%; vertical-align: top; border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div>[***]</div>
          </td>
          <td style="width: 1%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);" colspan="1">&#160;</td>
          <td style="width: 21.63%; vertical-align: top; border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div>[***]</div>
          </td>
          <td style="width: 1%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);" colspan="1">&#160;</td>
          <td style="width: 9.42%; vertical-align: top; border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div>[***]</div>
          </td>
          <td style="width: 1%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255); border-top: 2px solid rgb(0, 0, 0);" colspan="1">&#160;</td>
          <td style="width: 29%; vertical-align: top; border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255); border-top: 2px solid rgb(0, 0, 0);">
            <div>[***]</div>
          </td>
          <td style="width: 8.75%; vertical-align: top; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0) rgb(0, 0, 0) rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
        </tr>
        <tr>
          <td style="width: 1%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);" colspan="1">&#160;</td>
          <td style="width: 27%; vertical-align: top; border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div>[***]</div>
          </td>
          <td style="width: 1%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);" colspan="1">&#160;</td>
          <td style="width: 21.63%; vertical-align: top; border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div>[***]</div>
          </td>
          <td style="width: 1%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);" colspan="1">&#160;</td>
          <td style="width: 9.42%; vertical-align: top; border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div>[***]</div>
          </td>
          <td style="width: 1%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);" colspan="1">&#160;</td>
          <td style="width: 29%; vertical-align: top; border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div>[***]</div>
          </td>
          <td style="width: 8.75%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
        </tr>
        <tr>
          <td style="width: 1%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);" colspan="1">&#160;</td>
          <td style="width: 27%; vertical-align: top; border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div>[***]</div>
          </td>
          <td style="width: 1%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);" colspan="1">&#160;</td>
          <td style="width: 21.63%; vertical-align: top; border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div>[***]</div>
          </td>
          <td style="width: 1%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);" colspan="1">&#160;</td>
          <td style="width: 9.42%; vertical-align: top; border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div>[***]</div>
          </td>
          <td style="width: 1%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);" colspan="1">&#160;</td>
          <td style="width: 29%; vertical-align: top; border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div>[***]</div>
          </td>
          <td style="width: 8.75%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
        </tr>
        <tr>
          <td colspan="1" style="width: 1%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
          <td colspan="5" style="vertical-align: top; border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="font-weight: bold;">Reproductive and Developmental Toxicity</div>
          </td>
        </tr>
        <tr>
          <td style="width: 1%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);" colspan="1">&#160;</td>
          <td style="width: 27%; vertical-align: top; border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div>[***]</div>
          </td>
          <td style="width: 1%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);" colspan="1">&#160;</td>
          <td style="width: 21.63%; vertical-align: top; border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div>[***]</div>
          </td>
          <td style="width: 1%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);" colspan="1">&#160;</td>
          <td style="width: 9.42%; vertical-align: top; border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div>[***]</div>
          </td>
          <td style="width: 1%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255); border-top: 2px solid rgb(0, 0, 0);" colspan="1">&#160;</td>
          <td style="width: 29%; vertical-align: top; border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255); border-top: 2px solid rgb(0, 0, 0);">
            <div>[***]</div>
          </td>
          <td style="width: 8.75%; vertical-align: top; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0) rgb(0, 0, 0) rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
        </tr>
        <tr>
          <td colspan="1" style="width: 1%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
          <td colspan="5" style="vertical-align: top; border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="font-weight: bold;">Carcinogenicity</div>
          </td>
        </tr>
        <tr>
          <td style="width: 1%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);" colspan="1">&#160;</td>
          <td style="width: 27%; vertical-align: top; border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div>[***]</div>
          </td>
          <td style="width: 1%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);" colspan="1">&#160;</td>
          <td style="width: 21.63%; vertical-align: top; border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div>[***]</div>
          </td>
          <td style="width: 1%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);" colspan="1">&#160;</td>
          <td style="width: 9.42%; vertical-align: top; border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div>[***]</div>
          </td>
          <td style="width: 1%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255); border-top: 2px solid rgb(0, 0, 0);" colspan="1">&#160;</td>
          <td style="width: 29%; vertical-align: top; border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255); border-top: 2px solid rgb(0, 0, 0);">
            <div>[***]</div>
          </td>
          <td style="width: 8.75%; vertical-align: top; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0) rgb(0, 0, 0) rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
        </tr>
        <tr>
          <td style="width: 1%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);" colspan="1">&#160;</td>
          <td style="width: 27%; vertical-align: top; border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div>[***]</div>
          </td>
          <td style="width: 1%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);" colspan="1">&#160;</td>
          <td style="width: 21.63%; vertical-align: top; border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div>[***]</div>
          </td>
          <td style="width: 1%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);" colspan="1">&#160;</td>
          <td style="width: 9.42%; vertical-align: top; border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div>[***]</div>
          </td>
          <td style="width: 1%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);" colspan="1">&#160;</td>
          <td style="width: 29%; vertical-align: top; border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div>[***]</div>
          </td>
          <td style="width: 8.75%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
        </tr>
        <tr>
          <td style="width: 1%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);" colspan="1">&#160;</td>
          <td style="width: 27%; vertical-align: top; border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div>[***]</div>
          </td>
          <td style="width: 1%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);" colspan="1">&#160;</td>
          <td style="width: 21.63%; vertical-align: top; border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div>[***]</div>
          </td>
          <td style="width: 1%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);" colspan="1">&#160;</td>
          <td style="width: 9.42%; vertical-align: top; border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div>[***]</div>
          </td>
          <td style="width: 1%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);" colspan="1">&#160;</td>
          <td style="width: 29%; vertical-align: top; border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div>[***]</div>
          </td>
          <td style="width: 8.75%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
        </tr>
        <tr>
          <td colspan="1" style="width: 1%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
          <td colspan="5" style="vertical-align: top; border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="font-weight: bold;">Safety Pharmacology</div>
          </td>
        </tr>
        <tr>
          <td style="width: 1%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);" colspan="1">&#160;</td>
          <td style="width: 27%; vertical-align: top; border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div>[***]</div>
          </td>
          <td style="width: 1%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);" colspan="1">&#160;</td>
          <td style="width: 21.63%; vertical-align: top; border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div>[***]</div>
          </td>
          <td style="width: 1%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);" colspan="1">&#160;</td>
          <td style="width: 9.42%; vertical-align: top; border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div>[***]</div>
          </td>
          <td style="width: 1%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255); border-top: 2px solid rgb(0, 0, 0);" colspan="1">&#160;</td>
          <td style="width: 29%; vertical-align: top; border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255); border-top: 2px solid rgb(0, 0, 0);">
            <div>[***]</div>
          </td>
          <td style="width: 8.75%; vertical-align: top; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0) rgb(0, 0, 0) rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
        </tr>
        <tr>
          <td style="width: 1%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);" colspan="1">&#160;</td>
          <td style="width: 27%; vertical-align: top; border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div>[***]</div>
          </td>
          <td style="width: 1%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);" colspan="1">&#160;</td>
          <td style="width: 21.63%; vertical-align: top; border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div>[***]</div>
          </td>
          <td style="width: 1%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);" colspan="1">&#160;</td>
          <td style="width: 9.42%; vertical-align: top; border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div>[***]</div>
          </td>
          <td style="width: 1%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);" colspan="1">&#160;</td>
          <td style="width: 29%; vertical-align: top; border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div>[***]</div>
          </td>
          <td style="width: 8.75%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
        </tr>

    </table>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="font-size: 10pt;">[***]</div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
      <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">134</font></div>
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        <hr noshade="noshade" style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;"></div>
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        <tr>
          <td style="width: 54pt; vertical-align: top; color: rgb(0, 0, 0); font-weight: bold;">2.1.2.</td>
          <td style="width: auto; vertical-align: top;">
            <div style="color: rgb(0, 0, 0); font-weight: bold;">Pharmacokinetic Summary</div>
          </td>
        </tr>

    </table>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="font-size: 10pt;">[***]</div>
    <div style="font-size: 10pt;">&#160;</div>
    <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;" class="DSPFListTable" id="z597e06baa22b40c9a53f0180351fbf0a">

        <tr>
          <td style="width: 72pt; vertical-align: top; font-weight: bold;">Table 2:</td>
          <td style="width: auto; vertical-align: top;">
            <div style="font-weight: bold;">Summary of eplontersen Pharmacokinetic Studies.</div>
          </td>
        </tr>

    </table>
    <div style="font-size: 10pt;">&#160;</div>
    <table cellspacing="0" cellpadding="0" border="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; border-collapse: collapse; text-align: left; color: #000000;" id="z9b0be43a7d5340e782e97fa69d552633">

        <tr>
          <td style="width: 16.26%; vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0) rgb(0, 0, 0) rgb(0, 0, 0) rgb(0, 0, 0);">
            <div style="text-align: center; font-weight: bold;">Study No.</div>
          </td>
          <td style="width: 39%; vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0) rgb(0, 0, 0) rgb(0, 0, 0);">
            <div style="text-align: center; font-weight: bold;">Study Title</div>
          </td>
          <td style="width: 12.44%; vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0) rgb(0, 0, 0) rgb(0, 0, 0);">
            <div style="text-align: center; font-weight: bold;">Dosing Route</div>
          </td>
          <td style="width: 1%; vertical-align: middle; border-top: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); border-left: 2px solid rgb(0, 0, 0);" colspan="1">&#160;</td>
          <td style="width: 23%; vertical-align: middle; border-top: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center; font-weight: bold;">Doses and Regimen</div>
          </td>
          <td style="width: 8%; vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0) rgb(0, 0, 0) rgb(0, 0, 0) rgb(0, 0, 0);">
            <div style="text-align: center; font-weight: bold;">GLP</div>
          </td>
        </tr>
        <tr>
          <td style="width: 16.26%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 39%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div>[***]</div>
          </td>
          <td style="width: 12.44%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 1%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);" colspan="1">&#160;</td>
          <td style="width: 23%; vertical-align: top; border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div>[***]</div>
          </td>
          <td style="width: 8%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
        </tr>
        <tr>
          <td style="width: 16.26%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 39%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div>[***]</div>
          </td>
          <td style="width: 12.44%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 1%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);" colspan="1">&#160;</td>
          <td style="width: 23%; vertical-align: top; border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div>[***]</div>
          </td>
          <td style="width: 8%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
        </tr>
        <tr>
          <td style="width: 16.26%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 39%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div>[***]</div>
          </td>
          <td style="width: 12.44%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 1%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);" colspan="1">&#160;</td>
          <td style="width: 23%; vertical-align: top; border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div>[***]</div>
          </td>
          <td style="width: 8%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
        </tr>
        <tr>
          <td style="width: 16.26%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 39%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div>[***]</div>
          </td>
          <td style="width: 12.44%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 1%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);" colspan="1">&#160;</td>
          <td style="width: 23%; vertical-align: top; border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div>[***]</div>
          </td>
          <td style="width: 8%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
        </tr>
        <tr>
          <td style="width: 16.26%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 39%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div>[***]</div>
          </td>
          <td style="width: 12.44%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 1%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);" colspan="1">&#160;</td>
          <td style="width: 23%; vertical-align: top; border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div>[***]</div>
          </td>
          <td style="width: 8%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
        </tr>

    </table>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="font-size: 10pt;">[***]</div>
    <div style="font-size: 10pt;">&#160;</div>
    <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;" class="DSPFListTable" id="z0678052b9cc04f6f9913383891dfac84">

        <tr>
          <td style="width: 72pt; vertical-align: top; font-weight: bold;">2.2.</td>
          <td style="width: auto; vertical-align: top;">
            <div style="font-weight: bold;">Reproductive Toxicology Studies</div>
          </td>
        </tr>

    </table>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="font-size: 10pt;">[***]</div>
    <div style="font-size: 10pt;">&#160;</div>
    <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;" class="DSPFListTable" id="z1ab3dc057f8a448e8c74698a4723d110">

        <tr>
          <td style="width: 72pt; vertical-align: top; font-weight: bold;">2.3</td>
          <td style="width: auto; vertical-align: top;">
            <div style="font-weight: bold;">Carcinogenicity Studies</div>
          </td>
        </tr>

    </table>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="font-size: 10pt;">[***]</div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-indent: -72pt; margin-left: 72pt; font-weight: bold; font-size: 10pt;">Table 3:&#160; Key Dates for Mouse and Rat Carcinogenicity Studies.</div>
    <div style="font-size: 10pt;">&#160;</div>
    <table cellspacing="0" cellpadding="0" border="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; border-collapse: collapse; text-align: left; color: #000000;" id="zdf0a8b97eca54a5c974af1074bca2637">

        <tr>
          <td style="width: 19.78%; vertical-align: top; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0) rgb(0, 0, 0) rgb(0, 0, 0) rgb(0, 0, 0);">
            <div style="text-align: center; font-weight: bold;">Carc. Study</div>
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          <td style="width: 17.39%; vertical-align: top; border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); border-top: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center; font-weight: bold;">Start</div>
          </td>
          <td style="width: 16.51%; vertical-align: top; border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); border-top: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center; font-weight: bold;">End In-Life</div>
          </td>
          <td style="width: 17.26%; vertical-align: top; border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); border-top: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center; font-weight: bold;">Prelim. Data</div>
          </td>
          <td style="width: 29.05%; vertical-align: top; border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); border-top: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center; font-weight: bold;">Report</div>
          </td>
        </tr>
        <tr>
          <td style="width: 19.78%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 17.39%; vertical-align: top; border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 16.51%; vertical-align: top; border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 17.26%; vertical-align: top; border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 29.05%; vertical-align: top; border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
        </tr>
        <tr>
          <td style="width: 19.78%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 17.39%; vertical-align: top; border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 16.51%; vertical-align: top; border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 17.26%; vertical-align: top; border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 29.05%; vertical-align: top; border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
        </tr>
        <tr>
          <td style="width: 19.78%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 17.39%; vertical-align: top; border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 16.51%; vertical-align: top; border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 17.26%; vertical-align: top; border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 29.05%; vertical-align: top; border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
        </tr>

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    <div><font style="font-size: 10pt;"><br>
      </font> </div>
    <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
      <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">135</font></div>
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        <hr noshade="noshade" style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;"></div>
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      <div style="text-indent: -72pt; margin-left: 72pt; font-weight: bold; font-size: 10pt;">Table 4: Planned Actions and Studies for Carcinogenicity Program.</div>
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    <div> <br>
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    <table cellspacing="0" cellpadding="0" border="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; border-collapse: collapse; text-align: left; color: #000000;" id="z283fd243418f4f69bd3cb52b6771373e">

        <tr>
          <td style="width: 72.87%; vertical-align: top; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0) rgb(0, 0, 0) rgb(0, 0, 0) rgb(0, 0, 0);">
            <div style="text-align: center; font-weight: bold;">Action</div>
          </td>
          <td style="width: 27.13%; vertical-align: top; border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); border-top: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center; font-weight: bold;">Completion Date</div>
          </td>
        </tr>
        <tr>
          <td style="width: 72.87%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div>[***]</div>
          </td>
          <td style="width: 27.13%; vertical-align: top; border-right: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
        </tr>
        <tr>
          <td style="width: 72.87%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0);">
            <div style="margin-left: 37.3pt;">[***]</div>
          </td>
          <td style="width: 27.13%; vertical-align: top; border-right: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
        </tr>
        <tr>
          <td rowspan="1" style="width: 72.87%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">&#160;</td>
          <td rowspan="1" style="width: 27.13%; vertical-align: top; border-right: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">&#160;</td>
        </tr>
        <tr>
          <td style="width: 72.87%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="margin-left: 34.25pt;">[***]</div>
          </td>
          <td style="width: 27.13%; vertical-align: top; border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
        </tr>

    </table>
    <div style="font-size: 10pt;">&#160;</div>
    <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;" class="DSPFListTable" id="zbf816721718e4046af601fa50e8fa937">

        <tr>
          <td style="width: 72pt; vertical-align: top; font-weight: bold;">2.4</td>
          <td style="width: auto; vertical-align: top;">
            <div style="font-weight: bold;">Impurity Qualification Study</div>
          </td>
        </tr>

    </table>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="font-size: 10pt;">[***]</div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
      <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">136</font></div>
      <div style="page-break-after:always;" id="DSPFPageBreak">
        <hr noshade="noshade" style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;"></div>
    </div>
    <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;" class="DSPFListTable" id="z48527ec48a9a4fdf8950f7ad081b0934">

        <tr>
          <td style="width: 72pt; vertical-align: top; font-weight: bold;">Table 5:</td>
          <td style="width: auto; vertical-align: top;">
            <div style="font-weight: bold;">Key Dates for Mouse Impurity Qualification Study.</div>
          </td>
        </tr>

    </table>
    <div style="font-size: 10pt;">&#160;</div>
    <table cellspacing="0" cellpadding="0" border="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; border-collapse: collapse; text-align: left; color: #000000;" id="zfd0c61bb62f5465ea767dac95e94a8e8">

        <tr>
          <td style="width: 22%; vertical-align: top; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0) rgb(0, 0, 0) rgb(0, 0, 0) rgb(0, 0, 0);">
            <div style="text-align: center; font-weight: bold;">Qualification </div>
            <div style="text-align: center; font-weight: bold;">Study</div>
          </td>
          <td style="width: 19.79%; vertical-align: top; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0) rgb(0, 0, 0) rgb(0, 0, 0);">
            <div style="text-align: center; font-weight: bold;">Start</div>
          </td>
          <td style="width: 18.75%; vertical-align: top; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0) rgb(0, 0, 0) rgb(0, 0, 0);">
            <div style="text-align: center; font-weight: bold;">End In-Life</div>
          </td>
          <td style="width: 19.66%; vertical-align: top; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0) rgb(0, 0, 0) rgb(0, 0, 0);">
            <div style="text-align: center; font-weight: bold;">Prelim. Data*</div>
          </td>
          <td style="width: 19.26%; vertical-align: top; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0) rgb(0, 0, 0) rgb(0, 0, 0) rgb(0, 0, 0);">
            <div style="text-align: center; font-weight: bold;">Report</div>
          </td>
        </tr>
        <tr>
          <td style="width: 22%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 19.79%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 18.75%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 19.66%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 19.26%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
        </tr>

    </table>
    <div style="font-size: 10pt;">&#160;</div>
    <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;" class="DSPFListTable" id="zfdb2c681c923485983c63d7e349d0fdc">

        <tr>
          <td style="width: 72pt; vertical-align: top; font-weight: bold;">2.5</td>
          <td style="width: auto; vertical-align: top;">
            <div style="font-weight: bold;">Immunogenicity Assessment (Anti-Drug Antibody Analysis)</div>
          </td>
        </tr>

    </table>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="font-size: 10pt;">[***]</div>
    <div style="font-size: 10pt;">&#160;</div>
    <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;" class="DSPFListTable" id="z88808e808a1c40888acbe265d7f02190">

        <tr>
          <td style="width: 72pt; vertical-align: top; font-weight: bold;">Table 6:</td>
          <td style="width: auto; vertical-align: top;">
            <div style="font-weight: bold;">Key Dates for Immunogenicity Assessment for Preclinical Studies</div>
          </td>
        </tr>

    </table>
    <div style="font-size: 10pt;">&#160;</div>
    <table cellspacing="0" cellpadding="0" border="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; border-collapse: collapse; text-align: left; color: #000000;" id="z0608f7a5883a4cd6ac6c794bc5fd130e">

        <tr>
          <td style="width: 32%; vertical-align: top; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0) rgb(0, 0, 0) rgb(0, 0, 0) rgb(0, 0, 0);">
            <div style="text-align: center; font-weight: bold;">IM Assessment</div>
          </td>
          <td style="width: 14.6%; vertical-align: top; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0) rgb(0, 0, 0) rgb(0, 0, 0);">
            <div style="text-align: center; font-weight: bold;">Start</div>
          </td>
          <td style="width: 18.4%; vertical-align: top; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0) rgb(0, 0, 0) rgb(0, 0, 0);">
            <div style="text-align: center; font-weight: bold;">End</div>
          </td>
          <td style="width: 18.4%; vertical-align: top; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0) rgb(0, 0, 0) rgb(0, 0, 0);">
            <div style="text-align: center; font-weight: bold;">Prelim. Data*</div>
          </td>
          <td style="width: 17.31%; vertical-align: top; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0) rgb(0, 0, 0) rgb(0, 0, 0) rgb(0, 0, 0);">
            <div style="text-align: center; font-weight: bold;">Report</div>
          </td>
        </tr>
        <tr>
          <td style="width: 32%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 14.6%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 18.4%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 18.4%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 17.31%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
        </tr>
        <tr>
          <td style="width: 32%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 14.6%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 18.4%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 18.4%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 17.31%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
        </tr>
        <tr>
          <td style="width: 32%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 14.6%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 18.4%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 18.4%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 17.31%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
        </tr>

    </table>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
      <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">137</font></div>
      <div style="page-break-after:always;" id="DSPFPageBreak">
        <hr noshade="noshade" style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;"></div>
    </div>
    <div><font style="font-weight: bold; font-size: 10pt;">3.</font><font style="font-size: 10pt;">&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160; &#160; <font style="font-weight: bold;">CLINICAL DEVELOPMENT PLAN</font></font></div>
    <div style="font-size: 10pt;">&#160;</div>
    <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;" class="DSPFListTable" id="z3b9fea2a5c6247479ac36cecdfad42c8">

        <tr>
          <td style="width: 54pt; vertical-align: top; font-weight: bold;">3.1.</td>
          <td style="width: auto; vertical-align: top;">
            <div style="font-weight: bold;">ION-682884-CS2: Phase 3</div>
          </td>
        </tr>

    </table>
    <div style="font-size: 10pt;">&#160;</div>
    <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;" class="DSPFListTable" id="z89c157f5a765452798eee8276d51a7eb">

        <tr>
          <td style="width: 72pt; vertical-align: top; font-weight: bold;">Figure 1:</td>
          <td style="width: auto; vertical-align: top;">
            <div style="font-weight: bold;">CARDIO-TTRansform Study Schema</div>
          </td>
        </tr>

    </table>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="font-size: 10pt;">[***]</div>
    <div style="font-size: 10pt;">&#160;</div>
    <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;" class="DSPFListTable" id="z9f487f426bd2403ea64819c2b503585d">

        <tr>
          <td style="width: 54pt; vertical-align: top; font-weight: bold;">3.2.</td>
          <td style="width: auto; vertical-align: top;">
            <div style="font-weight: bold;">ION-682884-CS3: Phase 3</div>
          </td>
        </tr>

    </table>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="font-size: 10pt;">[***]</div>
    <div style="font-size: 10pt;">&#160;</div>
    <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;" class="DSPFListTable" id="ze93686a853b74bf9b08d6056e02e4cc5">

        <tr>
          <td style="width: 54pt; vertical-align: top; font-weight: bold;">3.3.</td>
          <td style="width: auto; vertical-align: top;">
            <div style="font-weight: bold;">ION-682884-CS20: Phase 1</div>
          </td>
        </tr>

    </table>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="font-size: 10pt;">[***]</div>
    <div style="font-size: 10pt;">&#160;</div>
    <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;" class="DSPFListTable" id="ze59fce94ee9b42d58b1b2320bb7d9b9f">

        <tr>
          <td style="width: 54pt; vertical-align: top; font-weight: bold;">3.3.1.</td>
          <td style="width: auto; vertical-align: top;">
            <div style="font-weight: bold;">Study Design</div>
          </td>
        </tr>

    </table>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="font-size: 10pt;">[***]</div>
    <div style="font-size: 10pt;">&#160;</div>
    <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;" class="DSPFListTable" id="zb0985ac46fd449ae8f34471ab6c14b2f">

        <tr>
          <td style="width: 72pt; vertical-align: top; font-weight: bold;">Table 7:</td>
          <td style="width: auto; vertical-align: top;">
            <div style="font-weight: bold;">Study ION-682884-CS20 Design and Current Extent of Exposure</div>
          </td>
        </tr>

    </table>
    <div style="font-size: 10pt;">&#160;</div>
    <table cellspacing="0" cellpadding="0" border="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; border-collapse: collapse; text-align: left; color: #000000;" id="za0d1357a61ed4112a72875004f964c1c">

        <tr>
          <td style="width: 1%; vertical-align: top; border-top: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); border-left: 2px solid rgb(0, 0, 0);" colspan="1">&#160;</td>
          <td style="width: 9.93%; vertical-align: top; border-top: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="font-weight: bold;">Cohort</div>
          </td>
          <td style="width: 1%; vertical-align: top; border-top: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);" colspan="1">&#160;</td>
          <td style="width: 33%; vertical-align: top; border-top: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="font-weight: bold;">Dose Level</div>
          </td>
          <td style="width: 1%; vertical-align: top; border-top: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); border-left: 2px solid rgb(0, 0, 0);" colspan="1">&#160;</td>
          <td style="width: 10.48%; vertical-align: top; border-top: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="font-weight: bold;">Doses</div>
          </td>
          <td style="width: 1%; vertical-align: top; border-top: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); border-left: 2px solid rgb(0, 0, 0);" colspan="1">&#160;</td>
          <td style="width: 15%; vertical-align: top; border-top: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="font-weight: bold;">Total Dose</div>
          </td>
          <td style="width: 1%; vertical-align: top; border-top: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); border-left: 2px solid rgb(0, 0, 0);" colspan="1">&#160;</td>
          <td style="width: 26.8%; vertical-align: top; border-top: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="font-weight: bold;">Subject N</div>
            <div style="font-weight: bold;">(Eplontersen: Placebo)</div>
          </td>
        </tr>
        <tr>
          <td style="width: 1%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);" colspan="1">&#160;</td>
          <td style="width: 9.93%; vertical-align: top; border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div>[***]</div>
          </td>
          <td style="width: 1%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);" colspan="1">&#160;</td>
          <td style="width: 33%; vertical-align: top; border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div>[***]</div>
          </td>
          <td style="width: 1%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);" colspan="1"><br>
          </td>
          <td style="width: 10.48%; vertical-align: top; border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 1%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);" colspan="1">&#160;</td>
          <td style="width: 15%; vertical-align: top; border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 1%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);" colspan="1">&#160;</td>
          <td style="width: 26.8%; vertical-align: top; border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
        </tr>
        <tr>
          <td style="width: 1%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);" colspan="1">&#160;</td>
          <td style="width: 9.93%; vertical-align: top; border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div>[***]</div>
          </td>
          <td style="width: 1%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);" colspan="1">&#160;</td>
          <td style="width: 33%; vertical-align: top; border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div>[***]</div>
          </td>
          <td style="width: 1%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);" colspan="1"><br>
          </td>
          <td style="width: 10.48%; vertical-align: top; border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 1%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);" colspan="1">&#160;</td>
          <td style="width: 15%; vertical-align: top; border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 1%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);" colspan="1">&#160;</td>
          <td style="width: 26.8%; vertical-align: top; border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
        </tr>
        <tr>
          <td style="width: 1%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);" colspan="1">&#160;</td>
          <td style="width: 9.93%; vertical-align: top; border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div>[***]</div>
          </td>
          <td style="width: 1%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);" colspan="1">&#160;</td>
          <td style="width: 33%; vertical-align: top; border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div>[***]</div>
          </td>
          <td style="width: 1%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);" colspan="1"><br>
          </td>
          <td style="width: 10.48%; vertical-align: top; border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 1%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);" colspan="1">&#160;</td>
          <td style="width: 15%; vertical-align: top; border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 1%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);" colspan="1">&#160;</td>
          <td style="width: 26.8%; vertical-align: top; border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
        </tr>
        <tr>
          <td style="width: 1%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);" colspan="1">&#160;</td>
          <td style="width: 9.93%; vertical-align: top; border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div>[***]</div>
          </td>
          <td style="width: 1%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);" colspan="1">&#160;</td>
          <td style="width: 33%; vertical-align: top; border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div>[***]</div>
          </td>
          <td style="width: 1%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);" colspan="1"><br>
          </td>
          <td style="width: 10.48%; vertical-align: top; border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 1%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);" colspan="1">&#160;</td>
          <td style="width: 15%; vertical-align: top; border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 1%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);" colspan="1">&#160;</td>
          <td style="width: 26.8%; vertical-align: top; border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
        </tr>

    </table>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="font-size: 10pt;">[***]</div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="font-weight: bold; font-size: 10pt;"><u>Summary of results:</u></div>
    <div style="font-size: 10pt;">&#160;</div>
    <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;" class="DSPFListTable" id="zc02876ac131c4161ae3af6ea2cec21d6">

        <tr>
          <td style="width: 18pt;"><br>
          </td>
          <td style="width: 18pt; vertical-align: top;">&#8226;</td>
          <td style="width: auto; vertical-align: top;">
            <div>[***]</div>
          </td>
        </tr>

    </table>
    <div style="font-size: 10pt;">&#160;</div>
    <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;" class="DSPFListTable" id="zf86f874c8f8747d7b4027c67eda13059">

        <tr>
          <td style="width: 18pt;"><br>
          </td>
          <td style="width: 18pt; vertical-align: top;">&#8226;</td>
          <td style="width: auto; vertical-align: top;">
            <div>[***]</div>
          </td>
        </tr>

    </table>
    <div style="font-size: 10pt;">&#160;</div>
    <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;" class="DSPFListTable" id="zf1a73c1b6ef248a8b1a2df3a174dbe38">

        <tr>
          <td style="width: 18pt;"><br>
          </td>
          <td style="width: 18pt; vertical-align: top;">&#8226;</td>
          <td style="width: auto; vertical-align: top;">
            <div>[***]</div>
          </td>
        </tr>

    </table>
    <div style="font-size: 10pt;">&#160;</div>
    <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;" class="DSPFListTable" id="ze4eecc422b704ef1b31e9b7fc03eea06">

        <tr>
          <td style="width: 54pt; vertical-align: top; font-weight: bold;">3.4.</td>
          <td style="width: auto; vertical-align: top;">
            <div style="font-weight: bold;">ION-682884-CS21: Phase 1</div>
          </td>
        </tr>

    </table>
    <div style="margin-left: 18pt; font-size: 10pt;"> <br>
    </div>
    <div style="margin-left: 18pt; font-size: 10pt;">[***]</div>
    <div style="font-size: 10pt;">&#160;</div>
    <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;" class="DSPFListTable" id="z898bb561c22d4751aaa92af6ab6786e9">

        <tr>
          <td style="width: 54pt; vertical-align: top; font-weight: bold;">3.4.1.</td>
          <td style="width: auto; vertical-align: top;">
            <div style="font-weight: bold;">Study Design</div>
          </td>
        </tr>

    </table>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="font-size: 10pt;">[***]</div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
      <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">138</font></div>
      <div style="page-break-after:always;" id="DSPFPageBreak">
        <hr noshade="noshade" style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;"></div>
    </div>
    <div style="font-weight: bold; font-size: 10pt;"><u>Primary Endpoint</u></div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="font-size: 10pt;">[***]</div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="font-weight: bold; font-size: 10pt;"><u>Secondary Endpoint</u></div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="font-size: 10pt;">[***]</div>
    <div style="font-size: 10pt;">&#160;</div>
    <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;" class="DSPFListTable" id="z1c1e306f824d49868d67a607c38a88c4">

        <tr>
          <td style="width: 54pt; vertical-align: top; font-weight: bold;">3.4.2.</td>
          <td style="width: auto; vertical-align: top;">
            <div style="font-weight: bold;">Drug Interaction Studies</div>
          </td>
        </tr>

    </table>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="font-size: 10pt;">[***].</div>
    <div style="font-size: 10pt;">&#160;</div>
    <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;" class="DSPFListTable" id="z5c3c3d629bce4d0280fd5762f857e056">

        <tr>
          <td style="width: 54pt; vertical-align: top; font-weight: bold;">3.4.3.</td>
          <td style="width: auto; vertical-align: top;">
            <div style="font-weight: bold;">Immunogenicity Assessment (Anti-Drug Antibody Assessment)</div>
          </td>
        </tr>

    </table>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="font-size: 10pt;">[***]</div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="font-size: 10pt;">[***]</div>
    <div style="font-size: 10pt;">&#160;</div>
    <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;" class="DSPFListTable" id="z8f4594fecfbb40d3976b9d6129f2e72d">

        <tr>
          <td style="width: 54pt; vertical-align: top; font-weight: bold;">Table 8:</td>
          <td style="width: auto; vertical-align: top;">
            <div style="font-weight: bold;">Key Dates for Immunogenicity Assessment</div>
          </td>
        </tr>

    </table>
    <div style="font-size: 10pt;">&#160;</div>
    <table cellspacing="0" cellpadding="0" border="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; border-collapse: collapse; text-align: left; color: #000000;" id="zb760e3f1c232449481b9da4ab4071aeb">

        <tr>
          <td style="width: 36%; vertical-align: top; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0) rgb(0, 0, 0) rgb(0, 0, 0) rgb(0, 0, 0);">
            <div style="text-align: center; font-weight: bold;">IM Assessment</div>
          </td>
          <td style="width: 11.49%; vertical-align: top; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0) rgb(0, 0, 0) rgb(0, 0, 0);">
            <div style="text-align: center; font-weight: bold;">Start</div>
          </td>
          <td style="width: 18.39%; vertical-align: top; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0) rgb(0, 0, 0) rgb(0, 0, 0);">
            <div style="text-align: center; font-weight: bold;">End</div>
          </td>
          <td style="width: 18.39%; vertical-align: top; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0) rgb(0, 0, 0) rgb(0, 0, 0);">
            <div style="text-align: center; font-weight: bold;">Prelim. Data*</div>
          </td>
          <td style="width: 17.29%; vertical-align: top; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0) rgb(0, 0, 0) rgb(0, 0, 0) rgb(0, 0, 0);">
            <div style="text-align: center; font-weight: bold;">Report</div>
          </td>
        </tr>
        <tr>
          <td style="width: 36%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.49%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 18.39%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 18.39%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 17.29%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
        </tr>
        <tr>
          <td style="width: 36%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.49%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 18.39%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 18.39%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 17.29%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
        </tr>
        <tr>
          <td style="width: 36%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.49%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 18.39%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 18.39%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 17.29%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
        </tr>
        <tr>
          <td style="width: 36%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.49%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 18.39%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 18.39%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 17.29%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
        </tr>
        <tr>
          <td style="width: 36%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 11.49%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 18.39%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 18.39%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 17.29%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
        </tr>

    </table>
    <div style="font-size: 10pt;">&#160;</div>
    <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;" class="DSPFListTable" id="z74b1c7f0a55b47adb864808dc0f6bdb3">

        <tr>
          <td style="width: 54pt; vertical-align: top; font-weight: bold;">3.4.4.</td>
          <td style="width: auto; vertical-align: top;">
            <div style="font-weight: bold;">Studies in Special Populations</div>
          </td>
        </tr>

    </table>
    <div style="font-size: 10pt;"> <br>
    </div>
    <div style="font-size: 10pt;">[***]</div>
    <div style="font-size: 10pt;">&#160;</div>
    <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;" class="DSPFListTable" id="z27122f9dda7b429788cfe5ca5bf1b273">

        <tr>
          <td style="width: 54pt; vertical-align: top; font-weight: bold;">3.4.5.</td>
          <td style="width: auto; vertical-align: top;">
            <div style="font-weight: bold;">&#8216;Thorough QT&#8217; Study</div>
          </td>
        </tr>

    </table>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="font-size: 10pt;">[***]</div>
    <div style="font-size: 10pt;">&#160;</div>
    <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;" class="DSPFListTable" id="zc792f0d0ad554fd387b3f2d72d0313c0">

        <tr>
          <td style="width: 72pt; vertical-align: top; font-weight: bold;">Table 9:</td>
          <td style="width: auto; vertical-align: top;">
            <div><font style="font-weight: bold;">Key Dates for </font>[***]</div>
          </td>
        </tr>

    </table>
    <div style="font-size: 10pt;">&#160;</div>
    <table cellspacing="0" cellpadding="0" border="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; border-collapse: collapse; text-align: left; color: #000000;" id="zc54e12a6cd7a43c2b8db9b28a1e352c6">

        <tr>
          <td style="width: 30%; vertical-align: top; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0) rgb(0, 0, 0) rgb(0, 0, 0) rgb(0, 0, 0);">
            <div style="text-align: center; font-weight: bold;">QT Assessment</div>
          </td>
          <td style="width: 14.91%; vertical-align: top; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0) rgb(0, 0, 0) rgb(0, 0, 0);">
            <div style="text-align: center; font-weight: bold;">Start</div>
          </td>
          <td style="width: 17.67%; vertical-align: top; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0) rgb(0, 0, 0) rgb(0, 0, 0);">
            <div style="text-align: center; font-weight: bold;">End</div>
          </td>
          <td style="width: 17.67%; vertical-align: top; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0) rgb(0, 0, 0) rgb(0, 0, 0);">
            <div style="text-align: center; font-weight: bold;">Prelim. Data*</div>
          </td>
          <td style="width: 18.59%; vertical-align: top; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0) rgb(0, 0, 0) rgb(0, 0, 0) rgb(0, 0, 0);">
            <div style="text-align: center; font-weight: bold;">Report</div>
          </td>
        </tr>
        <tr>
          <td style="width: 30%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 14.91%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 17.67%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 17.67%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 18.59%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: center;">[***]</div>
          </td>
        </tr>
        <tr>
          <td style="width: 30%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 14.91%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 17.67%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 17.67%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 18.59%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
        </tr>

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    <div style="font-size: 10pt;">&#160;</div>
    <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;" class="DSPFListTable" id="zfafaae0e71f141ce80e8d2e53f97e294">

        <tr>
          <td style="width: 54pt; vertical-align: top; font-weight: bold;">3.4.6.</td>
          <td style="width: auto; vertical-align: top;">
            <div style="font-weight: bold;">Human ADME Study</div>
          </td>
        </tr>

    </table>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="font-size: 10pt;">[***]</div>
    <div style="font-size: 10pt;">&#160;</div>
    <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;" class="DSPFListTable" id="z20293892d0be44bebad5e2cc99ae8cf6">

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          <td style="width: 54pt; vertical-align: top; font-weight: bold;">3.4.7.</td>
          <td style="width: auto; vertical-align: top;">
            <div style="font-weight: bold;">Population PK and PKPD Study</div>
          </td>
        </tr>

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    <div style="font-size: 10pt;">&#160;</div>
    <div style="font-size: 10pt;">[***]</div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
      <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">139</font></div>
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        <hr noshade="noshade" style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;"></div>
    </div>
    <div>
      <table cellspacing="0" cellpadding="0" style="width: 100%; font-family: 'Times New Roman'; font-size: 10pt;" id="zbcbfeeca1f824e1bbdd1ad682593a495" class="DSPFListTable">

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          </tr>

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    </div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="font-size: 10pt;">[***]</div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
      <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">140</font></div>
      <div style="page-break-after:always;" id="DSPFPageBreak">
        <hr noshade="noshade" style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;"></div>
    </div>
    <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;" class="DSPFListTable" id="z74992c3f3ff843fe83d979334137a4e4">

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          <td style="width: 54pt; vertical-align: top; font-weight: bold;">5.</td>
          <td style="width: auto; vertical-align: top;">
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          </td>
        </tr>

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    <div style="font-size: 10pt;">&#160;</div>
    <div style="font-size: 10pt;">[***]</div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
      <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">141</font></div>
      <div style="page-break-after:always;" id="DSPFPageBreak">
        <hr noshade="noshade" style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;"></div>
    </div>
    <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;" class="DSPFListTable" id="zc7dbf996299d42c4925e804192aac5db">

        <tr>
          <td style="width: 54pt; vertical-align: top; font-weight: bold;">6.</td>
          <td style="width: auto; vertical-align: top;">
            <div style="font-weight: bold;">ROLES AND RESPONSIBILITIES</div>
          </td>
        </tr>

    </table>
    <div style="font-size: 10pt;">&#160;</div>
    <table cellspacing="0" cellpadding="0" border="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; border-collapse: collapse; text-align: left; color: rgb(0, 0, 0);" id="ze5655b30b3e64828826639b9a6037b72">

        <tr>
          <td style="width: 29.12%; vertical-align: top; background-color: rgb(79, 129, 189);">
            <div>[***]</div>
          </td>
          <td style="width: 19.35%; vertical-align: top; background-color: rgb(79, 129, 189);">
            <div>[***]</div>
          </td>
          <td style="width: 51.53%; vertical-align: top; background-color: rgb(79, 129, 189);">
            <div>[***]</div>
          </td>
        </tr>
        <tr>
          <td style="width: 29.12%; vertical-align: top; background-color: rgb(219, 229, 241);">
            <div>[***]</div>
          </td>
          <td style="width: 19.35%; vertical-align: top; background-color: rgb(219, 229, 241);">
            <div>[***]</div>
          </td>
          <td style="width: 51.53%; vertical-align: top; background-color: rgb(219, 229, 241);">
            <div>[***]</div>
          </td>
        </tr>
        <tr>
          <td style="width: 29.12%; vertical-align: top;">
            <div>[***]</div>
          </td>
          <td style="width: 19.35%; vertical-align: top;">
            <div>[***]</div>
          </td>
          <td style="width: 51.53%; vertical-align: top;">
            <div>[***]</div>
          </td>
        </tr>
        <tr>
          <td style="width: 29.12%; vertical-align: top; background-color: rgb(219, 229, 241);">
            <div>[***]</div>
          </td>
          <td style="width: 19.35%; vertical-align: top; background-color: rgb(219, 229, 241);">
            <div>[***]</div>
          </td>
          <td style="width: 51.53%; vertical-align: top; background-color: rgb(219, 229, 241);">
            <div>[***]</div>
          </td>
        </tr>
        <tr>
          <td style="width: 29.12%; vertical-align: top;">
            <div>[***]</div>
          </td>
          <td style="width: 19.35%; vertical-align: top;">
            <div>[***]</div>
          </td>
          <td style="width: 51.53%; vertical-align: top;">
            <div>[***]</div>
          </td>
        </tr>
        <tr>
          <td style="width: 29.12%; vertical-align: top; background-color: rgb(222, 234, 246);">
            <div>[***]</div>
          </td>
          <td style="width: 19.35%; vertical-align: top; background-color: rgb(222, 234, 246);">
            <div>[***]</div>
          </td>
          <td style="width: 51.53%; vertical-align: top; background-color: rgb(222, 234, 246);">
            <div>[***]</div>
          </td>
        </tr>
        <tr>
          <td style="width: 29.12%; vertical-align: top;">
            <div>[***]</div>
          </td>
          <td style="width: 19.35%; vertical-align: top;">
            <div>[***]</div>
          </td>
          <td style="width: 51.53%; vertical-align: top;">
            <div>[***]</div>
          </td>
        </tr>
        <tr>
          <td style="width: 29.12%; vertical-align: top; background-color: rgb(222, 234, 246);">
            <div>[***]</div>
          </td>
          <td style="width: 19.35%; vertical-align: top; background-color: rgb(222, 234, 246);">
            <div>[***]</div>
          </td>
          <td style="width: 51.53%; vertical-align: top; background-color: rgb(222, 234, 246);">
            <div>[***]</div>
          </td>
        </tr>
        <tr>
          <td style="width: 29.12%; vertical-align: top;">
            <div>[***]</div>
          </td>
          <td style="width: 19.35%; vertical-align: top;">
            <div>[***]</div>
          </td>
          <td style="width: 51.53%; vertical-align: top;">
            <div>[***]</div>
          </td>
        </tr>
        <tr>
          <td style="width: 29.12%; vertical-align: top; background-color: rgb(222, 234, 246);">
            <div>[***]</div>
          </td>
          <td style="width: 19.35%; vertical-align: top; background-color: rgb(222, 234, 246);">
            <div>[***]</div>
          </td>
          <td style="width: 51.53%; vertical-align: top; background-color: rgb(222, 234, 246);">
            <div>[***]</div>
          </td>
        </tr>
        <tr>
          <td style="width: 29.12%; vertical-align: top;">
            <div>[***]</div>
          </td>
          <td style="width: 19.35%; vertical-align: top;">
            <div>[***]</div>
          </td>
          <td style="width: 51.53%; vertical-align: top;">
            <div>[***]</div>
          </td>
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    <div style="font-size: 10pt;">&#160;</div>
    <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
      <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">142</font></div>
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          </td>
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    <div style="font-size: 10pt;">&#160;</div>
    <div style="font-size: 10pt;">[***]</div>
    <div style="font-size: 10pt;">&#160;</div>
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          </td>
        </tr>

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    <div style="font-size: 10pt;">&#160;</div>
    <div style="font-size: 10pt;">[***]</div>
    <div> <font style="font-size: 10pt;"><br>
      </font> </div>
    <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
      <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">143</font></div>
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    <div style="text-align: center; font-weight: bold; font-size: 10pt;"><u>Schedule 3.2.1</u></div>
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    <div><font style="font-size: 10pt;"><br>
      </font> </div>
    <div style="font-size: 10pt;">[***]</div>
    <div><font style="font-size: 10pt;"><br>
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          <td style="width: 28%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
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            <div>[***]</div>
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          <td style="width: 11%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div>[***]</div>
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          <td style="width: 28%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div>[***]</div>
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          <td style="width: 36%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div>[***]</div>
          </td>
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        <tr>
          <td style="width: 11%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div>[***]</div>
          </td>
          <td style="width: 28%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div>[***]</div>
          </td>
          <td style="width: 36%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div>[***]</div>
          </td>
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        <tr>
          <td rowspan="8" style="width: 12%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div>[***]</div>
          </td>
          <td rowspan="2" style="width: 13.26%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div>[***]</div>
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          <td style="width: 11%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div>[***]</div>
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          <td style="width: 28%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
          <td style="width: 36%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div>[***]</div>
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        <tr>
          <td style="width: 11%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div>[***]</div>
          </td>
          <td style="width: 28%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
          <td style="width: 36%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div>[***]</div>
          </td>
        </tr>
        <tr>
          <td rowspan="2" style="width: 13.26%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div>[***]</div>
          </td>
          <td style="width: 11%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div>[***]</div>
          </td>
          <td style="width: 28%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
          <td style="width: 36%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div>[***]</div>
          </td>
        </tr>
        <tr>
          <td style="width: 11%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div>[***]</div>
          </td>
          <td style="width: 28%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
          <td style="width: 36%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div>[***]</div>
          </td>
        </tr>
        <tr>
          <td rowspan="2" style="width: 13.26%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div>[***]</div>
          </td>
          <td style="width: 11%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div>[***]</div>
          </td>
          <td style="width: 28%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
          <td style="width: 36%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div>[***]</div>
          </td>
        </tr>
        <tr>
          <td style="width: 11%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div>[***]</div>
          </td>
          <td style="width: 28%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
          <td style="width: 36%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div>[***]</div>
          </td>
        </tr>
        <tr>
          <td rowspan="2" style="width: 13.26%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div>[***]</div>
          </td>
          <td style="width: 11%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div>[***]</div>
          </td>
          <td style="width: 28%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
          <td style="width: 36%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div>[***]</div>
          </td>
        </tr>
        <tr>
          <td style="width: 11%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div>[***]</div>
          </td>
          <td style="width: 28%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
          <td style="width: 36%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div>[***]</div>
          </td>
        </tr>
        <tr>
          <td colspan="2" rowspan="2" style="vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div>[***]</div>
          </td>
          <td style="width: 11%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div>[***]</div>
          </td>
          <td style="width: 28%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div>[***]</div>
          </td>
          <td style="width: 36%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div>[***]</div>
          </td>
        </tr>
        <tr>
          <td style="width: 11%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div>[***]</div>
          </td>
          <td style="width: 28%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div>[***]</div>
          </td>
          <td style="width: 36%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div>[***]</div>
          </td>
        </tr>
        <tr>
          <td colspan="5" style="vertical-align: top; background-color: rgb(222, 234, 246); border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="font-weight: bold;">Customer-Facing Functions</div>
          </td>
        </tr>
        <tr>
          <td colspan="2" rowspan="2" style="vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div>[***]</div>
          </td>
          <td style="width: 11%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div>[***]</div>
          </td>
          <td style="width: 28%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
          <td style="width: 36%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div>[***]</div>
          </td>
        </tr>
        <tr>
          <td style="width: 11%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div>[***]</div>
          </td>
          <td style="width: 28%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
          <td style="width: 36%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div>[***]</div>
          </td>
        </tr>
        <tr>
          <td rowspan="6" style="width: 12%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div>[***]</div>
          </td>
          <td rowspan="2" style="width: 13.26%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div>[***]</div>
          </td>
          <td style="width: 11%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div>[***]</div>
          </td>
          <td style="width: 28%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div>[***]</div>
          </td>
          <td style="width: 36%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div>[***]</div>
          </td>
        </tr>
        <tr>
          <td style="width: 11%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div>[***]</div>
          </td>
          <td style="width: 28%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div>[***]</div>
          </td>
          <td style="width: 36%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div>[***]</div>
          </td>
        </tr>
        <tr>
          <td rowspan="2" style="width: 13.26%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div>[***]</div>
          </td>
          <td style="width: 11%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div>[***]</div>
          </td>
          <td style="width: 28%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
          <td style="width: 36%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div>[***]</div>
          </td>
        </tr>
        <tr>
          <td style="width: 11%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div>[***]</div>
          </td>
          <td style="width: 28%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
          <td style="width: 36%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div>[***]</div>
          </td>
        </tr>
        <tr>
          <td rowspan="2" style="width: 13.26%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div>[***]</div>
          </td>
          <td style="width: 11%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div>[***]</div>
          </td>
          <td style="width: 28%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div>[***]</div>
          </td>
          <td style="width: 36%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div>[***]</div>
          </td>
        </tr>
        <tr>
          <td style="width: 11%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div>[***]</div>
          </td>
          <td style="width: 28%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div>[***]</div>
          </td>
          <td style="width: 36%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div>[***]</div>
          </td>
        </tr>
        <tr>
          <td rowspan="2" style="width: 12%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div>[***]</div>
          </td>
          <td rowspan="2" style="width: 13.26%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div>[***]</div>
          </td>
          <td style="width: 11%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div>[***]</div>
          </td>
          <td style="width: 28%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div>[***]</div>
          </td>
          <td style="width: 36%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div>[***]</div>
          </td>
        </tr>
        <tr>
          <td style="width: 11%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div>[***]</div>
          </td>
          <td style="width: 28%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div>[***]</div>
          </td>
          <td style="width: 36%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div>[***]</div>
          </td>
        </tr>

    </table>
    <div><font style="font-size: 10pt;"><br>
      </font> </div>
    <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
      <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">144</font></div>
      <div style="page-break-after:always;" id="DSPFPageBreak">
        <hr noshade="noshade" style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;"></div>
    </div>
    <div style="text-align: center; font-weight: bold; font-size: 10pt;"><u>Schedule 3.2.3(b)</u></div>
    <div style="font-size: 10pt;">&#160;</div>
    <div style="text-align: center; font-weight: bold; font-size: 10pt;">Cost Share Scenarios</div>
    <div><br>
      <div style="font-weight: bold; font-size: 10pt;">US COMMERCIAL/MEDICAL AFFAIRS BUDGET EXAMPLE</div>
    </div>
    [***]

    <div style="clear: both;"><font style="font-size: 10pt;"><br>
      </font> </div>
    <table cellspacing="0" cellpadding="0" border="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; border-collapse: collapse; text-align: left; color: rgb(0, 0, 0);" id="zf9aee16497444519a67d4b64f393a92a">

        <tr>
          <td nowrap="nowrap" style="width: 23.88%; vertical-align: top; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); background-color: rgb(231, 230, 230);">
            <div>[***]</div>
          </td>
          <td nowrap="nowrap" colspan="7" style="vertical-align: top; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); background-color: rgb(231, 230, 230);">
            <div style="text-align: center;">[***]</div>
          </td>
        </tr>
        <tr>
          <td nowrap="nowrap" style="width: 23.88%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
          <td nowrap="nowrap" style="width: 7%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div>[***]</div>
          </td>
          <td nowrap="nowrap" style="width: 9%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div>[***]</div>
          </td>
          <td nowrap="nowrap" style="width: 7.18%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div>[***]</div>
          </td>
          <td nowrap="nowrap" style="width: 9.49%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div>[***]</div>
          </td>
          <td nowrap="nowrap" style="width: 13%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div>[***]</div>
          </td>
          <td nowrap="nowrap" style="width: 11.49%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div>[***]</div>
          </td>
          <td nowrap="nowrap" style="width: 20.36%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div>[***]</div>
          </td>
        </tr>
        <tr>
          <td nowrap="nowrap" style="width: 23.88%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div>[***]</div>
          </td>
          <td nowrap="nowrap" style="width: 7%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td nowrap="nowrap" style="width: 9%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td nowrap="nowrap" style="width: 7.18%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td nowrap="nowrap" style="width: 9.49%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
          <td nowrap="nowrap" style="width: 13%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td nowrap="nowrap" style="width: 11.49%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td nowrap="nowrap" style="width: 20.36%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div>[***]</div>
          </td>
        </tr>
        <tr>
          <td nowrap="nowrap" style="width: 23.88%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div>[***]</div>
          </td>
          <td nowrap="nowrap" style="width: 7%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td nowrap="nowrap" style="width: 9%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
          <td nowrap="nowrap" style="width: 7.18%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
          <td nowrap="nowrap" style="width: 9.49%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
          <td nowrap="nowrap" style="width: 13%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td nowrap="nowrap" style="width: 11.49%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 20.36%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div>[***]</div>
          </td>
        </tr>
        <tr>
          <td nowrap="nowrap" style="width: 23.88%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div>[***]</div>
          </td>
          <td nowrap="nowrap" style="width: 7%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td nowrap="nowrap" style="width: 9%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
          <td nowrap="nowrap" style="width: 7.18%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
          <td nowrap="nowrap" style="width: 9.49%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
          <td nowrap="nowrap" style="width: 13%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td nowrap="nowrap" style="width: 11.49%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 20.36%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div>[***]</div>
          </td>
        </tr>
        <tr>
          <td nowrap="nowrap" style="width: 23.88%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div>[***]</div>
          </td>
          <td nowrap="nowrap" style="width: 7%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
          <td nowrap="nowrap" style="width: 9%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
          <td nowrap="nowrap" style="width: 7.18%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td nowrap="nowrap" style="width: 9.49%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
          <td nowrap="nowrap" style="width: 13%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td nowrap="nowrap" style="width: 11.49%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td nowrap="nowrap" style="width: 20.36%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
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        <tr>
          <td nowrap="nowrap" style="width: 23.88%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div>[***]</div>
          </td>
          <td nowrap="nowrap" style="width: 7%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
          <td nowrap="nowrap" style="width: 9%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
          <td nowrap="nowrap" style="width: 7.18%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td nowrap="nowrap" style="width: 9.49%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
          <td nowrap="nowrap" style="width: 13%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
          <td nowrap="nowrap" style="width: 11.49%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
          <td nowrap="nowrap" style="width: 20.36%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
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        <tr>
          <td nowrap="nowrap" style="width: 23.88%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div>[***]</div>
          </td>
          <td nowrap="nowrap" style="width: 7%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
          <td nowrap="nowrap" style="width: 9%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
          <td nowrap="nowrap" style="width: 7.18%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td nowrap="nowrap" style="width: 9.49%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td nowrap="nowrap" style="width: 13%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
          <td nowrap="nowrap" style="width: 11.49%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
          <td nowrap="nowrap" style="width: 20.36%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
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    <div><font style="font-size: 10pt;"><br>
      </font> </div>
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        <tr>
          <td nowrap="nowrap" style="width: 23.88%; vertical-align: top; background-color: rgb(231, 230, 230); border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0) rgb(0, 0, 0) rgb(0, 0, 0) rgb(0, 0, 0);">
            <div>[***]</div>
          </td>
          <td nowrap="nowrap" colspan="7" style="vertical-align: top; background-color: rgb(231, 230, 230); border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0) rgb(0, 0, 0) rgb(0, 0, 0) rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
        </tr>
        <tr>
          <td nowrap="nowrap" style="width: 23.88%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
          <td nowrap="nowrap" style="width: 7%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div>[***]</div>
          </td>
          <td nowrap="nowrap" style="width: 9%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div>[***]</div>
          </td>
          <td nowrap="nowrap" style="width: 7.18%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div>[***]</div>
          </td>
          <td nowrap="nowrap" style="width: 9.49%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div>[***]</div>
          </td>
          <td nowrap="nowrap" style="width: 13%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div>[***]</div>
          </td>
          <td nowrap="nowrap" style="width: 11.49%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div>[***]</div>
          </td>
          <td nowrap="nowrap" style="width: 20.36%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div>[***]</div>
          </td>
        </tr>
        <tr>
          <td nowrap="nowrap" style="width: 23.88%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div>[***]</div>
          </td>
          <td nowrap="nowrap" style="width: 7%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td nowrap="nowrap" style="width: 9%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td nowrap="nowrap" style="width: 7.18%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td nowrap="nowrap" style="width: 9.49%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
          <td nowrap="nowrap" style="width: 13%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td nowrap="nowrap" style="width: 11.49%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 20.36%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div>[***]</div>
          </td>
        </tr>
        <tr>
          <td nowrap="nowrap" style="width: 23.88%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div>[***]</div>
          </td>
          <td nowrap="nowrap" style="width: 7%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td nowrap="nowrap" style="width: 9%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
          <td nowrap="nowrap" style="width: 7.18%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
          <td nowrap="nowrap" style="width: 9.49%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
          <td nowrap="nowrap" style="width: 13%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td nowrap="nowrap" style="width: 11.49%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 20.36%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div>[***]</div>
          </td>
        </tr>
        <tr>
          <td nowrap="nowrap" style="width: 23.88%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div>[***]</div>
          </td>
          <td nowrap="nowrap" style="width: 7%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td nowrap="nowrap" style="width: 9%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
          <td nowrap="nowrap" style="width: 7.18%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
          <td nowrap="nowrap" style="width: 9.49%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
          <td nowrap="nowrap" style="width: 13%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td nowrap="nowrap" style="width: 11.49%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 20.36%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div>[***]</div>
          </td>
        </tr>
        <tr>
          <td nowrap="nowrap" style="width: 23.88%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div>[***]</div>
          </td>
          <td nowrap="nowrap" style="width: 7%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
          <td nowrap="nowrap" style="width: 9%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
          <td nowrap="nowrap" style="width: 7.18%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td nowrap="nowrap" style="width: 9.49%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
          <td nowrap="nowrap" style="width: 13%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td nowrap="nowrap" style="width: 11.49%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td nowrap="nowrap" style="width: 20.36%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
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        <tr>
          <td nowrap="nowrap" style="width: 23.88%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div>[***]</div>
          </td>
          <td nowrap="nowrap" style="width: 7%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
          <td nowrap="nowrap" style="width: 9%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
          <td nowrap="nowrap" style="width: 7.18%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
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          <td nowrap="nowrap" style="width: 9.49%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
          <td nowrap="nowrap" style="width: 13%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
          <td nowrap="nowrap" style="width: 11.49%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
          <td nowrap="nowrap" style="width: 20.36%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
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        <tr>
          <td nowrap="nowrap" style="width: 23.88%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div>[***]</div>
          </td>
          <td nowrap="nowrap" style="width: 7%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
          <td nowrap="nowrap" style="width: 9%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
          <td nowrap="nowrap" style="width: 7.18%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td nowrap="nowrap" style="width: 9.49%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td nowrap="nowrap" style="width: 13%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
          <td nowrap="nowrap" style="width: 11.49%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
          <td nowrap="nowrap" style="width: 20.36%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
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      <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">145</font></div>
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          <td style="background-color: #E7E6E6; border-bottom: 2px solid #000000; border-left: 2px solid #000000; border-right: 2px solid #000000; border-top: 2px solid #000000; vertical-align: top; white-space: nowrap; width: 23.88%;" rowspan="1">[***]</td>
          <td style="background-color: #E7E6E6; border-bottom: 2px solid #000000; border-left: 2px solid #000000; border-right: 2px solid #000000; border-top: 2px solid #000000; vertical-align: top; white-space: nowrap; width: 6.95%; text-align: center;" rowspan="1" colspan="7">[***]</td>
        </tr>
        <tr>
          <td nowrap="nowrap" style="width: 23.88%; vertical-align: top; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0);">&#160;</td>
          <td nowrap="nowrap" style="width: 6.95%; vertical-align: top; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0);">
            <div>[***]</div>
          </td>
          <td nowrap="nowrap" style="width: 9%; vertical-align: top; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0);">
            <div>[***]</div>
          </td>
          <td nowrap="nowrap" style="width: 7.18%; vertical-align: top; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0);">
            <div>[***]</div>
          </td>
          <td nowrap="nowrap" style="width: 9.49%; vertical-align: top; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0);">
            <div>[***]</div>
          </td>
          <td nowrap="nowrap" style="width: 13%; vertical-align: top; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0);">
            <div>[***]</div>
          </td>
          <td nowrap="nowrap" style="width: 11.49%; vertical-align: top; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0);">
            <div>[***]</div>
          </td>
          <td nowrap="nowrap" style="width: 20.36%; vertical-align: top; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0);">
            <div>[***]</div>
          </td>
        </tr>
        <tr>
          <td nowrap="nowrap" style="width: 23.88%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div>[***]</div>
          </td>
          <td nowrap="nowrap" style="width: 6.95%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td nowrap="nowrap" style="width: 9%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td nowrap="nowrap" style="width: 7.18%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td nowrap="nowrap" style="width: 9.49%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
          <td nowrap="nowrap" style="width: 13%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td nowrap="nowrap" style="width: 11.49%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 20.36%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div>[***]</div>
          </td>
        </tr>
        <tr>
          <td nowrap="nowrap" style="width: 23.88%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div>[***]</div>
          </td>
          <td nowrap="nowrap" style="width: 6.95%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
          <td nowrap="nowrap" style="width: 9%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td nowrap="nowrap" style="width: 7.18%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
          <td nowrap="nowrap" style="width: 9.49%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
          <td nowrap="nowrap" style="width: 13%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td nowrap="nowrap" style="width: 11.49%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 20.36%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div>[***]</div>
          </td>
        </tr>
        <tr>
          <td nowrap="nowrap" style="width: 23.88%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div>[***]</div>
          </td>
          <td nowrap="nowrap" style="width: 6.95%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
          <td nowrap="nowrap" style="width: 9%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td nowrap="nowrap" style="width: 7.18%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
          <td nowrap="nowrap" style="width: 9.49%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
          <td nowrap="nowrap" style="width: 13%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td nowrap="nowrap" style="width: 11.49%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 20.36%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div>[***]</div>
          </td>
        </tr>
        <tr>
          <td nowrap="nowrap" style="width: 23.88%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div>[***]</div>
          </td>
          <td nowrap="nowrap" style="width: 6.95%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
          <td nowrap="nowrap" style="width: 9%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
          <td nowrap="nowrap" style="width: 7.18%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td nowrap="nowrap" style="width: 9.49%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
          <td nowrap="nowrap" style="width: 13%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td nowrap="nowrap" style="width: 11.49%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td nowrap="nowrap" style="width: 20.36%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
        </tr>
        <tr>
          <td nowrap="nowrap" style="width: 23.88%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div>[***]</div>
          </td>
          <td nowrap="nowrap" style="width: 6.95%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
          <td nowrap="nowrap" style="width: 9%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
          <td nowrap="nowrap" style="width: 7.18%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td nowrap="nowrap" style="width: 9.49%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
          <td nowrap="nowrap" style="width: 13%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
          <td nowrap="nowrap" style="width: 11.49%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
          <td nowrap="nowrap" style="width: 20.36%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
        </tr>
        <tr>
          <td nowrap="nowrap" style="width: 23.88%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div>[***]</div>
          </td>
          <td nowrap="nowrap" style="width: 6.95%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
          <td nowrap="nowrap" style="width: 9%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
          <td nowrap="nowrap" style="width: 7.18%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td nowrap="nowrap" style="width: 9.49%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td nowrap="nowrap" style="width: 13%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
          <td nowrap="nowrap" style="width: 11.49%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
          <td nowrap="nowrap" style="width: 20.36%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
        </tr>

    </table>
    <div><font style="font-size: 10pt;"><br>
      </font> </div>
    <table cellspacing="0" cellpadding="0" border="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; border-collapse: collapse; text-align: left; color: #000000;" id="z07b3508ac3fe476fb58fabe7ab3c02a7">

        <tr>
          <td nowrap="nowrap" style="width: 23.88%; vertical-align: top; background-color: rgb(231, 230, 230); border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0) rgb(0, 0, 0) rgb(0, 0, 0) rgb(0, 0, 0);">
            <div>[***]</div>
          </td>
          <td nowrap="nowrap" colspan="7" style="vertical-align: top; background-color: rgb(231, 230, 230); border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0) rgb(0, 0, 0) rgb(0, 0, 0) rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
        </tr>
        <tr>
          <td nowrap="nowrap" style="width: 23.88%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
          <td nowrap="nowrap" style="width: 6.95%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div>[***]</div>
          </td>
          <td nowrap="nowrap" style="width: 9%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div>[***]</div>
          </td>
          <td nowrap="nowrap" style="width: 7.18%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div>[***]</div>
          </td>
          <td nowrap="nowrap" style="width: 9.49%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div>[***]</div>
          </td>
          <td nowrap="nowrap" style="width: 13%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div>[***]</div>
          </td>
          <td nowrap="nowrap" style="width: 11.49%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div>[***]</div>
          </td>
          <td nowrap="nowrap" style="width: 20.36%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div>[***]</div>
          </td>
        </tr>
        <tr>
          <td nowrap="nowrap" style="width: 23.88%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div>[***]</div>
          </td>
          <td nowrap="nowrap" style="width: 6.95%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td nowrap="nowrap" style="width: 9%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td nowrap="nowrap" style="width: 7.18%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td nowrap="nowrap" style="width: 9.49%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
          <td nowrap="nowrap" style="width: 13%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td nowrap="nowrap" style="width: 11.49%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 20.36%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div>[***]</div>
          </td>
        </tr>
        <tr>
          <td nowrap="nowrap" style="width: 23.88%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div>[***]</div>
          </td>
          <td nowrap="nowrap" style="width: 6.95%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td nowrap="nowrap" style="width: 9%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
          <td nowrap="nowrap" style="width: 7.18%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
          <td nowrap="nowrap" style="width: 9.49%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
          <td nowrap="nowrap" style="width: 13%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td nowrap="nowrap" style="width: 11.49%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 20.36%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div>[***]</div>
          </td>
        </tr>
        <tr>
          <td nowrap="nowrap" style="width: 23.88%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div>[***]</div>
          </td>
          <td nowrap="nowrap" style="width: 6.95%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td nowrap="nowrap" style="width: 9%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
          <td nowrap="nowrap" style="width: 7.18%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
          <td nowrap="nowrap" style="width: 9.49%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
          <td nowrap="nowrap" style="width: 13%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td nowrap="nowrap" style="width: 11.49%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 20.36%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div>[***]</div>
          </td>
        </tr>
        <tr>
          <td nowrap="nowrap" style="width: 23.88%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div>[***]</div>
          </td>
          <td nowrap="nowrap" style="width: 6.95%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
          <td nowrap="nowrap" style="width: 9%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
          <td nowrap="nowrap" style="width: 7.18%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td nowrap="nowrap" style="width: 9.49%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
          <td nowrap="nowrap" style="width: 13%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
          <td nowrap="nowrap" style="width: 11.49%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
          <td nowrap="nowrap" style="width: 20.36%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
        </tr>
        <tr>
          <td nowrap="nowrap" style="width: 23.88%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div>[***]</div>
          </td>
          <td nowrap="nowrap" style="width: 6.95%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
          <td nowrap="nowrap" style="width: 9%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
          <td nowrap="nowrap" style="width: 7.18%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td nowrap="nowrap" style="width: 9.49%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
          <td nowrap="nowrap" style="width: 13%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
          <td nowrap="nowrap" style="width: 11.49%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
          <td nowrap="nowrap" style="width: 20.36%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
        </tr>
        <tr>
          <td nowrap="nowrap" style="width: 23.88%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div>[***]</div>
          </td>
          <td nowrap="nowrap" style="width: 6.95%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
          <td nowrap="nowrap" style="width: 9%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
          <td nowrap="nowrap" style="width: 7.18%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td nowrap="nowrap" style="width: 9.49%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td nowrap="nowrap" style="width: 13%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
          <td nowrap="nowrap" style="width: 11.49%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
          <td nowrap="nowrap" style="width: 20.36%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
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    </table>
    <div><font style="font-size: 10pt;"><br>
      </font> </div>
    <table cellspacing="0" cellpadding="0" border="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; border-collapse: collapse; text-align: left; color: #000000;" id="ze49f6e3abc974c858ae239c40b7e6d15">

        <tr>
          <td nowrap="nowrap" style="width: 23.88%; vertical-align: top; background-color: rgb(231, 230, 230); border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0) rgb(0, 0, 0) rgb(0, 0, 0) rgb(0, 0, 0);">
            <div>[***]</div>
          </td>
          <td nowrap="nowrap" colspan="7" style="vertical-align: top; background-color: rgb(231, 230, 230); border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0) rgb(0, 0, 0) rgb(0, 0, 0) rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
        </tr>
        <tr>
          <td nowrap="nowrap" style="width: 23.88%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
          <td nowrap="nowrap" style="width: 6.95%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div>[***]</div>
          </td>
          <td nowrap="nowrap" style="width: 9%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div>[***]</div>
          </td>
          <td nowrap="nowrap" style="width: 7.18%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div>[***]</div>
          </td>
          <td nowrap="nowrap" style="width: 9.49%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div>[***]</div>
          </td>
          <td nowrap="nowrap" style="width: 13%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div>[***]</div>
          </td>
          <td nowrap="nowrap" style="width: 11.49%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div>[***]</div>
          </td>
          <td nowrap="nowrap" style="width: 20.36%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div>[***]</div>
          </td>
        </tr>
        <tr>
          <td nowrap="nowrap" style="width: 23.88%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div>[***]</div>
          </td>
          <td nowrap="nowrap" style="width: 6.95%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td nowrap="nowrap" style="width: 9%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td nowrap="nowrap" style="width: 7.18%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td nowrap="nowrap" style="width: 9.49%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
          <td nowrap="nowrap" style="width: 13%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td nowrap="nowrap" style="width: 11.49%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 20.36%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div>[***]</div>
          </td>
        </tr>
        <tr>
          <td nowrap="nowrap" style="width: 23.88%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div>[***]</div>
          </td>
          <td nowrap="nowrap" style="width: 6.95%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
          <td nowrap="nowrap" style="width: 9%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td nowrap="nowrap" style="width: 7.18%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
          <td nowrap="nowrap" style="width: 9.49%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
          <td nowrap="nowrap" style="width: 13%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td nowrap="nowrap" style="width: 11.49%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 20.36%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div>[***]</div>
          </td>
        </tr>
        <tr>
          <td nowrap="nowrap" style="width: 23.88%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div>[***]</div>
          </td>
          <td nowrap="nowrap" style="width: 6.95%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
          <td nowrap="nowrap" style="width: 9%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td nowrap="nowrap" style="width: 7.18%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
          <td nowrap="nowrap" style="width: 9.49%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
          <td nowrap="nowrap" style="width: 13%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td nowrap="nowrap" style="width: 11.49%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td style="width: 20.36%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div>[***]</div>
          </td>
        </tr>
        <tr>
          <td nowrap="nowrap" style="width: 23.88%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div>[***]</div>
          </td>
          <td nowrap="nowrap" style="width: 6.95%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
          <td nowrap="nowrap" style="width: 9%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
          <td nowrap="nowrap" style="width: 7.18%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td nowrap="nowrap" style="width: 9.49%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
          <td nowrap="nowrap" style="width: 13%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td nowrap="nowrap" style="width: 11.49%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td nowrap="nowrap" style="width: 20.36%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
        </tr>
        <tr>
          <td nowrap="nowrap" style="width: 23.88%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div>[***]</div>
          </td>
          <td nowrap="nowrap" style="width: 6.95%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
          <td nowrap="nowrap" style="width: 9%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
          <td nowrap="nowrap" style="width: 7.18%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td nowrap="nowrap" style="width: 9.49%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
          <td nowrap="nowrap" style="width: 13%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
          <td nowrap="nowrap" style="width: 11.49%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
          <td nowrap="nowrap" style="width: 20.36%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
        </tr>
        <tr>
          <td nowrap="nowrap" style="width: 23.88%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div>[***]</div>
          </td>
          <td nowrap="nowrap" style="width: 6.95%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
          <td nowrap="nowrap" style="width: 9%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
          <td nowrap="nowrap" style="width: 7.18%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td nowrap="nowrap" style="width: 9.49%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td nowrap="nowrap" style="width: 13%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
          <td nowrap="nowrap" style="width: 11.49%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
          <td nowrap="nowrap" style="width: 20.36%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
        </tr>

    </table>
    <div><font style="font-size: 10pt;"><br>
      </font> </div>
    <table cellspacing="0" cellpadding="0" border="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; border-collapse: collapse; text-align: left; color: #000000;" id="za5af492e1b5c47b098991551f7f07039">

        <tr>
          <td nowrap="nowrap" style="width: 23.88%; vertical-align: top; background-color: rgb(231, 230, 230); border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0) rgb(0, 0, 0) rgb(0, 0, 0) rgb(0, 0, 0);">
            <div>[***]</div>
          </td>
          <td nowrap="nowrap" colspan="7" style="vertical-align: top; background-color: rgb(231, 230, 230); border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0) rgb(0, 0, 0) rgb(0, 0, 0) rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
        </tr>
        <tr>
          <td nowrap="nowrap" style="width: 23.88%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
          <td nowrap="nowrap" style="width: 6.95%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div>[***]</div>
          </td>
          <td nowrap="nowrap" style="width: 9%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div>[***]</div>
          </td>
          <td nowrap="nowrap" style="width: 7.18%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div>[***]</div>
          </td>
          <td nowrap="nowrap" style="width: 9.49%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div>[***]</div>
          </td>
          <td nowrap="nowrap" style="width: 13%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div>[***]</div>
          </td>
          <td nowrap="nowrap" style="width: 11.49%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div>[***]</div>
          </td>
          <td nowrap="nowrap" style="width: 20.36%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div>[***]</div>
          </td>
        </tr>
        <tr>
          <td nowrap="nowrap" style="width: 23.88%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div>[***]</div>
          </td>
          <td nowrap="nowrap" style="width: 6.95%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
          <td nowrap="nowrap" style="width: 9%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;">[***]</div>
          </td>
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</DOCUMENT>
<DOCUMENT>
<TYPE>EX-21.1
<SEQUENCE>7
<FILENAME>exhibit21-1.htm
<DESCRIPTION>EXHIBIT 21.1
<TEXT>
<html><head>
    <title>&nbsp;</title>
    <!-- Licensed to: Ionis Pharmaceuticals
         Document created using EDGARfilings PROfile 8.1.0.0
         Copyright 1995 - 2022 Broadridge -->
  </head><body style="font-family: 'Times New Roman'; font-size: 10pt;"><div id="TRGRSegment:f499a0ae-02f9-48a9-add8-20f1dcaf844d"><div style="text-align: right; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Exhibit&#160;21.1</div><div style="text-align: right; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#160;</div><div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">LIST OF SUBSIDIARIES FOR THE REGISTRANT</div><div><br></div><div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#160;</div><div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Akcea Therapeutics, Inc., a Delaware Corporation</div><div><br></div><div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Akcea Therapeutics Canada Inc., a Canadian Corporation</div><div><br></div><div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Akcea Therapeutics France SAS, a French Company</div><div><br></div><div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Akcea Therapeutics Germany GmbH, a German Corporation</div><div><br></div><div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Akcea Therapeutics UK Limited, a United Kingdom Limited Private Company</div><div><br></div><div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Akcea Securities Corporation., a Massachusetts Corporation</div><div><br></div><div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Akcea Therapeutics Ireland Limited, an Irish Private Company</div><div><br></div><div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Isis USA Limited, a United Kingdom Limited Private Company</div><div><br></div><div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Osprey Therapeutics, Inc., a Delaware Corporation</div><div><br></div><div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">PerIsis I Development Corporation, a Delaware Corporation*</div><div><br></div><div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Symphony GenIsis,&#160;Inc., a Delaware Corporation*</div><div><br></div><div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Ionis Development (Ireland) Limited, an Irish Private Company</div><div><br></div><div style="text-align: left;"><br></div><table style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;" class="DSPFListTable" cellpadding="0" cellspacing="0" id="zcb87dd2b7d504d188f50f1ea074e808f"><tr><td style="width: 18pt; vertical-align: top; align: right; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">*</td><td style="width: auto; vertical-align: top; text-align: left;"><div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;">PerIsis I Development Corporation and Symphony GenIsis,&#160;Inc. were dissolved in September 2021.</div></td></tr></table></div></body></html>
</TEXT>
</DOCUMENT>
<DOCUMENT>
<TYPE>EX-23.1
<SEQUENCE>8
<FILENAME>exhibit23-1.htm
<DESCRIPTION>EXHIBIT 23.1
<TEXT>
<html><head>
    <title>&nbsp;</title>
    <!-- Licensed to: Ionis Pharmaceuticals
         Document created using EDGARfilings PROfile 8.1.0.0
         Copyright 1995 - 2022 Broadridge -->
  </head><body style="font-family: 'Times New Roman'; font-size: 10pt;"><div id="TRGRSegment:b8cd2a2a-2f7b-470b-8887-e5b31a337448"><div style="text-align: right; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Exhibit 23.1</div><div style="text-align: center;"><br></div><div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">CONSENT OF INDEPENDENT REGISTERED PUBLIC ACCOUNTING FIRM</div><div><br></div><div style="text-align: justify; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We consent to the incorporation by reference in the Registration Statements on Form S-3 (Nos. 333-71911, 333-90811, 333-38844, 333-71116, 333-71176, 333-89066, 333-89626, 333-128156, 333-130639, 333-134380, 333-141447, 333-151076, 333-188407, 333-217422 and 333-242382) and in the related Prospectuses, as applicable, and in the Registration Statements on Form S-8 (Nos.333-05825, 333-55683, 333-40336, 333-59296, 333-91572, 333-106859, 333-116962, 333-125911, 333-133853, 333-142777, 333-151996, 333-160269, 333-168674, 333-176136, 333-184788, 333-190408, 333-207900, 333-219801, 333-233143, 333-242386, 333-251855, and 333-258503) of Ionis Pharmaceuticals, Inc. of our reports dated February 24, 2022, with respect to the consolidated financial statements of Ionis Pharmaceuticals, Inc. and the effectiveness of internal control over financial reporting of Ionis Pharmaceuticals, Inc. included in this Annual Report (Form 10-K) for the year ended December 31, 2021.</div><div style="text-align: left;"><br></div><table cellpadding="0" cellspacing="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; border-collapse: collapse; text-align: left; color: #000000;" id="z45676a44d2a54b39a1bb63197794f671"><tr><td style="width: 50.57%; vertical-align: top;">&#160;</td><td style="width: 49.43%; vertical-align: top;"><div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">/s/ ERNST &amp; YOUNG LLP</div></td></tr><tr><td style="width: 50.57%; vertical-align: top;">&#160;</td><td style="width: 49.43%; vertical-align: top;">&#160;</td></tr><tr><td style="width: 50.57%; vertical-align: top;"><div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">San Diego, California</div></td><td style="width: 49.43%; vertical-align: top;">&#160;</td></tr><tr><td style="width: 50.57%; vertical-align: top;"><div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">February 24, 2022</div></td><td style="width: 49.43%; vertical-align: top;">&#160;</td></tr></table><div style="text-align: left;"><br></div></div></body></html>
</TEXT>
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<DOCUMENT>
<TYPE>EX-31.1
<SEQUENCE>9
<FILENAME>exhibit31-1.htm
<DESCRIPTION>EXHIBIT 31.1
<TEXT>
<html><head>
    <title>&nbsp;</title>
    <!-- Licensed to: Ionis Pharmaceuticals
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  </head><body style="font-family: 'Times New Roman'; font-size: 10pt;"><div id="TRGRSegment:27688458-8a95-448c-9822-a3a5e0da6065"><div style="text-align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Exhibit 31.1</div><div><br></div><div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">CERTIFICATION</div><div><br></div><div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">I, Brett P. Monia, certify that:</div><div><br></div><table style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;" class="DSPFListTable" cellpadding="0" cellspacing="0" id="z20a83f0e2de7427c92e85a1aba37a65d"><tr><td style="width: 27pt; vertical-align: top; align: right;"><div style="text-align: left; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">1.</div></td><td style="width: auto; vertical-align: top;"><div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">I have reviewed this Annual Report on Form 10-K of Ionis Pharmaceuticals, Inc.;</div></td></tr></table><div><br></div><table style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;" class="DSPFListTable" cellpadding="0" cellspacing="0" id="zd6924914dab7409aa32d28ebe3b01176"><tr><td style="width: 27pt; vertical-align: top; align: right;"><div style="text-align: left; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">2.</div></td><td style="width: auto; vertical-align: top;"><div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Based on my knowledge, this annual report does not contain any untrue statement of a material fact or omit to state a material fact necessary to make the statements made, in light of the circumstances under which such statements were made, not misleading with respect to the period covered by this annual report;</div></td></tr></table><div><br></div><table style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;" class="DSPFListTable" cellpadding="0" cellspacing="0" id="zf71deda223cb4e1c84564834d0a4acdc"><tr><td style="width: 27pt; vertical-align: top; align: right;"><div style="text-align: left; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">3.</div></td><td style="width: auto; vertical-align: top;"><div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Based on my knowledge, the consolidated financial statements, and other financial information included in this annual report, fairly present in all material respects the financial condition, consolidated results of operations and consolidated cash flows of the registrant as of, and for, the periods presented in this annual report;</div></td></tr></table><div><br></div><table style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;" class="DSPFListTable" cellpadding="0" cellspacing="0" id="z599b53b63b074f2cafa19fd0a5dafeea"><tr><td style="width: 27pt; vertical-align: top; align: right;"><div style="text-align: left; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">4.</div></td><td style="width: auto; vertical-align: top;"><div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">The registrant&#8217;s other certifying officer and I are responsible for establishing and maintaining disclosure controls and procedures (as defined in Exchange Act Rules 13a-15(e) and 15d-15(e)) and internal control over financial reporting (as defined in Exchange Act Rules 13a-15(f) and 15d-15(f)) for the registrant and have:</div></td></tr></table><div><br></div><table style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;" class="DSPFListTable" cellpadding="0" cellspacing="0" id="z96257ca9ff264a61a1f5f9755dfa1270"><tr><td style="width: 45pt; vertical-align: top; align: right;"><div style="text-align: left; margin-left: 27pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">a)</div></td><td style="width: auto; vertical-align: top;"><div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Designed such disclosure controls and procedures, or caused such disclosure controls and procedures to be designed under our supervision, to ensure that material information relating to the registrant, including its consolidated subsidiaries, is made known to us by others within those entities, particularly during the period in which this report is being prepared;</div></td></tr></table><div><br></div><table style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;" class="DSPFListTable" cellpadding="0" cellspacing="0" id="zbf38aae1cd8443b8b2c1091e8ce69a52"><tr><td style="width: 45pt; vertical-align: top; align: right;"><div style="text-align: left; margin-left: 27pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">b)</div></td><td style="width: auto; vertical-align: top;"><div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Designed such internal control over financial reporting, or caused such internal control over financial reporting to be designed under our supervision, to provide reasonable assurance regarding the reliability of financial reporting and the preparation of financial statements for external purposes in accordance with generally accepted accounting principles;</div></td></tr></table><div><br></div><table style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;" class="DSPFListTable" cellpadding="0" cellspacing="0" id="zad8a679ce3a94cf4a4bc5b51abb6bd7c"><tr><td style="width: 45pt; vertical-align: top; align: right;"><div style="text-align: left; margin-left: 27pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">c)</div></td><td style="width: auto; vertical-align: top;"><div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Evaluated the effectiveness of the registrant&#8217;s disclosure controls and procedures and presented in this report our conclusions about the effectiveness of the disclosure controls and procedures, as of the end of the period covered by this report based on such evaluation; and</div></td></tr></table><div><br></div><table style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;" class="DSPFListTable" cellpadding="0" cellspacing="0" id="z0dbaf40cecef4b4fbf3b661f24ce3554"><tr><td style="width: 45pt; vertical-align: top; align: right;"><div style="text-align: left; margin-left: 27pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">d)</div></td><td style="width: auto; vertical-align: top;"><div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Disclosed in this report any change in the registrant&#8217;s internal control over financial reporting that occurred during the registrant&#8217;s most recent fiscal quarter (the registrant&#8217;s fourth fiscal quarter in the case of an annual report) that has materially affected, or is reasonably likely to materially affect, the registrant&#8217;s internal control over financial reporting; and</div></td></tr></table><div><br></div><table style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;" class="DSPFListTable" cellpadding="0" cellspacing="0" id="zda198ca9a7864206a71e1a319e497590"><tr><td style="width: 27pt; 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font-family: 'Times New Roman', Times, serif; font-size: 10pt;">a)</div></td><td style="width: auto; vertical-align: top;"><div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">All significant deficiencies and material weaknesses in the design or operation of internal control over financial reporting which are reasonably likely to adversely affect the registrant&#8217;s ability to record, process, summarize and report financial information; and</div></td></tr></table><div><br></div><table style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;" class="DSPFListTable" cellpadding="0" cellspacing="0" id="z1b027b9522114bd7987d7e816f6ce862"><tr><td style="width: 45pt; vertical-align: top; align: right;"><div style="text-align: left; margin-left: 27pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">b)</div></td><td style="width: auto; vertical-align: top;"><div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Any fraud, whether or not material, that involves management or other employees who have a significant role in the registrant&#8217;s internal control over financial reporting.</div></td></tr></table><div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#160;&#160;</div><table cellpadding="0" cellspacing="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; border-collapse: collapse; text-align: left; color: #000000;" id="z873c5b848cf6475f9ca8fce54d015680"><tr><td style="width: 41.41%; vertical-align: top;"><div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Dated: February 24, 2022</div></td><td style="width: 58.59%; vertical-align: top;"><div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#160;</div></td></tr><tr><td style="width: 41.41%; vertical-align: top;"><div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#160;</div></td><td style="width: 58.59%; vertical-align: top;"><div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#160;</div></td></tr><tr><td style="width: 41.41%; vertical-align: top; border-bottom: #000000 2px solid;"><div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">/s/ BRETT P. MONIA</div></td><td style="width: 58.59%; vertical-align: top;"><div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#160;</div></td></tr><tr><td style="width: 41.41%; vertical-align: top;"><div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Brett P. Monia, Ph.D.</div></td><td style="width: 58.59%; vertical-align: top;"><div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#160;</div></td></tr><tr><td style="width: 41.41%; vertical-align: top;"><div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;">Chief Executive Officer</div></td><td style="width: 58.59%; vertical-align: top;"><div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#160;</div></td></tr></table><div><br></div></div></body></html>
</TEXT>
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<DOCUMENT>
<TYPE>EX-31.2
<SEQUENCE>10
<FILENAME>exhibit31-2.htm
<DESCRIPTION>EXHIBIT 31.2
<TEXT>
<html><head>
    <title>&nbsp;</title>
    <!-- Licensed to: Ionis Pharmaceuticals
         Document created using EDGARfilings PROfile 8.1.0.0
         Copyright 1995 - 2022 Broadridge -->
  </head><body style="font-family: 'Times New Roman'; font-size: 10pt;"><div id="TRGRSegment:f325a129-9b94-442a-a705-509884803066"><div style="text-align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Exhibit 31.2</div><div><br></div><div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">CERTIFICATION</div><div><br></div><div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">I, Elizabeth L. Hougen, certify that:</div><div><br></div><table style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;" class="DSPFListTable" cellpadding="0" cellspacing="0" id="z0e20d083664f44cfa88da1f1f176e8e6"><tr><td style="width: 27pt; vertical-align: top; align: right;"><div style="text-align: left; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">1.</div></td><td style="width: auto; vertical-align: top;"><div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">I have reviewed this Annual Report on Form 10-K of Ionis Pharmaceuticals, Inc.;</div></td></tr></table><div><br></div><table style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;" class="DSPFListTable" cellpadding="0" cellspacing="0" id="z3d06033c234e4cedb9178477b2cc18d9"><tr><td style="width: 27pt; vertical-align: top; align: right;"><div style="text-align: left; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">2.</div></td><td style="width: auto; vertical-align: top;"><div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Based on my knowledge, this annual report does not contain any untrue statement of a material fact or omit to state a material fact necessary to make the statements made, in light of the circumstances under which such statements were made, not misleading with respect to the period covered by this annual report;</div></td></tr></table><div><br></div><table style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;" class="DSPFListTable" cellpadding="0" cellspacing="0" id="ze8e545e8927045e18461dc6d8c3c1c7d"><tr><td style="width: 27pt; vertical-align: top; align: right;"><div style="text-align: left; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">3.</div></td><td style="width: auto; vertical-align: top;"><div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Based on my knowledge, the consolidated financial statements, and other financial information included in this annual report, fairly present in all material respects the financial condition, consolidated results of operations and consolidated cash flows of the registrant as of, and for, the periods presented in this annual report;</div></td></tr></table><div><br></div><table style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;" class="DSPFListTable" cellpadding="0" cellspacing="0" id="z632155da1c89436392b2a977bb7b3861"><tr><td style="width: 27pt; vertical-align: top; align: right;"><div style="text-align: left; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">4.</div></td><td style="width: auto; vertical-align: top;"><div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">The registrant&#8217;s other certifying officer and I are responsible for establishing and maintaining disclosure controls and procedures (as defined in Exchange Act Rules 13a-15(e) and 15d-15(e)) and internal control over financial reporting (as defined in Exchange Act Rules 13a-15(f) and 15d-15(f)) for the registrant and have:</div></td></tr></table><div><br></div><table style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;" class="DSPFListTable" cellpadding="0" cellspacing="0" id="zf989b9810a1a4cc2a92947fa4cc437e0"><tr><td style="width: 45pt; vertical-align: top; align: right;"><div style="text-align: left; margin-left: 27pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">a)</div></td><td style="width: auto; vertical-align: top;"><div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Designed such disclosure controls and procedures, or caused such disclosure controls and procedures to be designed under our supervision, to ensure that material information relating to the registrant, including its consolidated subsidiaries, is made known to us by others within those entities, particularly during the period in which this report is being prepared;</div></td></tr></table><div><br></div><table style="font-family: 'Times New Roman'; 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color: #000000;" class="DSPFListTable" cellpadding="0" cellspacing="0" id="z373ab9374db649a1b676f7591c05074e"><tr><td style="width: 45pt; vertical-align: top; align: right;"><div style="text-align: left; margin-left: 27pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">c)</div></td><td style="width: auto; vertical-align: top;"><div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Evaluated the effectiveness of the registrant&#8217;s disclosure controls and procedures and presented in this report our conclusions about the effectiveness of the disclosure controls and procedures, as of the end of the period covered by this report based on such evaluation; and</div></td></tr></table><div><br></div><table style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;" class="DSPFListTable" cellpadding="0" cellspacing="0" id="zba46f7a1d6b2461eba3092d63aa3b171"><tr><td style="width: 45pt; vertical-align: top; align: right;"><div style="text-align: left; margin-left: 27pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">d)</div></td><td style="width: auto; vertical-align: top;"><div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Disclosed in this report any change in the registrant&#8217;s internal control over financial reporting that occurred during the registrant&#8217;s most recent fiscal quarter (the registrant&#8217;s fourth fiscal quarter in the case of an annual report) that has materially affected, or is reasonably likely to materially affect, the registrant&#8217;s internal control over financial reporting; and</div></td></tr></table><div><br></div><table style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;" class="DSPFListTable" cellpadding="0" cellspacing="0" id="zb8d651bbdea1470d989307efb4024d11"><tr><td style="width: 27pt; 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        <link:usedOn>link:calculationLink</link:usedOn>
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      <link:roleType roleURI="http://ionispharma.com/role/AkceaMergerTables" id="AkceaMergerTables">
        <!--Parent Role: Akcea Merger-->
        <link:definition>080700 - Disclosure - Akcea Merger (Tables)</link:definition>
        <link:usedOn>link:presentationLink</link:usedOn>
        <link:usedOn>link:calculationLink</link:usedOn>
        <link:usedOn>link:definitionLink</link:usedOn>
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      <link:roleType roleURI="http://ionispharma.com/role/SeveranceAndRetentionCostsRelatedToOurRestructuredOperationsTables" id="SeveranceAndRetentionCostsRelatedToOurRestructuredOperationsTables">
        <!--Parent Role: Severance and Retention Costs related to our Restructured Operations-->
        <link:definition>080800 - Disclosure - Severance and Retention Costs related to our Restructured Operations (Tables)</link:definition>
        <link:usedOn>link:presentationLink</link:usedOn>
        <link:usedOn>link:calculationLink</link:usedOn>
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      <link:roleType roleURI="http://ionispharma.com/role/FourthQuarterFinancialDataUnauditedTables" id="FourthQuarterFinancialDataUnauditedTables">
        <!--Parent Role: Fourth Quarter Financial Data (Unaudited)-->
        <link:definition>081100 - Disclosure - Fourth Quarter Financial Data (Unaudited) (Tables)</link:definition>
        <link:usedOn>link:presentationLink</link:usedOn>
        <link:usedOn>link:calculationLink</link:usedOn>
        <link:usedOn>link:definitionLink</link:usedOn>
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        <!--Parent Role: Organization and Significant Accounting Policies-->
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        <link:usedOn>link:calculationLink</link:usedOn>
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        <!--Parent Role: Organization and Significant Accounting Policies-->
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        <!--Parent Role: Organization and Significant Accounting Policies-->
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        <link:usedOn>link:calculationLink</link:usedOn>
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      <link:roleType roleURI="http://ionispharma.com/role/OrganizationAndSignificantAccountingPoliciesRevenueRecognitionDetails" id="OrganizationAndSignificantAccountingPoliciesRevenueRecognitionDetails">
        <!--Parent Role: Organization and Significant Accounting Policies-->
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        <!--Parent Role: Organization and Significant Accounting Policies-->
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        <link:usedOn>link:presentationLink</link:usedOn>
        <link:usedOn>link:calculationLink</link:usedOn>
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        <link:usedOn>link:presentationLink</link:usedOn>
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      <link:roleType roleURI="http://ionispharma.com/role/InvestmentsSummaryOfInvestmentsDetailsCalc2" id="InvestmentsSummaryOfInvestmentsDetailsCalc2">
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        <link:usedOn>link:presentationLink</link:usedOn>
        <link:usedOn>link:calculationLink</link:usedOn>
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        <link:usedOn>link:presentationLink</link:usedOn>
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        <link:usedOn>link:presentationLink</link:usedOn>
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        <link:usedOn>link:presentationLink</link:usedOn>
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        <link:usedOn>link:presentationLink</link:usedOn>
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        <link:usedOn>link:presentationLink</link:usedOn>
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        <link:usedOn>link:presentationLink</link:usedOn>
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        <link:usedOn>link:presentationLink</link:usedOn>
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<SEQUENCE>15
<FILENAME>ions-20211231_lab.xml
<DESCRIPTION>XBRL TAXONOMY EXTENSION LABEL LINKBASE
<TEXT>
<XBRL>
<?xml version="1.0" encoding="us-ascii"?>
<!--Generated by EDGARfilings PROfile 8.0.0.0 Broadridge-->
<link:linkbase xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" xsi:schemaLocation="http://www.xbrl.org/2003/linkbase http://www.xbrl.org/2003/xbrl-linkbase-2003-12-31.xsd" xmlns:link="http://www.xbrl.org/2003/linkbase" xmlns:xlink="http://www.w3.org/1999/xlink" xmlns:xbrli="http://www.xbrl.org/2003/instance">
  <link:roleRef roleURI="http://www.xbrl.org/2009/role/netLabel" xlink:type="simple" xlink:href="http://www.xbrl.org/lrr/role/net-2009-12-16.xsd#netLabel" />
  <link:roleRef roleURI="http://www.xbrl.org/2009/role/negatedTotalLabel" xlink:type="simple" xlink:href="http://www.xbrl.org/lrr/role/negated-2009-12-16.xsd#negatedTotalLabel" />
  <link:roleRef roleURI="http://www.xbrl.org/2009/role/negatedNetLabel" xlink:type="simple" xlink:href="http://www.xbrl.org/lrr/role/negated-2009-12-16.xsd#negatedNetLabel" />
  <link:roleRef roleURI="http://www.xbrl.org/2009/role/negatedTerseLabel" xlink:type="simple" xlink:href="http://www.xbrl.org/lrr/role/negated-2009-12-16.xsd#negatedTerseLabel" />
  <link:roleRef roleURI="http://www.xbrl.org/2009/role/negatedPeriodEndLabel" xlink:type="simple" xlink:href="http://www.xbrl.org/lrr/role/negated-2009-12-16.xsd#negatedPeriodEndLabel" />
  <link:roleRef roleURI="http://www.xbrl.org/2009/role/negatedPeriodStartLabel" xlink:type="simple" xlink:href="http://www.xbrl.org/lrr/role/negated-2009-12-16.xsd#negatedPeriodStartLabel" />
  <link:roleRef roleURI="http://www.xbrl.org/2009/role/negatedLabel" xlink:type="simple" xlink:href="http://www.xbrl.org/lrr/role/negated-2009-12-16.xsd#negatedLabel" />
  <link:labelLink xlink:type="extended" xlink:role="http://www.xbrl.org/2003/role/link">
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_AociIncludingPortionAttributableToNoncontrollingInterestMember" xlink:label="AociIncludingPortionAttributableToNoncontrollingInterestMember" xlink:title="AociIncludingPortionAttributableToNoncontrollingInterestMember" />
    <link:label xlink:type="resource" xlink:label="us-gaap_AociIncludingPortionAttributableToNoncontrollingInterestMember_lbl" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="us-gaap_AociIncludingPortionAttributableToNoncontrollingInterestMember_lbl" xml:lang="en-US" id="us-gaap_AociIncludingPortionAttributableToNoncontrollingInterestMember_lbl">Accumulated Other Comprehensive Loss [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="AociIncludingPortionAttributableToNoncontrollingInterestMember" xlink:to="us-gaap_AociIncludingPortionAttributableToNoncontrollingInterestMember_lbl" xlink:title="label: AociIncludingPortionAttributableToNoncontrollingInterestMember to us-gaap_AociIncludingPortionAttributableToNoncontrollingInterestMember_lbl" />
    <link:label xlink:type="resource" xlink:label="us-gaap_AociIncludingPortionAttributableToNoncontrollingInterestMember_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_AociIncludingPortionAttributableToNoncontrollingInterestMember_lbl1" xml:lang="en-US" id="us-gaap_AociIncludingPortionAttributableToNoncontrollingInterestMember_lbl1">AOCI Including Portion Attributable to Noncontrolling Interest [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="AociIncludingPortionAttributableToNoncontrollingInterestMember" xlink:to="us-gaap_AociIncludingPortionAttributableToNoncontrollingInterestMember_lbl1" xlink:title="label: AociIncludingPortionAttributableToNoncontrollingInterestMember to us-gaap_AociIncludingPortionAttributableToNoncontrollingInterestMember_lbl1" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_AwardDateAxis" xlink:label="AwardDateAxis" xlink:title="AwardDateAxis" />
    <link:label xlink:type="resource" xlink:label="us-gaap_AwardDateAxis_lbl" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_AwardDateAxis_lbl" xml:lang="en-US" id="us-gaap_AwardDateAxis_lbl">Award Date [Axis]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="AwardDateAxis" xlink:to="us-gaap_AwardDateAxis_lbl" xlink:title="label: AwardDateAxis to us-gaap_AwardDateAxis_lbl" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_AwardDateDomain" xlink:label="AwardDateDomain" xlink:title="AwardDateDomain" />
    <link:label xlink:type="resource" xlink:label="us-gaap_AwardDateDomain_lbl" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_AwardDateDomain_lbl" xml:lang="en-US" id="us-gaap_AwardDateDomain_lbl">Award Date [Domain]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="AwardDateDomain" xlink:to="us-gaap_AwardDateDomain_lbl" xlink:title="label: AwardDateDomain to us-gaap_AwardDateDomain_lbl" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_AwardTypeAxis" xlink:label="AwardTypeAxis" xlink:title="AwardTypeAxis" />
    <link:label xlink:type="resource" xlink:label="us-gaap_AwardTypeAxis_lbl" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_AwardTypeAxis_lbl" xml:lang="en-US" id="us-gaap_AwardTypeAxis_lbl">Award Type [Axis]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="AwardTypeAxis" xlink:to="us-gaap_AwardTypeAxis_lbl" xlink:title="label: AwardTypeAxis to us-gaap_AwardTypeAxis_lbl" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_ArrangementsAndNonarrangementTransactionsMember" xlink:label="ArrangementsAndNonarrangementTransactionsMember" xlink:title="ArrangementsAndNonarrangementTransactionsMember" />
    <link:label xlink:type="resource" xlink:label="us-gaap_ArrangementsAndNonarrangementTransactionsMember_lbl" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_ArrangementsAndNonarrangementTransactionsMember_lbl" xml:lang="en-US" id="us-gaap_ArrangementsAndNonarrangementTransactionsMember_lbl">Arrangements and Non-arrangement Transactions [Domain]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="ArrangementsAndNonarrangementTransactionsMember" xlink:to="us-gaap_ArrangementsAndNonarrangementTransactionsMember_lbl" xlink:title="label: ArrangementsAndNonarrangementTransactionsMember to us-gaap_ArrangementsAndNonarrangementTransactionsMember_lbl" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_AccountingStandardsUpdate202006Member" xlink:label="AccountingStandardsUpdate202006Member" xlink:title="AccountingStandardsUpdate202006Member" />
    <link:label xlink:type="resource" xlink:label="us-gaap_AccountingStandardsUpdate202006Member_lbl" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="us-gaap_AccountingStandardsUpdate202006Member_lbl" xml:lang="en-US" id="us-gaap_AccountingStandardsUpdate202006Member_lbl">ASU 2020-06 [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="AccountingStandardsUpdate202006Member" xlink:to="us-gaap_AccountingStandardsUpdate202006Member_lbl" xlink:title="label: AccountingStandardsUpdate202006Member to us-gaap_AccountingStandardsUpdate202006Member_lbl" />
    <link:label xlink:type="resource" xlink:label="us-gaap_AccountingStandardsUpdate202006Member_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_AccountingStandardsUpdate202006Member_lbl1" xml:lang="en-US" id="us-gaap_AccountingStandardsUpdate202006Member_lbl1">Accounting Standards Update 2020-06 [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="AccountingStandardsUpdate202006Member" xlink:to="us-gaap_AccountingStandardsUpdate202006Member_lbl1" xlink:title="label: AccountingStandardsUpdate202006Member to us-gaap_AccountingStandardsUpdate202006Member_lbl1" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_AccountsPayableCurrent" xlink:label="AccountsPayableCurrent" xlink:title="AccountsPayableCurrent" />
    <link:label xlink:type="resource" xlink:label="us-gaap_AccountsPayableCurrent_lbl" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="us-gaap_AccountsPayableCurrent_lbl" xml:lang="en-US" id="us-gaap_AccountsPayableCurrent_lbl">Accounts payable</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="AccountsPayableCurrent" xlink:to="us-gaap_AccountsPayableCurrent_lbl" xlink:title="label: AccountsPayableCurrent to us-gaap_AccountsPayableCurrent_lbl" />
    <link:label xlink:type="resource" xlink:label="us-gaap_AccountsPayableCurrent_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_AccountsPayableCurrent_lbl1" xml:lang="en-US" id="us-gaap_AccountsPayableCurrent_lbl1">Accounts Payable, Current</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="AccountsPayableCurrent" xlink:to="us-gaap_AccountsPayableCurrent_lbl1" xlink:title="label: AccountsPayableCurrent to us-gaap_AccountsPayableCurrent_lbl1" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_AccountsReceivableMember" xlink:label="AccountsReceivableMember" xlink:title="AccountsReceivableMember" />
    <link:label xlink:type="resource" xlink:label="us-gaap_AccountsReceivableMember_lbl" xlink:role="http://www.xbrl.org/2003/role/verboseLabel" xlink:title="us-gaap_AccountsReceivableMember_lbl" xml:lang="en-US" id="us-gaap_AccountsReceivableMember_lbl">Contracts Receivables [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="AccountsReceivableMember" xlink:to="us-gaap_AccountsReceivableMember_lbl" xlink:title="label: AccountsReceivableMember to us-gaap_AccountsReceivableMember_lbl" />
    <link:label xlink:type="resource" xlink:label="us-gaap_AccountsReceivableMember_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_AccountsReceivableMember_lbl1" xml:lang="en-US" id="us-gaap_AccountsReceivableMember_lbl1">Accounts Receivable [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="AccountsReceivableMember" xlink:to="us-gaap_AccountsReceivableMember_lbl1" xlink:title="label: AccountsReceivableMember to us-gaap_AccountsReceivableMember_lbl1" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_AccretionAmortizationOfDiscountsAndPremiumsInvestments" xlink:label="AccretionAmortizationOfDiscountsAndPremiumsInvestments" xlink:title="AccretionAmortizationOfDiscountsAndPremiumsInvestments" />
    <link:label xlink:type="resource" xlink:label="us-gaap_AccretionAmortizationOfDiscountsAndPremiumsInvestments_lbl" xlink:role="http://www.xbrl.org/2009/role/negatedLabel" xlink:title="us-gaap_AccretionAmortizationOfDiscountsAndPremiumsInvestments_lbl" xml:lang="en-US" id="us-gaap_AccretionAmortizationOfDiscountsAndPremiumsInvestments_lbl">Amortization of premium (discount) on investments, net</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="AccretionAmortizationOfDiscountsAndPremiumsInvestments" xlink:to="us-gaap_AccretionAmortizationOfDiscountsAndPremiumsInvestments_lbl" xlink:title="label: AccretionAmortizationOfDiscountsAndPremiumsInvestments to us-gaap_AccretionAmortizationOfDiscountsAndPremiumsInvestments_lbl" />
    <link:label xlink:type="resource" xlink:label="us-gaap_AccretionAmortizationOfDiscountsAndPremiumsInvestments_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_AccretionAmortizationOfDiscountsAndPremiumsInvestments_lbl1" xml:lang="en-US" id="us-gaap_AccretionAmortizationOfDiscountsAndPremiumsInvestments_lbl1">Accretion (Amortization) of Discounts and Premiums, Investments</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="AccretionAmortizationOfDiscountsAndPremiumsInvestments" xlink:to="us-gaap_AccretionAmortizationOfDiscountsAndPremiumsInvestments_lbl1" xlink:title="label: AccretionAmortizationOfDiscountsAndPremiumsInvestments to us-gaap_AccretionAmortizationOfDiscountsAndPremiumsInvestments_lbl1" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_AccruedLiabilitiesCurrent" xlink:label="AccruedLiabilitiesCurrent" xlink:title="AccruedLiabilitiesCurrent" />
    <link:label xlink:type="resource" xlink:label="us-gaap_AccruedLiabilitiesCurrent_lbl" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="us-gaap_AccruedLiabilitiesCurrent_lbl" xml:lang="en-US" id="us-gaap_AccruedLiabilitiesCurrent_lbl">Accrued liabilities</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="AccruedLiabilitiesCurrent" xlink:to="us-gaap_AccruedLiabilitiesCurrent_lbl" xlink:title="label: AccruedLiabilitiesCurrent to us-gaap_AccruedLiabilitiesCurrent_lbl" />
    <link:label xlink:type="resource" xlink:label="us-gaap_AccruedLiabilitiesCurrent_lbl1" xlink:role="http://www.xbrl.org/2003/role/totalLabel" xlink:title="us-gaap_AccruedLiabilitiesCurrent_lbl1" xml:lang="en-US" id="us-gaap_AccruedLiabilitiesCurrent_lbl1">Total accrued liabilities</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="AccruedLiabilitiesCurrent" xlink:to="us-gaap_AccruedLiabilitiesCurrent_lbl1" xlink:title="label: AccruedLiabilitiesCurrent to us-gaap_AccruedLiabilitiesCurrent_lbl1" />
    <link:label xlink:type="resource" xlink:label="us-gaap_AccruedLiabilitiesCurrent_lbl2" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_AccruedLiabilitiesCurrent_lbl2" xml:lang="en-US" id="us-gaap_AccruedLiabilitiesCurrent_lbl2">Accrued Liabilities, Current</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="AccruedLiabilitiesCurrent" xlink:to="us-gaap_AccruedLiabilitiesCurrent_lbl2" xlink:title="label: AccruedLiabilitiesCurrent to us-gaap_AccruedLiabilitiesCurrent_lbl2" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_AccruedLiabilitiesCurrentAbstract" xlink:label="AccruedLiabilitiesCurrentAbstract" xlink:title="AccruedLiabilitiesCurrentAbstract" />
    <link:label xlink:type="resource" xlink:label="us-gaap_AccruedLiabilitiesCurrentAbstract_lbl" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="us-gaap_AccruedLiabilitiesCurrentAbstract_lbl" xml:lang="en-US" id="us-gaap_AccruedLiabilitiesCurrentAbstract_lbl">Accrued Liabilities [Abstract]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="AccruedLiabilitiesCurrentAbstract" xlink:to="us-gaap_AccruedLiabilitiesCurrentAbstract_lbl" xlink:title="label: AccruedLiabilitiesCurrentAbstract to us-gaap_AccruedLiabilitiesCurrentAbstract_lbl" />
    <link:label xlink:type="resource" xlink:label="us-gaap_AccruedLiabilitiesCurrentAbstract_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_AccruedLiabilitiesCurrentAbstract_lbl1" xml:lang="en-US" id="us-gaap_AccruedLiabilitiesCurrentAbstract_lbl1">Accrued Liabilities, Current [Abstract]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="AccruedLiabilitiesCurrentAbstract" xlink:to="us-gaap_AccruedLiabilitiesCurrentAbstract_lbl1" xlink:title="label: AccruedLiabilitiesCurrentAbstract to us-gaap_AccruedLiabilitiesCurrentAbstract_lbl1" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_AccruedIncomeTaxesCurrent" xlink:label="AccruedIncomeTaxesCurrent" xlink:title="AccruedIncomeTaxesCurrent" />
    <link:label xlink:type="resource" xlink:label="us-gaap_AccruedIncomeTaxesCurrent_lbl" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="us-gaap_AccruedIncomeTaxesCurrent_lbl" xml:lang="en-US" id="us-gaap_AccruedIncomeTaxesCurrent_lbl">Income taxes payable</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="AccruedIncomeTaxesCurrent" xlink:to="us-gaap_AccruedIncomeTaxesCurrent_lbl" xlink:title="label: AccruedIncomeTaxesCurrent to us-gaap_AccruedIncomeTaxesCurrent_lbl" />
    <link:label xlink:type="resource" xlink:label="us-gaap_AccruedIncomeTaxesCurrent_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_AccruedIncomeTaxesCurrent_lbl1" xml:lang="en-US" id="us-gaap_AccruedIncomeTaxesCurrent_lbl1">Accrued Income Taxes, Current</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="AccruedIncomeTaxesCurrent" xlink:to="us-gaap_AccruedIncomeTaxesCurrent_lbl1" xlink:title="label: AccruedIncomeTaxesCurrent to us-gaap_AccruedIncomeTaxesCurrent_lbl1" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_AccumulatedNetInvestmentGainLossIncludingPortionAttributableToNoncontrollingInterestMember" xlink:label="AccumulatedNetInvestmentGainLossIncludingPortionAttributableToNoncontrollingInterestMember" xlink:title="AccumulatedNetInvestmentGainLossIncludingPortionAttributableToNoncontrollingInterestMember" />
    <link:label xlink:type="resource" xlink:label="us-gaap_AccumulatedNetInvestmentGainLossIncludingPortionAttributableToNoncontrollingInterestMember_lbl" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="us-gaap_AccumulatedNetInvestmentGainLossIncludingPortionAttributableToNoncontrollingInterestMember_lbl" xml:lang="en-US" id="us-gaap_AccumulatedNetInvestmentGainLossIncludingPortionAttributableToNoncontrollingInterestMember_lbl">Unrealized Gains (Losses) on Securities [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="AccumulatedNetInvestmentGainLossIncludingPortionAttributableToNoncontrollingInterestMember" xlink:to="us-gaap_AccumulatedNetInvestmentGainLossIncludingPortionAttributableToNoncontrollingInterestMember_lbl" xlink:title="label: AccumulatedNetInvestmentGainLossIncludingPortionAttributableToNoncontrollingInterestMember to us-gaap_AccumulatedNetInvestmentGainLossIncludingPortionAttributableToNoncontrollingInterestMember_lbl" />
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    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="AccumulatedNetInvestmentGainLossIncludingPortionAttributableToNoncontrollingInterestMember" xlink:to="us-gaap_AccumulatedNetInvestmentGainLossIncludingPortionAttributableToNoncontrollingInterestMember_lbl1" xlink:title="label: AccumulatedNetInvestmentGainLossIncludingPortionAttributableToNoncontrollingInterestMember to us-gaap_AccumulatedNetInvestmentGainLossIncludingPortionAttributableToNoncontrollingInterestMember_lbl1" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_AccumulatedOtherComprehensiveIncomeLossTable" xlink:label="AccumulatedOtherComprehensiveIncomeLossTable" xlink:title="AccumulatedOtherComprehensiveIncomeLossTable" />
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    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="ClassOfStockDisclosuresAbstract" xlink:to="us-gaap_ClassOfStockDisclosuresAbstract_lbl1" xlink:title="label: ClassOfStockDisclosuresAbstract to us-gaap_ClassOfStockDisclosuresAbstract_lbl1" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_CollaborativeArrangementDisclosureTextBlock" xlink:label="CollaborativeArrangementDisclosureTextBlock" xlink:title="CollaborativeArrangementDisclosureTextBlock" />
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    <link:label xlink:type="resource" xlink:label="us-gaap_ContractualObligationDueAfterFifthYear_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_ContractualObligationDueAfterFifthYear_lbl1" xml:lang="en-US" id="us-gaap_ContractualObligationDueAfterFifthYear_lbl1">Contractual Obligation, to be Paid, after Year Five</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="ContractualObligationDueAfterFifthYear" xlink:to="us-gaap_ContractualObligationDueAfterFifthYear_lbl1" xlink:title="label: ContractualObligationDueAfterFifthYear to us-gaap_ContractualObligationDueAfterFifthYear_lbl1" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_ContractualObligationDueInNextTwelveMonths" xlink:label="ContractualObligationDueInNextTwelveMonths" xlink:title="ContractualObligationDueInNextTwelveMonths" />
    <link:label xlink:type="resource" xlink:label="us-gaap_ContractualObligationDueInNextTwelveMonths_lbl" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="us-gaap_ContractualObligationDueInNextTwelveMonths_lbl" xml:lang="en-US" id="us-gaap_ContractualObligationDueInNextTwelveMonths_lbl">2022</link:label>
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    <link:label xlink:type="resource" xlink:label="us-gaap_ContractualObligationDueInNextTwelveMonths_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_ContractualObligationDueInNextTwelveMonths_lbl1" xml:lang="en-US" id="us-gaap_ContractualObligationDueInNextTwelveMonths_lbl1">Contractual Obligation, to be Paid, Year One</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="ContractualObligationDueInNextTwelveMonths" xlink:to="us-gaap_ContractualObligationDueInNextTwelveMonths_lbl1" xlink:title="label: ContractualObligationDueInNextTwelveMonths to us-gaap_ContractualObligationDueInNextTwelveMonths_lbl1" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_ContractualObligation" xlink:label="ContractualObligation" xlink:title="ContractualObligation" />
    <link:label xlink:type="resource" xlink:label="us-gaap_ContractualObligation_lbl" xlink:role="http://www.xbrl.org/2003/role/totalLabel" xlink:title="us-gaap_ContractualObligation_lbl" xml:lang="en-US" id="us-gaap_ContractualObligation_lbl">Subtotal</link:label>
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    <link:label xlink:type="resource" xlink:label="us-gaap_ContractualObligation_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_ContractualObligation_lbl1" xml:lang="en-US" id="us-gaap_ContractualObligation_lbl1">Contractual Obligation</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="ContractualObligation" xlink:to="us-gaap_ContractualObligation_lbl1" xlink:title="label: ContractualObligation to us-gaap_ContractualObligation_lbl1" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_ContractualObligationDueInThirdYear" xlink:label="ContractualObligationDueInThirdYear" xlink:title="ContractualObligationDueInThirdYear" />
    <link:label xlink:type="resource" xlink:label="us-gaap_ContractualObligationDueInThirdYear_lbl" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="us-gaap_ContractualObligationDueInThirdYear_lbl" xml:lang="en-US" id="us-gaap_ContractualObligationDueInThirdYear_lbl">2024</link:label>
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    <link:label xlink:type="resource" xlink:label="us-gaap_ContractualObligationDueInThirdYear_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_ContractualObligationDueInThirdYear_lbl1" xml:lang="en-US" id="us-gaap_ContractualObligationDueInThirdYear_lbl1">Contractual Obligation, to be Paid, Year Three</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="ContractualObligationDueInThirdYear" xlink:to="us-gaap_ContractualObligationDueInThirdYear_lbl1" xlink:title="label: ContractualObligationDueInThirdYear to us-gaap_ContractualObligationDueInThirdYear_lbl1" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_ContractualObligationDueInFourthYear" xlink:label="ContractualObligationDueInFourthYear" xlink:title="ContractualObligationDueInFourthYear" />
    <link:label xlink:type="resource" xlink:label="us-gaap_ContractualObligationDueInFourthYear_lbl" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="us-gaap_ContractualObligationDueInFourthYear_lbl" xml:lang="en-US" id="us-gaap_ContractualObligationDueInFourthYear_lbl">2025</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="ContractualObligationDueInFourthYear" xlink:to="us-gaap_ContractualObligationDueInFourthYear_lbl" xlink:title="label: ContractualObligationDueInFourthYear to us-gaap_ContractualObligationDueInFourthYear_lbl" />
    <link:label xlink:type="resource" xlink:label="us-gaap_ContractualObligationDueInFourthYear_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_ContractualObligationDueInFourthYear_lbl1" xml:lang="en-US" id="us-gaap_ContractualObligationDueInFourthYear_lbl1">Contractual Obligation, to be Paid, Year Four</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="ContractualObligationDueInFourthYear" xlink:to="us-gaap_ContractualObligationDueInFourthYear_lbl1" xlink:title="label: ContractualObligationDueInFourthYear to us-gaap_ContractualObligationDueInFourthYear_lbl1" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_ContractualObligationDueInSecondYear" xlink:label="ContractualObligationDueInSecondYear" xlink:title="ContractualObligationDueInSecondYear" />
    <link:label xlink:type="resource" xlink:label="us-gaap_ContractualObligationDueInSecondYear_lbl" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="us-gaap_ContractualObligationDueInSecondYear_lbl" xml:lang="en-US" id="us-gaap_ContractualObligationDueInSecondYear_lbl">2023</link:label>
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    <link:label xlink:type="resource" xlink:label="us-gaap_ContractualObligationDueInSecondYear_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_ContractualObligationDueInSecondYear_lbl1" xml:lang="en-US" id="us-gaap_ContractualObligationDueInSecondYear_lbl1">Contractual Obligation, to be Paid, Year Two</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="ContractualObligationDueInSecondYear" xlink:to="us-gaap_ContractualObligationDueInSecondYear_lbl1" xlink:title="label: ContractualObligationDueInSecondYear to us-gaap_ContractualObligationDueInSecondYear_lbl1" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_ConvertibleDebtNoncurrent" xlink:label="ConvertibleDebtNoncurrent" xlink:title="ConvertibleDebtNoncurrent" />
    <link:label xlink:type="resource" xlink:label="us-gaap_ConvertibleDebtNoncurrent_lbl" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="us-gaap_ConvertibleDebtNoncurrent_lbl" xml:lang="en-US" id="us-gaap_ConvertibleDebtNoncurrent_lbl">Convertible senior notes, net</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="ConvertibleDebtNoncurrent" xlink:to="us-gaap_ConvertibleDebtNoncurrent_lbl" xlink:title="label: ConvertibleDebtNoncurrent to us-gaap_ConvertibleDebtNoncurrent_lbl" />
    <link:label xlink:type="resource" xlink:label="us-gaap_ConvertibleDebtNoncurrent_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_ConvertibleDebtNoncurrent_lbl1" xml:lang="en-US" id="us-gaap_ConvertibleDebtNoncurrent_lbl1">Convertible senior notes</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="ConvertibleDebtNoncurrent" xlink:to="us-gaap_ConvertibleDebtNoncurrent_lbl1" xlink:title="label: ConvertibleDebtNoncurrent to us-gaap_ConvertibleDebtNoncurrent_lbl1" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_ConvertibleDebtCurrent" xlink:label="ConvertibleDebtCurrent" xlink:title="ConvertibleDebtCurrent" />
    <link:label xlink:type="resource" xlink:label="us-gaap_ConvertibleDebtCurrent_lbl" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="us-gaap_ConvertibleDebtCurrent_lbl" xml:lang="en-US" id="us-gaap_ConvertibleDebtCurrent_lbl">1 percent convertible senior notes, net</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="ConvertibleDebtCurrent" xlink:to="us-gaap_ConvertibleDebtCurrent_lbl" xlink:title="label: ConvertibleDebtCurrent to us-gaap_ConvertibleDebtCurrent_lbl" />
    <link:label xlink:type="resource" xlink:label="us-gaap_ConvertibleDebtCurrent_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_ConvertibleDebtCurrent_lbl1" xml:lang="en-US" id="us-gaap_ConvertibleDebtCurrent_lbl1">1 percent convertible senior notes, net</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="ConvertibleDebtCurrent" xlink:to="us-gaap_ConvertibleDebtCurrent_lbl1" xlink:title="label: ConvertibleDebtCurrent to us-gaap_ConvertibleDebtCurrent_lbl1" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_ConvertibleLongtermNotesPayableCurrentAndNoncurrentAbstract" xlink:label="ConvertibleLongtermNotesPayableCurrentAndNoncurrentAbstract" xlink:title="ConvertibleLongtermNotesPayableCurrentAndNoncurrentAbstract" />
    <link:label xlink:type="resource" xlink:label="us-gaap_ConvertibleLongtermNotesPayableCurrentAndNoncurrentAbstract_lbl" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="us-gaap_ConvertibleLongtermNotesPayableCurrentAndNoncurrentAbstract_lbl" xml:lang="en-US" id="us-gaap_ConvertibleLongtermNotesPayableCurrentAndNoncurrentAbstract_lbl">Convertible Debt [Abstract]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="ConvertibleLongtermNotesPayableCurrentAndNoncurrentAbstract" xlink:to="us-gaap_ConvertibleLongtermNotesPayableCurrentAndNoncurrentAbstract_lbl" xlink:title="label: ConvertibleLongtermNotesPayableCurrentAndNoncurrentAbstract to us-gaap_ConvertibleLongtermNotesPayableCurrentAndNoncurrentAbstract_lbl" />
    <link:label xlink:type="resource" xlink:label="us-gaap_ConvertibleLongtermNotesPayableCurrentAndNoncurrentAbstract_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_ConvertibleLongtermNotesPayableCurrentAndNoncurrentAbstract_lbl1" xml:lang="en-US" id="us-gaap_ConvertibleLongtermNotesPayableCurrentAndNoncurrentAbstract_lbl1">Convertible Notes Payable [Abstract]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="ConvertibleLongtermNotesPayableCurrentAndNoncurrentAbstract" xlink:to="us-gaap_ConvertibleLongtermNotesPayableCurrentAndNoncurrentAbstract_lbl1" xlink:title="label: ConvertibleLongtermNotesPayableCurrentAndNoncurrentAbstract to us-gaap_ConvertibleLongtermNotesPayableCurrentAndNoncurrentAbstract_lbl1" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_ConvertibleDebt" xlink:label="ConvertibleDebt" xlink:title="ConvertibleDebt" />
    <link:label xlink:type="resource" xlink:label="us-gaap_ConvertibleDebt_lbl" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="us-gaap_ConvertibleDebt_lbl" xml:lang="en-US" id="us-gaap_ConvertibleDebt_lbl">Convertible senior notes</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="ConvertibleDebt" xlink:to="us-gaap_ConvertibleDebt_lbl" xlink:title="label: ConvertibleDebt to us-gaap_ConvertibleDebt_lbl" />
    <link:label xlink:type="resource" xlink:label="us-gaap_ConvertibleDebt_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_ConvertibleDebt_lbl1" xml:lang="en-US" id="us-gaap_ConvertibleDebt_lbl1">Convertible Debt</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="ConvertibleDebt" xlink:to="us-gaap_ConvertibleDebt_lbl1" xlink:title="label: ConvertibleDebt to us-gaap_ConvertibleDebt_lbl1" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_ConvertibleDebtTableTextBlock" xlink:label="ConvertibleDebtTableTextBlock" xlink:title="ConvertibleDebtTableTextBlock" />
    <link:label xlink:type="resource" xlink:label="us-gaap_ConvertibleDebtTableTextBlock_lbl" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="us-gaap_ConvertibleDebtTableTextBlock_lbl" xml:lang="en-US" id="us-gaap_ConvertibleDebtTableTextBlock_lbl">Convertible Senior Notes</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="ConvertibleDebtTableTextBlock" xlink:to="us-gaap_ConvertibleDebtTableTextBlock_lbl" xlink:title="label: ConvertibleDebtTableTextBlock to us-gaap_ConvertibleDebtTableTextBlock_lbl" />
    <link:label xlink:type="resource" xlink:label="us-gaap_ConvertibleDebtTableTextBlock_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_ConvertibleDebtTableTextBlock_lbl1" xml:lang="en-US" id="us-gaap_ConvertibleDebtTableTextBlock_lbl1">Convertible Debt [Table Text Block]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="ConvertibleDebtTableTextBlock" xlink:to="us-gaap_ConvertibleDebtTableTextBlock_lbl1" xlink:title="label: ConvertibleDebtTableTextBlock to us-gaap_ConvertibleDebtTableTextBlock_lbl1" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_CorporateDebtSecuritiesMember" xlink:label="CorporateDebtSecuritiesMember" xlink:title="CorporateDebtSecuritiesMember" />
    <link:label xlink:type="resource" xlink:label="us-gaap_CorporateDebtSecuritiesMember_lbl" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="us-gaap_CorporateDebtSecuritiesMember_lbl" xml:lang="en-US" id="us-gaap_CorporateDebtSecuritiesMember_lbl">Corporate Debt Securities [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="CorporateDebtSecuritiesMember" xlink:to="us-gaap_CorporateDebtSecuritiesMember_lbl" xlink:title="label: CorporateDebtSecuritiesMember to us-gaap_CorporateDebtSecuritiesMember_lbl" />
    <link:label xlink:type="resource" xlink:label="us-gaap_CorporateDebtSecuritiesMember_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_CorporateDebtSecuritiesMember_lbl1" xml:lang="en-US" id="us-gaap_CorporateDebtSecuritiesMember_lbl1">Corporate Debt Securities [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="CorporateDebtSecuritiesMember" xlink:to="us-gaap_CorporateDebtSecuritiesMember_lbl1" xlink:title="label: CorporateDebtSecuritiesMember to us-gaap_CorporateDebtSecuritiesMember_lbl1" />
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    <link:label xlink:type="resource" xlink:label="us-gaap_CostOfGoodsAndServicesSold_lbl" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="us-gaap_CostOfGoodsAndServicesSold_lbl" xml:lang="en-US" id="us-gaap_CostOfGoodsAndServicesSold_lbl">Cost of sales</link:label>
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    <link:label xlink:type="resource" xlink:label="us-gaap_CostOfGoodsAndServicesSold_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_CostOfGoodsAndServicesSold_lbl1" xml:lang="en-US" id="us-gaap_CostOfGoodsAndServicesSold_lbl1">Cost of Goods and Services Sold</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="CostOfGoodsAndServicesSold" xlink:to="us-gaap_CostOfGoodsAndServicesSold_lbl1" xlink:title="label: CostOfGoodsAndServicesSold to us-gaap_CostOfGoodsAndServicesSold_lbl1" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_CostOfSalesPolicyTextBlock" xlink:label="CostOfSalesPolicyTextBlock" xlink:title="CostOfSalesPolicyTextBlock" />
    <link:label xlink:type="resource" xlink:label="us-gaap_CostOfSalesPolicyTextBlock_lbl" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="us-gaap_CostOfSalesPolicyTextBlock_lbl" xml:lang="en-US" id="us-gaap_CostOfSalesPolicyTextBlock_lbl">Cost of Sales</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="CostOfSalesPolicyTextBlock" xlink:to="us-gaap_CostOfSalesPolicyTextBlock_lbl" xlink:title="label: CostOfSalesPolicyTextBlock to us-gaap_CostOfSalesPolicyTextBlock_lbl" />
    <link:label xlink:type="resource" xlink:label="us-gaap_CostOfSalesPolicyTextBlock_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_CostOfSalesPolicyTextBlock_lbl1" xml:lang="en-US" id="us-gaap_CostOfSalesPolicyTextBlock_lbl1">Cost of Goods and Service [Policy Text Block]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="CostOfSalesPolicyTextBlock" xlink:to="us-gaap_CostOfSalesPolicyTextBlock_lbl1" xlink:title="label: CostOfSalesPolicyTextBlock to us-gaap_CostOfSalesPolicyTextBlock_lbl1" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_CostOfSalesMember" xlink:label="CostOfSalesMember" xlink:title="CostOfSalesMember" />
    <link:label xlink:type="resource" xlink:label="us-gaap_CostOfSalesMember_lbl" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="us-gaap_CostOfSalesMember_lbl" xml:lang="en-US" id="us-gaap_CostOfSalesMember_lbl">Cost of Sales [Member]</link:label>
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    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_CurrentIncomeTaxExpenseBenefitContinuingOperationsAbstract" xlink:label="CurrentIncomeTaxExpenseBenefitContinuingOperationsAbstract" xlink:title="CurrentIncomeTaxExpenseBenefitContinuingOperationsAbstract" />
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    <link:label xlink:type="resource" xlink:label="us-gaap_DeferredTaxLiabilitiesAbstract_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_DeferredTaxLiabilitiesAbstract_lbl1" xml:lang="en-US" id="us-gaap_DeferredTaxLiabilitiesAbstract_lbl1">Deferred Tax Liabilities, Gross [Abstract]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="DeferredTaxLiabilitiesAbstract" xlink:to="us-gaap_DeferredTaxLiabilitiesAbstract_lbl1" xlink:title="label: DeferredTaxLiabilitiesAbstract to us-gaap_DeferredTaxLiabilitiesAbstract_lbl1" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_DeferredTaxAssetsValuationAllowance" xlink:label="DeferredTaxAssetsValuationAllowance" xlink:title="DeferredTaxAssetsValuationAllowance" />
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    <link:label xlink:type="resource" xlink:label="us-gaap_DeferredTaxLiabilitiesOther_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_DeferredTaxLiabilitiesOther_lbl1" xml:lang="en-US" id="us-gaap_DeferredTaxLiabilitiesOther_lbl1">Deferred Tax Liabilities, Other</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="DeferredTaxLiabilitiesOther" xlink:to="us-gaap_DeferredTaxLiabilitiesOther_lbl1" xlink:title="label: DeferredTaxLiabilitiesOther to us-gaap_DeferredTaxLiabilitiesOther_lbl1" />
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    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_DeferredTaxLiabilitiesFinancingArrangements" xlink:label="DeferredTaxLiabilitiesFinancingArrangements" xlink:title="DeferredTaxLiabilitiesFinancingArrangements" />
    <link:label xlink:type="resource" xlink:label="us-gaap_DeferredTaxLiabilitiesFinancingArrangements_lbl" xlink:role="http://www.xbrl.org/2009/role/negatedLabel" xlink:title="us-gaap_DeferredTaxLiabilitiesFinancingArrangements_lbl" xml:lang="en-US" id="us-gaap_DeferredTaxLiabilitiesFinancingArrangements_lbl">Convertible debt</link:label>
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    <link:label xlink:type="resource" xlink:label="us-gaap_DeferredTaxLiabilitiesFinancingArrangements_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_DeferredTaxLiabilitiesFinancingArrangements_lbl1" xml:lang="en-US" id="us-gaap_DeferredTaxLiabilitiesFinancingArrangements_lbl1">Deferred Tax Liabilities, Financing Arrangements</link:label>
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    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_DefinedContributionPlanTable" xlink:label="DefinedContributionPlanTable" xlink:title="DefinedContributionPlanTable" />
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    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_EmployeeServiceShareBasedCompensationNonvestedAwardsTotalCompensationCostNotYetRecognizedStockOptions" xlink:label="EmployeeServiceShareBasedCompensationNonvestedAwardsTotalCompensationCostNotYetRecognizedStockOptions" xlink:title="EmployeeServiceShareBasedCompensationNonvestedAwardsTotalCompensationCostNotYetRecognizedStockOptions" />
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    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="EntityWideRevenueMajorCustomerLineItems" xlink:to="us-gaap_EntityWideRevenueMajorCustomerLineItems_lbl" xlink:title="label: EntityWideRevenueMajorCustomerLineItems to us-gaap_EntityWideRevenueMajorCustomerLineItems_lbl" />
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    <link:label xlink:type="resource" xlink:label="us-gaap_EquitySecuritiesFvNiUnrealizedGain_lbl" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="us-gaap_EquitySecuritiesFvNiUnrealizedGain_lbl" xml:lang="en-US" id="us-gaap_EquitySecuritiesFvNiUnrealizedGain_lbl">Gross unrealized gains</link:label>
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    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="EquitySecuritiesFvNiUnrealizedLoss" xlink:to="us-gaap_EquitySecuritiesFvNiUnrealizedLoss_lbl1" xlink:title="label: EquitySecuritiesFvNiUnrealizedLoss to us-gaap_EquitySecuritiesFvNiUnrealizedLoss_lbl1" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_EquitySecuritiesFvNi" xlink:label="EquitySecuritiesFvNi" xlink:title="EquitySecuritiesFvNi" />
    <link:label xlink:type="resource" xlink:label="us-gaap_EquitySecuritiesFvNi_lbl" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="us-gaap_EquitySecuritiesFvNi_lbl" xml:lang="en-US" id="us-gaap_EquitySecuritiesFvNi_lbl">Investment</link:label>
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    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="EquitySecuritiesFvNi" xlink:to="us-gaap_EquitySecuritiesFvNi_lbl2" xlink:title="label: EquitySecuritiesFvNi to us-gaap_EquitySecuritiesFvNi_lbl2" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_EquitySecuritiesFvNiCost" xlink:label="EquitySecuritiesFvNiCost" xlink:title="EquitySecuritiesFvNiCost" />
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    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_EquitySecuritiesMember" xlink:label="EquitySecuritiesMember" xlink:title="EquitySecuritiesMember" />
    <link:label xlink:type="resource" xlink:label="us-gaap_EquitySecuritiesMember_lbl" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="us-gaap_EquitySecuritiesMember_lbl" xml:lang="en-US" id="us-gaap_EquitySecuritiesMember_lbl">Equity Securities [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="EquitySecuritiesMember" xlink:to="us-gaap_EquitySecuritiesMember_lbl" xlink:title="label: EquitySecuritiesMember to us-gaap_EquitySecuritiesMember_lbl" />
    <link:label xlink:type="resource" xlink:label="us-gaap_EquitySecuritiesMember_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_EquitySecuritiesMember_lbl1" xml:lang="en-US" id="us-gaap_EquitySecuritiesMember_lbl1">Equity Securities [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="EquitySecuritiesMember" xlink:to="us-gaap_EquitySecuritiesMember_lbl1" xlink:title="label: EquitySecuritiesMember to us-gaap_EquitySecuritiesMember_lbl1" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_FairValueNetAssetLiabilityAbstract" xlink:label="FairValueNetAssetLiabilityAbstract" xlink:title="FairValueNetAssetLiabilityAbstract" />
    <link:label xlink:type="resource" xlink:label="us-gaap_FairValueNetAssetLiabilityAbstract_lbl" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="us-gaap_FairValueNetAssetLiabilityAbstract_lbl" xml:lang="en-US" id="us-gaap_FairValueNetAssetLiabilityAbstract_lbl">Fair Value Measurements [Abstract]</link:label>
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    <link:label xlink:type="resource" xlink:label="us-gaap_FairValueMeasurementPolicyPolicyTextBlock_lbl" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="us-gaap_FairValueMeasurementPolicyPolicyTextBlock_lbl" xml:lang="en-US" id="us-gaap_FairValueMeasurementPolicyPolicyTextBlock_lbl">Fair Value Measurements</link:label>
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    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_FairValueByFairValueHierarchyLevelAxis" xlink:label="FairValueByFairValueHierarchyLevelAxis" xlink:title="FairValueByFairValueHierarchyLevelAxis" />
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    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_IntangibleAssetsFiniteLivedPolicy" xlink:label="IntangibleAssetsFiniteLivedPolicy" xlink:title="IntangibleAssetsFiniteLivedPolicy" />
    <link:label xlink:type="resource" xlink:label="us-gaap_IntangibleAssetsFiniteLivedPolicy_lbl" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="us-gaap_IntangibleAssetsFiniteLivedPolicy_lbl" xml:lang="en-US" id="us-gaap_IntangibleAssetsFiniteLivedPolicy_lbl">Patent Expenses</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="IntangibleAssetsFiniteLivedPolicy" xlink:to="us-gaap_IntangibleAssetsFiniteLivedPolicy_lbl" xlink:title="label: IntangibleAssetsFiniteLivedPolicy to us-gaap_IntangibleAssetsFiniteLivedPolicy_lbl" />
    <link:label xlink:type="resource" xlink:label="us-gaap_IntangibleAssetsFiniteLivedPolicy_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_IntangibleAssetsFiniteLivedPolicy_lbl1" xml:lang="en-US" id="us-gaap_IntangibleAssetsFiniteLivedPolicy_lbl1">Intangible Assets, Finite-Lived, Policy [Policy Text Block]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="IntangibleAssetsFiniteLivedPolicy" xlink:to="us-gaap_IntangibleAssetsFiniteLivedPolicy_lbl1" xlink:title="label: IntangibleAssetsFiniteLivedPolicy to us-gaap_IntangibleAssetsFiniteLivedPolicy_lbl1" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_InterestPayableCurrentAndNoncurrent" xlink:label="InterestPayableCurrentAndNoncurrent" xlink:title="InterestPayableCurrentAndNoncurrent" />
    <link:label xlink:type="resource" xlink:label="us-gaap_InterestPayableCurrentAndNoncurrent_lbl" xlink:role="http://www.xbrl.org/2009/role/negatedLabel" xlink:title="us-gaap_InterestPayableCurrentAndNoncurrent_lbl" xml:lang="en-US" id="us-gaap_InterestPayableCurrentAndNoncurrent_lbl">Less: fixed and determinable interest</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="InterestPayableCurrentAndNoncurrent" xlink:to="us-gaap_InterestPayableCurrentAndNoncurrent_lbl" xlink:title="label: InterestPayableCurrentAndNoncurrent to us-gaap_InterestPayableCurrentAndNoncurrent_lbl" />
    <link:label xlink:type="resource" xlink:label="us-gaap_InterestPayableCurrentAndNoncurrent_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_InterestPayableCurrentAndNoncurrent_lbl1" xml:lang="en-US" id="us-gaap_InterestPayableCurrentAndNoncurrent_lbl1">Interest Payable</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="InterestPayableCurrentAndNoncurrent" xlink:to="us-gaap_InterestPayableCurrentAndNoncurrent_lbl1" xlink:title="label: InterestPayableCurrentAndNoncurrent to us-gaap_InterestPayableCurrentAndNoncurrent_lbl1" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_InterestExpense" xlink:label="InterestExpense" xlink:title="InterestExpense" />
    <link:label xlink:type="resource" xlink:label="us-gaap_InterestExpense_lbl" xlink:role="http://www.xbrl.org/2009/role/negatedLabel" xlink:title="us-gaap_InterestExpense_lbl" xml:lang="en-US" id="us-gaap_InterestExpense_lbl">Interest expense</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="InterestExpense" xlink:to="us-gaap_InterestExpense_lbl" xlink:title="label: InterestExpense to us-gaap_InterestExpense_lbl" />
    <link:label xlink:type="resource" xlink:label="us-gaap_InterestExpense_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_InterestExpense_lbl1" xml:lang="en-US" id="us-gaap_InterestExpense_lbl1">Interest Expense</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="InterestExpense" xlink:to="us-gaap_InterestExpense_lbl1" xlink:title="label: InterestExpense to us-gaap_InterestExpense_lbl1" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_InterestPaidNet" xlink:label="InterestPaidNet" xlink:title="InterestPaidNet" />
    <link:label xlink:type="resource" xlink:label="us-gaap_InterestPaidNet_lbl" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="us-gaap_InterestPaidNet_lbl" xml:lang="en-US" id="us-gaap_InterestPaidNet_lbl">Interest paid</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="InterestPaidNet" xlink:to="us-gaap_InterestPaidNet_lbl" xlink:title="label: InterestPaidNet to us-gaap_InterestPaidNet_lbl" />
    <link:label xlink:type="resource" xlink:label="us-gaap_InterestPaidNet_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_InterestPaidNet_lbl1" xml:lang="en-US" id="us-gaap_InterestPaidNet_lbl1">Interest Paid, Excluding Capitalized Interest, Operating Activities</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="InterestPaidNet" xlink:to="us-gaap_InterestPaidNet_lbl1" xlink:title="label: InterestPaidNet to us-gaap_InterestPaidNet_lbl1" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_InternalRevenueServiceIRSMember" xlink:label="InternalRevenueServiceIRSMember" xlink:title="InternalRevenueServiceIRSMember" />
    <link:label xlink:type="resource" xlink:label="us-gaap_InternalRevenueServiceIRSMember_lbl" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_InternalRevenueServiceIRSMember_lbl" xml:lang="en-US" id="us-gaap_InternalRevenueServiceIRSMember_lbl">Federal [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="InternalRevenueServiceIRSMember" xlink:to="us-gaap_InternalRevenueServiceIRSMember_lbl" xlink:title="label: InternalRevenueServiceIRSMember to us-gaap_InternalRevenueServiceIRSMember_lbl" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_InventoryLineItems" xlink:label="InventoryLineItems" xlink:title="InventoryLineItems" />
    <link:label xlink:type="resource" xlink:label="us-gaap_InventoryLineItems_lbl" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_InventoryLineItems_lbl" xml:lang="en-US" id="us-gaap_InventoryLineItems_lbl">Inventory [Line Items]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="InventoryLineItems" xlink:to="us-gaap_InventoryLineItems_lbl" xlink:title="label: InventoryLineItems to us-gaap_InventoryLineItems_lbl" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_InventoryWriteDown" xlink:label="InventoryWriteDown" xlink:title="InventoryWriteDown" />
    <link:label xlink:type="resource" xlink:label="us-gaap_InventoryWriteDown_lbl" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="us-gaap_InventoryWriteDown_lbl" xml:lang="en-US" id="us-gaap_InventoryWriteDown_lbl">Inventory write-off</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="InventoryWriteDown" xlink:to="us-gaap_InventoryWriteDown_lbl" xlink:title="label: InventoryWriteDown to us-gaap_InventoryWriteDown_lbl" />
    <link:label xlink:type="resource" xlink:label="us-gaap_InventoryWriteDown_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_InventoryWriteDown_lbl1" xml:lang="en-US" id="us-gaap_InventoryWriteDown_lbl1">Inventory Write-down</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="InventoryWriteDown" xlink:to="us-gaap_InventoryWriteDown_lbl1" xlink:title="label: InventoryWriteDown to us-gaap_InventoryWriteDown_lbl1" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_InventoryCurrentTable" xlink:label="InventoryCurrentTable" xlink:title="InventoryCurrentTable" />
    <link:label xlink:type="resource" xlink:label="us-gaap_InventoryCurrentTable_lbl" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_InventoryCurrentTable_lbl" xml:lang="en-US" id="us-gaap_InventoryCurrentTable_lbl">Inventory, Current [Table]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="InventoryCurrentTable" xlink:to="us-gaap_InventoryCurrentTable_lbl" xlink:title="label: InventoryCurrentTable to us-gaap_InventoryCurrentTable_lbl" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_InventoryFinishedGoods" xlink:label="InventoryFinishedGoods" xlink:title="InventoryFinishedGoods" />
    <link:label xlink:type="resource" xlink:label="us-gaap_InventoryFinishedGoods_lbl" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="us-gaap_InventoryFinishedGoods_lbl" xml:lang="en-US" id="us-gaap_InventoryFinishedGoods_lbl">Finished goods</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="InventoryFinishedGoods" xlink:to="us-gaap_InventoryFinishedGoods_lbl" xlink:title="label: InventoryFinishedGoods to us-gaap_InventoryFinishedGoods_lbl" />
    <link:label xlink:type="resource" xlink:label="us-gaap_InventoryFinishedGoods_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_InventoryFinishedGoods_lbl1" xml:lang="en-US" id="us-gaap_InventoryFinishedGoods_lbl1">Inventory, Finished Goods, Gross</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="InventoryFinishedGoods" xlink:to="us-gaap_InventoryFinishedGoods_lbl1" xlink:title="label: InventoryFinishedGoods to us-gaap_InventoryFinishedGoods_lbl1" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_InventoryWorkInProcess" xlink:label="InventoryWorkInProcess" xlink:title="InventoryWorkInProcess" />
    <link:label xlink:type="resource" xlink:label="us-gaap_InventoryWorkInProcess_lbl" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="us-gaap_InventoryWorkInProcess_lbl" xml:lang="en-US" id="us-gaap_InventoryWorkInProcess_lbl">Work in process</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="InventoryWorkInProcess" xlink:to="us-gaap_InventoryWorkInProcess_lbl" xlink:title="label: InventoryWorkInProcess to us-gaap_InventoryWorkInProcess_lbl" />
    <link:label xlink:type="resource" xlink:label="us-gaap_InventoryWorkInProcess_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_InventoryWorkInProcess_lbl1" xml:lang="en-US" id="us-gaap_InventoryWorkInProcess_lbl1">Inventory, Work in Process, Gross</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="InventoryWorkInProcess" xlink:to="us-gaap_InventoryWorkInProcess_lbl1" xlink:title="label: InventoryWorkInProcess to us-gaap_InventoryWorkInProcess_lbl1" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_InventoryPolicyTextBlock" xlink:label="InventoryPolicyTextBlock" xlink:title="InventoryPolicyTextBlock" />
    <link:label xlink:type="resource" xlink:label="us-gaap_InventoryPolicyTextBlock_lbl" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="us-gaap_InventoryPolicyTextBlock_lbl" xml:lang="en-US" id="us-gaap_InventoryPolicyTextBlock_lbl">Inventory Valuation</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="InventoryPolicyTextBlock" xlink:to="us-gaap_InventoryPolicyTextBlock_lbl" xlink:title="label: InventoryPolicyTextBlock to us-gaap_InventoryPolicyTextBlock_lbl" />
    <link:label xlink:type="resource" xlink:label="us-gaap_InventoryPolicyTextBlock_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_InventoryPolicyTextBlock_lbl1" xml:lang="en-US" id="us-gaap_InventoryPolicyTextBlock_lbl1">Inventory, Policy [Policy Text Block]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="InventoryPolicyTextBlock" xlink:to="us-gaap_InventoryPolicyTextBlock_lbl1" xlink:title="label: InventoryPolicyTextBlock to us-gaap_InventoryPolicyTextBlock_lbl1" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_InventoryNet" xlink:label="InventoryNet" xlink:title="InventoryNet" />
    <link:label xlink:type="resource" xlink:label="us-gaap_InventoryNet_lbl" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="us-gaap_InventoryNet_lbl" xml:lang="en-US" id="us-gaap_InventoryNet_lbl">Inventories</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="InventoryNet" xlink:to="us-gaap_InventoryNet_lbl" xlink:title="label: InventoryNet to us-gaap_InventoryNet_lbl" />
    <link:label xlink:type="resource" xlink:label="us-gaap_InventoryNet_lbl1" xlink:role="http://www.xbrl.org/2003/role/totalLabel" xlink:title="us-gaap_InventoryNet_lbl1" xml:lang="en-US" id="us-gaap_InventoryNet_lbl1">Total inventory</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="InventoryNet" xlink:to="us-gaap_InventoryNet_lbl1" xlink:title="label: InventoryNet to us-gaap_InventoryNet_lbl1" />
    <link:label xlink:type="resource" xlink:label="us-gaap_InventoryNet_lbl2" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_InventoryNet_lbl2" xml:lang="en-US" id="us-gaap_InventoryNet_lbl2">Inventory, Net</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="InventoryNet" xlink:to="us-gaap_InventoryNet_lbl2" xlink:title="label: InventoryNet to us-gaap_InventoryNet_lbl2" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_InventoryNetAbstract" xlink:label="InventoryNetAbstract" xlink:title="InventoryNetAbstract" />
    <link:label xlink:type="resource" xlink:label="us-gaap_InventoryNetAbstract_lbl" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="us-gaap_InventoryNetAbstract_lbl" xml:lang="en-US" id="us-gaap_InventoryNetAbstract_lbl">Inventory Valuation [Abstract]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="InventoryNetAbstract" xlink:to="us-gaap_InventoryNetAbstract_lbl" xlink:title="label: InventoryNetAbstract to us-gaap_InventoryNetAbstract_lbl" />
    <link:label xlink:type="resource" xlink:label="us-gaap_InventoryNetAbstract_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_InventoryNetAbstract_lbl1" xml:lang="en-US" id="us-gaap_InventoryNetAbstract_lbl1">Inventory, Net [Abstract]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="InventoryNetAbstract" xlink:to="us-gaap_InventoryNetAbstract_lbl1" xlink:title="label: InventoryNetAbstract to us-gaap_InventoryNetAbstract_lbl1" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_InventoryRawMaterials" xlink:label="InventoryRawMaterials" xlink:title="InventoryRawMaterials" />
    <link:label xlink:type="resource" xlink:label="us-gaap_InventoryRawMaterials_lbl" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="us-gaap_InventoryRawMaterials_lbl" xml:lang="en-US" id="us-gaap_InventoryRawMaterials_lbl">Raw materials</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="InventoryRawMaterials" xlink:to="us-gaap_InventoryRawMaterials_lbl" xlink:title="label: InventoryRawMaterials to us-gaap_InventoryRawMaterials_lbl" />
    <link:label xlink:type="resource" xlink:label="us-gaap_InventoryRawMaterials_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_InventoryRawMaterials_lbl1" xml:lang="en-US" id="us-gaap_InventoryRawMaterials_lbl1">Inventory, Raw Materials, Gross</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="InventoryRawMaterials" xlink:to="us-gaap_InventoryRawMaterials_lbl1" xlink:title="label: InventoryRawMaterials to us-gaap_InventoryRawMaterials_lbl1" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_InvestmentTextBlock" xlink:label="InvestmentTextBlock" xlink:title="InvestmentTextBlock" />
    <link:label xlink:type="resource" xlink:label="us-gaap_InvestmentTextBlock_lbl" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_InvestmentTextBlock_lbl" xml:lang="en-US" id="us-gaap_InvestmentTextBlock_lbl">Investments</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="InvestmentTextBlock" xlink:to="us-gaap_InvestmentTextBlock_lbl" xlink:title="label: InvestmentTextBlock to us-gaap_InvestmentTextBlock_lbl" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_InvestmentHoldingsLineItems" xlink:label="InvestmentHoldingsLineItems" xlink:title="InvestmentHoldingsLineItems" />
    <link:label xlink:type="resource" xlink:label="us-gaap_InvestmentHoldingsLineItems_lbl" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_InvestmentHoldingsLineItems_lbl" xml:lang="en-US" id="us-gaap_InvestmentHoldingsLineItems_lbl">Investment Holdings [Line Items]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="InvestmentHoldingsLineItems" xlink:to="us-gaap_InvestmentHoldingsLineItems_lbl" xlink:title="label: InvestmentHoldingsLineItems to us-gaap_InvestmentHoldingsLineItems_lbl" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_InvestmentIncomeNet" xlink:label="InvestmentIncomeNet" xlink:title="InvestmentIncomeNet" />
    <link:label xlink:type="resource" xlink:label="us-gaap_InvestmentIncomeNet_lbl" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="us-gaap_InvestmentIncomeNet_lbl" xml:lang="en-US" id="us-gaap_InvestmentIncomeNet_lbl">Investment income</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="InvestmentIncomeNet" xlink:to="us-gaap_InvestmentIncomeNet_lbl" xlink:title="label: InvestmentIncomeNet to us-gaap_InvestmentIncomeNet_lbl" />
    <link:label xlink:type="resource" xlink:label="us-gaap_InvestmentIncomeNet_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_InvestmentIncomeNet_lbl1" xml:lang="en-US" id="us-gaap_InvestmentIncomeNet_lbl1">Investment Income, Net</link:label>
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    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_InvestmentPolicyTextBlock" xlink:label="InvestmentPolicyTextBlock" xlink:title="InvestmentPolicyTextBlock" />
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    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_InvestmentsAllOtherInvestmentsAbstract" xlink:label="InvestmentsAllOtherInvestmentsAbstract" xlink:title="InvestmentsAllOtherInvestmentsAbstract" />
    <link:label xlink:type="resource" xlink:label="us-gaap_InvestmentsAllOtherInvestmentsAbstract_lbl" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="us-gaap_InvestmentsAllOtherInvestmentsAbstract_lbl" xml:lang="en-US" id="us-gaap_InvestmentsAllOtherInvestmentsAbstract_lbl">Ownership Interests in Private and Public Companies [Abstract]</link:label>
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    <link:label xlink:type="resource" xlink:label="us-gaap_LessorOperatingLeasePaymentsToBeReceived_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_LessorOperatingLeasePaymentsToBeReceived_lbl1" xml:lang="en-US" id="us-gaap_LessorOperatingLeasePaymentsToBeReceived_lbl1">Lessor, Operating Lease, Payments to be Received</link:label>
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    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_LesseeLeasesPolicyTextBlock" xlink:label="LesseeLeasesPolicyTextBlock" xlink:title="LesseeLeasesPolicyTextBlock" />
    <link:label xlink:type="resource" xlink:label="us-gaap_LesseeLeasesPolicyTextBlock_lbl" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="us-gaap_LesseeLeasesPolicyTextBlock_lbl" xml:lang="en-US" id="us-gaap_LesseeLeasesPolicyTextBlock_lbl">Leases</link:label>
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    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="LesseeOperatingLeaseLiabilityUndiscountedExcessAmount" xlink:to="us-gaap_LesseeOperatingLeaseLiabilityUndiscountedExcessAmount_lbl1" xlink:title="label: LesseeOperatingLeaseLiabilityUndiscountedExcessAmount to us-gaap_LesseeOperatingLeaseLiabilityUndiscountedExcessAmount_lbl1" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_LesseeOperatingLeaseLiabilityPaymentsDueYearFive" xlink:label="LesseeOperatingLeaseLiabilityPaymentsDueYearFive" xlink:title="LesseeOperatingLeaseLiabilityPaymentsDueYearFive" />
    <link:label xlink:type="resource" xlink:label="us-gaap_LesseeOperatingLeaseLiabilityPaymentsDueYearFive_lbl" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="us-gaap_LesseeOperatingLeaseLiabilityPaymentsDueYearFive_lbl" xml:lang="en-US" id="us-gaap_LesseeOperatingLeaseLiabilityPaymentsDueYearFive_lbl">2026</link:label>
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    <link:label xlink:type="resource" xlink:label="us-gaap_LesseeOperatingLeaseLiabilityPaymentsDueYearFive_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_LesseeOperatingLeaseLiabilityPaymentsDueYearFive_lbl1" xml:lang="en-US" id="us-gaap_LesseeOperatingLeaseLiabilityPaymentsDueYearFive_lbl1">Lessee, Operating Lease, Liability, to be Paid, Year Five</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="LesseeOperatingLeaseLiabilityPaymentsDueYearFive" xlink:to="us-gaap_LesseeOperatingLeaseLiabilityPaymentsDueYearFive_lbl1" xlink:title="label: LesseeOperatingLeaseLiabilityPaymentsDueYearFive to us-gaap_LesseeOperatingLeaseLiabilityPaymentsDueYearFive_lbl1" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_LesseeOperatingLeaseLiabilityPaymentsDueYearFour" xlink:label="LesseeOperatingLeaseLiabilityPaymentsDueYearFour" xlink:title="LesseeOperatingLeaseLiabilityPaymentsDueYearFour" />
    <link:label xlink:type="resource" xlink:label="us-gaap_LesseeOperatingLeaseLiabilityPaymentsDueYearFour_lbl" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="us-gaap_LesseeOperatingLeaseLiabilityPaymentsDueYearFour_lbl" xml:lang="en-US" id="us-gaap_LesseeOperatingLeaseLiabilityPaymentsDueYearFour_lbl">2025</link:label>
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    <link:label xlink:type="resource" xlink:label="us-gaap_LesseeOperatingLeaseLiabilityPaymentsDueYearFour_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_LesseeOperatingLeaseLiabilityPaymentsDueYearFour_lbl1" xml:lang="en-US" id="us-gaap_LesseeOperatingLeaseLiabilityPaymentsDueYearFour_lbl1">Lessee, Operating Lease, Liability, to be Paid, Year Four</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="LesseeOperatingLeaseLiabilityPaymentsDueYearFour" xlink:to="us-gaap_LesseeOperatingLeaseLiabilityPaymentsDueYearFour_lbl1" xlink:title="label: LesseeOperatingLeaseLiabilityPaymentsDueYearFour to us-gaap_LesseeOperatingLeaseLiabilityPaymentsDueYearFour_lbl1" />
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    <link:label xlink:type="resource" xlink:label="us-gaap_LesseeOperatingLeaseTermOfContract_lbl" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="us-gaap_LesseeOperatingLeaseTermOfContract_lbl" xml:lang="en-US" id="us-gaap_LesseeOperatingLeaseTermOfContract_lbl">Initial term of operating lease</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="LesseeOperatingLeaseTermOfContract" xlink:to="us-gaap_LesseeOperatingLeaseTermOfContract_lbl" xlink:title="label: LesseeOperatingLeaseTermOfContract to us-gaap_LesseeOperatingLeaseTermOfContract_lbl" />
    <link:label xlink:type="resource" xlink:label="us-gaap_LesseeOperatingLeaseTermOfContract_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_LesseeOperatingLeaseTermOfContract_lbl1" xml:lang="en-US" id="us-gaap_LesseeOperatingLeaseTermOfContract_lbl1">Lessee, Operating Lease, Term of Contract</link:label>
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    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_LesseeOperatingLeaseRenewalTerm" xlink:label="LesseeOperatingLeaseRenewalTerm" xlink:title="LesseeOperatingLeaseRenewalTerm" />
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    <link:label xlink:type="resource" xlink:label="us-gaap_LesseeOperatingLeaseRenewalTerm_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_LesseeOperatingLeaseRenewalTerm_lbl1" xml:lang="en-US" id="us-gaap_LesseeOperatingLeaseRenewalTerm_lbl1">Lessee, Operating Lease, Renewal Term</link:label>
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    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_LesseeOperatingLeaseLiabilityPaymentsDueYearThree" xlink:label="LesseeOperatingLeaseLiabilityPaymentsDueYearThree" xlink:title="LesseeOperatingLeaseLiabilityPaymentsDueYearThree" />
    <link:label xlink:type="resource" xlink:label="us-gaap_LesseeOperatingLeaseLiabilityPaymentsDueYearThree_lbl" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="us-gaap_LesseeOperatingLeaseLiabilityPaymentsDueYearThree_lbl" xml:lang="en-US" id="us-gaap_LesseeOperatingLeaseLiabilityPaymentsDueYearThree_lbl">2024</link:label>
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    <link:label xlink:type="resource" xlink:label="us-gaap_LesseeOperatingLeaseLiabilityPaymentsDueYearThree_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_LesseeOperatingLeaseLiabilityPaymentsDueYearThree_lbl1" xml:lang="en-US" id="us-gaap_LesseeOperatingLeaseLiabilityPaymentsDueYearThree_lbl1">Lessee, Operating Lease, Liability, to be Paid, Year Three</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="LesseeOperatingLeaseLiabilityPaymentsDueYearThree" xlink:to="us-gaap_LesseeOperatingLeaseLiabilityPaymentsDueYearThree_lbl1" xlink:title="label: LesseeOperatingLeaseLiabilityPaymentsDueYearThree to us-gaap_LesseeOperatingLeaseLiabilityPaymentsDueYearThree_lbl1" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_LesseeOperatingLeaseLiabilityMaturityTableTextBlock" xlink:label="LesseeOperatingLeaseLiabilityMaturityTableTextBlock" xlink:title="LesseeOperatingLeaseLiabilityMaturityTableTextBlock" />
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    <link:label xlink:type="resource" xlink:label="us-gaap_LesseeOperatingLeaseLiabilityMaturityTableTextBlock_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_LesseeOperatingLeaseLiabilityMaturityTableTextBlock_lbl1" xml:lang="en-US" id="us-gaap_LesseeOperatingLeaseLiabilityMaturityTableTextBlock_lbl1">Lessee, Operating Lease, Liability, Maturity [Table Text Block]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="LesseeOperatingLeaseLiabilityMaturityTableTextBlock" xlink:to="us-gaap_LesseeOperatingLeaseLiabilityMaturityTableTextBlock_lbl1" xlink:title="label: LesseeOperatingLeaseLiabilityMaturityTableTextBlock to us-gaap_LesseeOperatingLeaseLiabilityMaturityTableTextBlock_lbl1" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_LesseeOperatingLeaseLiabilityPaymentsDueYearTwo" xlink:label="LesseeOperatingLeaseLiabilityPaymentsDueYearTwo" xlink:title="LesseeOperatingLeaseLiabilityPaymentsDueYearTwo" />
    <link:label xlink:type="resource" xlink:label="us-gaap_LesseeOperatingLeaseLiabilityPaymentsDueYearTwo_lbl" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="us-gaap_LesseeOperatingLeaseLiabilityPaymentsDueYearTwo_lbl" xml:lang="en-US" id="us-gaap_LesseeOperatingLeaseLiabilityPaymentsDueYearTwo_lbl">2023</link:label>
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    <link:label xlink:type="resource" xlink:label="us-gaap_LesseeOperatingLeaseLiabilityPaymentsDueYearTwo_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_LesseeOperatingLeaseLiabilityPaymentsDueYearTwo_lbl1" xml:lang="en-US" id="us-gaap_LesseeOperatingLeaseLiabilityPaymentsDueYearTwo_lbl1">Lessee, Operating Lease, Liability, to be Paid, Year Two</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="LesseeOperatingLeaseLiabilityPaymentsDueYearTwo" xlink:to="us-gaap_LesseeOperatingLeaseLiabilityPaymentsDueYearTwo_lbl1" xlink:title="label: LesseeOperatingLeaseLiabilityPaymentsDueYearTwo to us-gaap_LesseeOperatingLeaseLiabilityPaymentsDueYearTwo_lbl1" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_LesseeDisclosureAbstract" xlink:label="LesseeDisclosureAbstract" xlink:title="LesseeDisclosureAbstract" />
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    <link:label xlink:type="resource" xlink:label="us-gaap_LesseeDisclosureAbstract_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_LesseeDisclosureAbstract_lbl1" xml:lang="en-US" id="us-gaap_LesseeDisclosureAbstract_lbl1">Lessee Disclosure [Abstract]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="LesseeDisclosureAbstract" xlink:to="us-gaap_LesseeDisclosureAbstract_lbl1" xlink:title="label: LesseeDisclosureAbstract to us-gaap_LesseeDisclosureAbstract_lbl1" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_LesseeLeaseDescriptionTable" xlink:label="LesseeLeaseDescriptionTable" xlink:title="LesseeLeaseDescriptionTable" />
    <link:label xlink:type="resource" xlink:label="us-gaap_LesseeLeaseDescriptionTable_lbl" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_LesseeLeaseDescriptionTable_lbl" xml:lang="en-US" id="us-gaap_LesseeLeaseDescriptionTable_lbl">Lessee, Lease, Description [Table]</link:label>
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    <link:label xlink:type="resource" xlink:label="us-gaap_LesseeLeaseDescriptionLineItems_lbl" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_LesseeLeaseDescriptionLineItems_lbl" xml:lang="en-US" id="us-gaap_LesseeLeaseDescriptionLineItems_lbl">Lessee, Lease, Description [Line Items]</link:label>
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    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_LongtermDebtCurrentAndNoncurrentAbstract" xlink:label="LongtermDebtCurrentAndNoncurrentAbstract" xlink:title="LongtermDebtCurrentAndNoncurrentAbstract" />
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    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_LandMember" xlink:label="LandMember" xlink:title="LandMember" />
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    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="LandMember" xlink:to="us-gaap_LandMember_lbl" xlink:title="label: LandMember to us-gaap_LandMember_lbl" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_LandImprovementsMember" xlink:label="LandImprovementsMember" xlink:title="LandImprovementsMember" />
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    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="LandImprovementsMember" xlink:to="us-gaap_LandImprovementsMember_lbl" xlink:title="label: LandImprovementsMember to us-gaap_LandImprovementsMember_lbl" />
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    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="LandImprovementsMember" xlink:to="us-gaap_LandImprovementsMember_lbl1" xlink:title="label: LandImprovementsMember to us-gaap_LandImprovementsMember_lbl1" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_LeaseholdImprovementsMember" xlink:label="LeaseholdImprovementsMember" xlink:title="LeaseholdImprovementsMember" />
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    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_LegalMattersAndContingenciesTextBlock" xlink:label="LegalMattersAndContingenciesTextBlock" xlink:title="LegalMattersAndContingenciesTextBlock" />
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    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="LiabilitiesAndStockholdersEquityAbstract" xlink:to="us-gaap_LiabilitiesAndStockholdersEquityAbstract_lbl" xlink:title="label: LiabilitiesAndStockholdersEquityAbstract to us-gaap_LiabilitiesAndStockholdersEquityAbstract_lbl" />
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    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_LiabilitiesCurrent" xlink:label="LiabilitiesCurrent" xlink:title="LiabilitiesCurrent" />
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    <link:label xlink:type="resource" xlink:label="us-gaap_LiabilitiesCurrentAbstract_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_LiabilitiesCurrentAbstract_lbl1" xml:lang="en-US" id="us-gaap_LiabilitiesCurrentAbstract_lbl1">Liabilities, Current [Abstract]</link:label>
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    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_LitigationSettlementAmountAwardedFromOtherParty" xlink:label="LitigationSettlementAmountAwardedFromOtherParty" xlink:title="LitigationSettlementAmountAwardedFromOtherParty" />
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    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_LoansPayableToBank" xlink:label="LoansPayableToBank" xlink:title="LoansPayableToBank" />
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    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_LongTermDebtByComponentsCurrentAndNoncurrentAlternativeAbstract" xlink:label="LongTermDebtByComponentsCurrentAndNoncurrentAlternativeAbstract" xlink:title="LongTermDebtByComponentsCurrentAndNoncurrentAlternativeAbstract" />
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    <link:label xlink:type="resource" xlink:label="us-gaap_NetCashProvidedByUsedInFinancingActivities_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_NetCashProvidedByUsedInFinancingActivities_lbl1" xml:lang="en-US" id="us-gaap_NetCashProvidedByUsedInFinancingActivities_lbl1">Net Cash Provided by (Used in) Financing Activities</link:label>
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    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_OperatingLeaseRightOfUseAssetStatementOfFinancialPositionExtensibleList" xlink:label="OperatingLeaseRightOfUseAssetStatementOfFinancialPositionExtensibleList" xlink:title="OperatingLeaseRightOfUseAssetStatementOfFinancialPositionExtensibleList" />
    <link:label xlink:type="resource" xlink:label="us-gaap_OperatingLeaseRightOfUseAssetStatementOfFinancialPositionExtensibleList_lbl" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_OperatingLeaseRightOfUseAssetStatementOfFinancialPositionExtensibleList_lbl" xml:lang="en-US" id="us-gaap_OperatingLeaseRightOfUseAssetStatementOfFinancialPositionExtensibleList_lbl">Operating Lease, Right-of-Use Asset, Statement of Financial Position [Extensible List]</link:label>
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    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_OperatingIncomeLoss" xlink:label="OperatingIncomeLoss" xlink:title="OperatingIncomeLoss" />
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    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_PaymentsForHedgeFinancingActivities" xlink:label="PaymentsForHedgeFinancingActivities" xlink:title="PaymentsForHedgeFinancingActivities" />
    <link:label xlink:type="resource" xlink:label="us-gaap_PaymentsForHedgeFinancingActivities_lbl" xlink:role="http://www.xbrl.org/2009/role/negatedLabel" xlink:title="us-gaap_PaymentsForHedgeFinancingActivities_lbl" xml:lang="en-US" id="us-gaap_PaymentsForHedgeFinancingActivities_lbl">Purchase of note hedges</link:label>
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    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_PaymentsRelatedToTaxWithholdingForShareBasedCompensation" xlink:label="PaymentsRelatedToTaxWithholdingForShareBasedCompensation" xlink:title="PaymentsRelatedToTaxWithholdingForShareBasedCompensation" />
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    <link:label xlink:type="resource" xlink:label="us-gaap_PaymentsForRepurchaseOfCommonStock_lbl1" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="us-gaap_PaymentsForRepurchaseOfCommonStock_lbl1" xml:lang="en-US" id="us-gaap_PaymentsForRepurchaseOfCommonStock_lbl1">Shares repurchased</link:label>
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    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_PaymentsOfDebtIssuanceCosts" xlink:label="PaymentsOfDebtIssuanceCosts" xlink:title="PaymentsOfDebtIssuanceCosts" />
    <link:label xlink:type="resource" xlink:label="us-gaap_PaymentsOfDebtIssuanceCosts_lbl" xlink:role="http://www.xbrl.org/2009/role/negatedLabel" xlink:title="us-gaap_PaymentsOfDebtIssuanceCosts_lbl" xml:lang="en-US" id="us-gaap_PaymentsOfDebtIssuanceCosts_lbl">Convertible senior notes issuance costs</link:label>
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    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_PaymentsToAcquireAvailableForSaleSecuritiesDebt" xlink:label="PaymentsToAcquireAvailableForSaleSecuritiesDebt" xlink:title="PaymentsToAcquireAvailableForSaleSecuritiesDebt" />
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    <link:label xlink:type="resource" xlink:label="us-gaap_PaymentsForRestructuring_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_PaymentsForRestructuring_lbl1" xml:lang="en-US" id="us-gaap_PaymentsForRestructuring_lbl1">Payments for Restructuring</link:label>
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    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_PaymentsToAcquireBuildings" xlink:label="PaymentsToAcquireBuildings" xlink:title="PaymentsToAcquireBuildings" />
    <link:label xlink:type="resource" xlink:label="us-gaap_PaymentsToAcquireBuildings_lbl" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_PaymentsToAcquireBuildings_lbl" xml:lang="en-US" id="us-gaap_PaymentsToAcquireBuildings_lbl">Payment to acquire building</link:label>
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    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_PaymentsToAcquireIntangibleAssets" xlink:label="PaymentsToAcquireIntangibleAssets" xlink:title="PaymentsToAcquireIntangibleAssets" />
    <link:label xlink:type="resource" xlink:label="us-gaap_PaymentsToAcquireIntangibleAssets_lbl" xlink:role="http://www.xbrl.org/2009/role/negatedLabel" xlink:title="us-gaap_PaymentsToAcquireIntangibleAssets_lbl" xml:lang="en-US" id="us-gaap_PaymentsToAcquireIntangibleAssets_lbl">Acquisition of licenses and other assets, net</link:label>
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    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_PaymentsToAcquirePropertyPlantAndEquipmentAbstract" xlink:label="PaymentsToAcquirePropertyPlantAndEquipmentAbstract" xlink:title="PaymentsToAcquirePropertyPlantAndEquipmentAbstract" />
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    <link:label xlink:type="resource" xlink:label="us-gaap_ProductMember_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_ProductMember_lbl1" xml:lang="en-US" id="us-gaap_ProductMember_lbl1">TEGSEDI and WAYLIVRA [Member]</link:label>
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    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_ProfitLoss" xlink:label="ProfitLoss" xlink:title="ProfitLoss" />
    <link:label xlink:type="resource" xlink:label="us-gaap_ProfitLoss_lbl" xlink:role="http://www.xbrl.org/2003/role/totalLabel" xlink:title="us-gaap_ProfitLoss_lbl" xml:lang="en-US" id="us-gaap_ProfitLoss_lbl">Net income (loss)</link:label>
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    <link:label xlink:type="resource" xlink:label="us-gaap_ProfitLoss_lbl1" xlink:role="http://www.xbrl.org/2003/role/verboseLabel" xlink:title="us-gaap_ProfitLoss_lbl1" xml:lang="en-US" id="us-gaap_ProfitLoss_lbl1">Net income (loss)</link:label>
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    <link:label xlink:type="resource" xlink:label="us-gaap_PropertyPlantAndEquipmentLineItems_lbl" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_PropertyPlantAndEquipmentLineItems_lbl" xml:lang="en-US" id="us-gaap_PropertyPlantAndEquipmentLineItems_lbl">Property, Plant and Equipment [Line Items]</link:label>
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    <link:label xlink:type="resource" xlink:label="us-gaap_PropertyPlantAndEquipmentUsefulLife_lbl" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="us-gaap_PropertyPlantAndEquipmentUsefulLife_lbl" xml:lang="en-US" id="us-gaap_PropertyPlantAndEquipmentUsefulLife_lbl">Estimated useful lives</link:label>
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    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_PropertyPlantAndEquipmentAbstract" xlink:label="PropertyPlantAndEquipmentAbstract" xlink:title="PropertyPlantAndEquipmentAbstract" />
    <link:label xlink:type="resource" xlink:label="us-gaap_PropertyPlantAndEquipmentAbstract_lbl" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="us-gaap_PropertyPlantAndEquipmentAbstract_lbl" xml:lang="en-US" id="us-gaap_PropertyPlantAndEquipmentAbstract_lbl">Property, Plant and Equipment [Abstract]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="PropertyPlantAndEquipmentAbstract" xlink:to="us-gaap_PropertyPlantAndEquipmentAbstract_lbl" xlink:title="label: PropertyPlantAndEquipmentAbstract to us-gaap_PropertyPlantAndEquipmentAbstract_lbl" />
    <link:label xlink:type="resource" xlink:label="us-gaap_PropertyPlantAndEquipmentAbstract_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_PropertyPlantAndEquipmentAbstract_lbl1" xml:lang="en-US" id="us-gaap_PropertyPlantAndEquipmentAbstract_lbl1">Property, Plant and Equipment [Abstract]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="PropertyPlantAndEquipmentAbstract" xlink:to="us-gaap_PropertyPlantAndEquipmentAbstract_lbl1" xlink:title="label: PropertyPlantAndEquipmentAbstract to us-gaap_PropertyPlantAndEquipmentAbstract_lbl1" />
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    <link:label xlink:type="resource" xlink:label="us-gaap_PropertyPlantAndEquipmentTextBlock_lbl" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="us-gaap_PropertyPlantAndEquipmentTextBlock_lbl" xml:lang="en-US" id="us-gaap_PropertyPlantAndEquipmentTextBlock_lbl">Property, Plant and Equipment</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="PropertyPlantAndEquipmentTextBlock" xlink:to="us-gaap_PropertyPlantAndEquipmentTextBlock_lbl" xlink:title="label: PropertyPlantAndEquipmentTextBlock to us-gaap_PropertyPlantAndEquipmentTextBlock_lbl" />
    <link:label xlink:type="resource" xlink:label="us-gaap_PropertyPlantAndEquipmentTextBlock_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_PropertyPlantAndEquipmentTextBlock_lbl1" xml:lang="en-US" id="us-gaap_PropertyPlantAndEquipmentTextBlock_lbl1">Property, Plant and Equipment [Table Text Block]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="PropertyPlantAndEquipmentTextBlock" xlink:to="us-gaap_PropertyPlantAndEquipmentTextBlock_lbl1" xlink:title="label: PropertyPlantAndEquipmentTextBlock to us-gaap_PropertyPlantAndEquipmentTextBlock_lbl1" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_PropertyPlantAndEquipmentByTypeAxis" xlink:label="PropertyPlantAndEquipmentByTypeAxis" xlink:title="PropertyPlantAndEquipmentByTypeAxis" />
    <link:label xlink:type="resource" xlink:label="us-gaap_PropertyPlantAndEquipmentByTypeAxis_lbl" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_PropertyPlantAndEquipmentByTypeAxis_lbl" xml:lang="en-US" id="us-gaap_PropertyPlantAndEquipmentByTypeAxis_lbl">Long-Lived Tangible Asset [Axis]</link:label>
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    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_PropertyPlantAndEquipmentTypeDomain" xlink:label="PropertyPlantAndEquipmentTypeDomain" xlink:title="PropertyPlantAndEquipmentTypeDomain" />
    <link:label xlink:type="resource" xlink:label="us-gaap_PropertyPlantAndEquipmentTypeDomain_lbl" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_PropertyPlantAndEquipmentTypeDomain_lbl" xml:lang="en-US" id="us-gaap_PropertyPlantAndEquipmentTypeDomain_lbl">Long-Lived Tangible Asset [Domain]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="PropertyPlantAndEquipmentTypeDomain" xlink:to="us-gaap_PropertyPlantAndEquipmentTypeDomain_lbl" xlink:title="label: PropertyPlantAndEquipmentTypeDomain to us-gaap_PropertyPlantAndEquipmentTypeDomain_lbl" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_PropertyPlantAndEquipmentNet" xlink:label="PropertyPlantAndEquipmentNet" xlink:title="PropertyPlantAndEquipmentNet" />
    <link:label xlink:type="resource" xlink:label="us-gaap_PropertyPlantAndEquipmentNet_lbl" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="us-gaap_PropertyPlantAndEquipmentNet_lbl" xml:lang="en-US" id="us-gaap_PropertyPlantAndEquipmentNet_lbl">Property, plant and equipment, net</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="PropertyPlantAndEquipmentNet" xlink:to="us-gaap_PropertyPlantAndEquipmentNet_lbl" xlink:title="label: PropertyPlantAndEquipmentNet to us-gaap_PropertyPlantAndEquipmentNet_lbl" />
    <link:label xlink:type="resource" xlink:label="us-gaap_PropertyPlantAndEquipmentNet_lbl1" xlink:role="http://www.xbrl.org/2003/role/totalLabel" xlink:title="us-gaap_PropertyPlantAndEquipmentNet_lbl1" xml:lang="en-US" id="us-gaap_PropertyPlantAndEquipmentNet_lbl1">Property, plant and equipment, net</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="PropertyPlantAndEquipmentNet" xlink:to="us-gaap_PropertyPlantAndEquipmentNet_lbl1" xlink:title="label: PropertyPlantAndEquipmentNet to us-gaap_PropertyPlantAndEquipmentNet_lbl1" />
    <link:label xlink:type="resource" xlink:label="us-gaap_PropertyPlantAndEquipmentNet_lbl2" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_PropertyPlantAndEquipmentNet_lbl2" xml:lang="en-US" id="us-gaap_PropertyPlantAndEquipmentNet_lbl2">Property, Plant and Equipment, Net</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="PropertyPlantAndEquipmentNet" xlink:to="us-gaap_PropertyPlantAndEquipmentNet_lbl2" xlink:title="label: PropertyPlantAndEquipmentNet to us-gaap_PropertyPlantAndEquipmentNet_lbl2" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_PropertyPlantAndEquipmentPolicyTextBlock" xlink:label="PropertyPlantAndEquipmentPolicyTextBlock" xlink:title="PropertyPlantAndEquipmentPolicyTextBlock" />
    <link:label xlink:type="resource" xlink:label="us-gaap_PropertyPlantAndEquipmentPolicyTextBlock_lbl" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="us-gaap_PropertyPlantAndEquipmentPolicyTextBlock_lbl" xml:lang="en-US" id="us-gaap_PropertyPlantAndEquipmentPolicyTextBlock_lbl">Property, Plant and Equipment</link:label>
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    <link:label xlink:type="resource" xlink:label="us-gaap_PropertyPlantAndEquipmentPolicyTextBlock_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_PropertyPlantAndEquipmentPolicyTextBlock_lbl1" xml:lang="en-US" id="us-gaap_PropertyPlantAndEquipmentPolicyTextBlock_lbl1">Property, Plant and Equipment, Policy [Policy Text Block]</link:label>
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    <link:label xlink:type="resource" xlink:label="us-gaap_PropertyPlantAndEquipmentGross_lbl" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="us-gaap_PropertyPlantAndEquipmentGross_lbl" xml:lang="en-US" id="us-gaap_PropertyPlantAndEquipmentGross_lbl">Property, plant and equipment</link:label>
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    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_PublicUtilitiesInventoryAxis" xlink:label="PublicUtilitiesInventoryAxis" xlink:title="PublicUtilitiesInventoryAxis" />
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    <link:label xlink:type="resource" xlink:label="us-gaap_RestructuringCostAndReserveAxis_lbl" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_RestructuringCostAndReserveAxis_lbl" xml:lang="en-US" id="us-gaap_RestructuringCostAndReserveAxis_lbl">Restructuring Type [Axis]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="RestructuringCostAndReserveAxis" xlink:to="us-gaap_RestructuringCostAndReserveAxis_lbl" xlink:title="label: RestructuringCostAndReserveAxis to us-gaap_RestructuringCostAndReserveAxis_lbl" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_RestructuringReserveAccrualAdjustment1" xlink:label="RestructuringReserveAccrualAdjustment1" xlink:title="RestructuringReserveAccrualAdjustment1" />
    <link:label xlink:type="resource" xlink:label="us-gaap_RestructuringReserveAccrualAdjustment1_lbl" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="us-gaap_RestructuringReserveAccrualAdjustment1_lbl" xml:lang="en-US" id="us-gaap_RestructuringReserveAccrualAdjustment1_lbl">Reserve adjustments during the year</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="RestructuringReserveAccrualAdjustment1" xlink:to="us-gaap_RestructuringReserveAccrualAdjustment1_lbl" xlink:title="label: RestructuringReserveAccrualAdjustment1 to us-gaap_RestructuringReserveAccrualAdjustment1_lbl" />
    <link:label xlink:type="resource" xlink:label="us-gaap_RestructuringReserveAccrualAdjustment1_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_RestructuringReserveAccrualAdjustment1_lbl1" xml:lang="en-US" id="us-gaap_RestructuringReserveAccrualAdjustment1_lbl1">Restructuring Reserve, Accrual Adjustment</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="RestructuringReserveAccrualAdjustment1" xlink:to="us-gaap_RestructuringReserveAccrualAdjustment1_lbl1" xlink:title="label: RestructuringReserveAccrualAdjustment1 to us-gaap_RestructuringReserveAccrualAdjustment1_lbl1" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_RestructuringCostAndReserveLineItems" xlink:label="RestructuringCostAndReserveLineItems" xlink:title="RestructuringCostAndReserveLineItems" />
    <link:label xlink:type="resource" xlink:label="us-gaap_RestructuringCostAndReserveLineItems_lbl" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_RestructuringCostAndReserveLineItems_lbl" xml:lang="en-US" id="us-gaap_RestructuringCostAndReserveLineItems_lbl">Restructuring Cost and Reserve [Line Items]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="RestructuringCostAndReserveLineItems" xlink:to="us-gaap_RestructuringCostAndReserveLineItems_lbl" xlink:title="label: RestructuringCostAndReserveLineItems to us-gaap_RestructuringCostAndReserveLineItems_lbl" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_RestructuringAndRelatedActivitiesAbstract" xlink:label="RestructuringAndRelatedActivitiesAbstract" xlink:title="RestructuringAndRelatedActivitiesAbstract" />
    <link:label xlink:type="resource" xlink:label="us-gaap_RestructuringAndRelatedActivitiesAbstract_lbl" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_RestructuringAndRelatedActivitiesAbstract_lbl" xml:lang="en-US" id="us-gaap_RestructuringAndRelatedActivitiesAbstract_lbl">Severance and Retention Costs related to our Restructured Operations [Abstract]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="RestructuringAndRelatedActivitiesAbstract" xlink:to="us-gaap_RestructuringAndRelatedActivitiesAbstract_lbl" xlink:title="label: RestructuringAndRelatedActivitiesAbstract to us-gaap_RestructuringAndRelatedActivitiesAbstract_lbl" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_RestructuringCharges" xlink:label="RestructuringCharges" xlink:title="RestructuringCharges" />
    <link:label xlink:type="resource" xlink:label="us-gaap_RestructuringCharges_lbl" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="us-gaap_RestructuringCharges_lbl" xml:lang="en-US" id="us-gaap_RestructuringCharges_lbl">Amount expensed during the year</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="RestructuringCharges" xlink:to="us-gaap_RestructuringCharges_lbl" xlink:title="label: RestructuringCharges to us-gaap_RestructuringCharges_lbl" />
    <link:label xlink:type="resource" xlink:label="us-gaap_RestructuringCharges_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_RestructuringCharges_lbl1" xml:lang="en-US" id="us-gaap_RestructuringCharges_lbl1">Net amount expensed during the year</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="RestructuringCharges" xlink:to="us-gaap_RestructuringCharges_lbl1" xlink:title="label: RestructuringCharges to us-gaap_RestructuringCharges_lbl1" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_RestructuringCostsAbstract" xlink:label="RestructuringCostsAbstract" xlink:title="RestructuringCostsAbstract" />
    <link:label xlink:type="resource" xlink:label="us-gaap_RestructuringCostsAbstract_lbl" xlink:role="http://www.xbrl.org/2003/role/verboseLabel" xlink:title="us-gaap_RestructuringCostsAbstract_lbl" xml:lang="en-US" id="us-gaap_RestructuringCostsAbstract_lbl">Severance and Retention Costs related to our Restructured European Operations [Abstract]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="RestructuringCostsAbstract" xlink:to="us-gaap_RestructuringCostsAbstract_lbl" xlink:title="label: RestructuringCostsAbstract to us-gaap_RestructuringCostsAbstract_lbl" />
    <link:label xlink:type="resource" xlink:label="us-gaap_RestructuringCostsAbstract_lbl1" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="us-gaap_RestructuringCostsAbstract_lbl1" xml:lang="en-US" id="us-gaap_RestructuringCostsAbstract_lbl1">Severance and Retention Costs [Abstract]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="RestructuringCostsAbstract" xlink:to="us-gaap_RestructuringCostsAbstract_lbl1" xlink:title="label: RestructuringCostsAbstract to us-gaap_RestructuringCostsAbstract_lbl1" />
    <link:label xlink:type="resource" xlink:label="us-gaap_RestructuringCostsAbstract_lbl2" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_RestructuringCostsAbstract_lbl2" xml:lang="en-US" id="us-gaap_RestructuringCostsAbstract_lbl2">Restructuring Costs [Abstract]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="RestructuringCostsAbstract" xlink:to="us-gaap_RestructuringCostsAbstract_lbl2" xlink:title="label: RestructuringCostsAbstract to us-gaap_RestructuringCostsAbstract_lbl2" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_RestructuringReserve" xlink:label="RestructuringReserve" xlink:title="RestructuringReserve" />
    <link:label xlink:type="resource" xlink:label="us-gaap_RestructuringReserve_lbl" xlink:role="http://www.xbrl.org/2003/role/periodEndLabel" xlink:title="us-gaap_RestructuringReserve_lbl" xml:lang="en-US" id="us-gaap_RestructuringReserve_lbl">Ending balance</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="RestructuringReserve" xlink:to="us-gaap_RestructuringReserve_lbl" xlink:title="label: RestructuringReserve to us-gaap_RestructuringReserve_lbl" />
    <link:label xlink:type="resource" xlink:label="us-gaap_RestructuringReserve_lbl1" xlink:role="http://www.xbrl.org/2003/role/periodStartLabel" xlink:title="us-gaap_RestructuringReserve_lbl1" xml:lang="en-US" id="us-gaap_RestructuringReserve_lbl1">Beginning balance</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="RestructuringReserve" xlink:to="us-gaap_RestructuringReserve_lbl1" xlink:title="label: RestructuringReserve to us-gaap_RestructuringReserve_lbl1" />
    <link:label xlink:type="resource" xlink:label="us-gaap_RestructuringReserve_lbl2" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_RestructuringReserve_lbl2" xml:lang="en-US" id="us-gaap_RestructuringReserve_lbl2">Restructuring Reserve</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="RestructuringReserve" xlink:to="us-gaap_RestructuringReserve_lbl2" xlink:title="label: RestructuringReserve to us-gaap_RestructuringReserve_lbl2" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_RestructuringAndRelatedActivitiesDisclosureTextBlock" xlink:label="RestructuringAndRelatedActivitiesDisclosureTextBlock" xlink:title="RestructuringAndRelatedActivitiesDisclosureTextBlock" />
    <link:label xlink:type="resource" xlink:label="us-gaap_RestructuringAndRelatedActivitiesDisclosureTextBlock_lbl" xlink:role="http://www.xbrl.org/2003/role/verboseLabel" xlink:title="us-gaap_RestructuringAndRelatedActivitiesDisclosureTextBlock_lbl" xml:lang="en-US" id="us-gaap_RestructuringAndRelatedActivitiesDisclosureTextBlock_lbl">Severance and Retention Costs related to our Restructured Operations</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="RestructuringAndRelatedActivitiesDisclosureTextBlock" xlink:to="us-gaap_RestructuringAndRelatedActivitiesDisclosureTextBlock_lbl" xlink:title="label: RestructuringAndRelatedActivitiesDisclosureTextBlock to us-gaap_RestructuringAndRelatedActivitiesDisclosureTextBlock_lbl" />
    <link:label xlink:type="resource" xlink:label="us-gaap_RestructuringAndRelatedActivitiesDisclosureTextBlock_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_RestructuringAndRelatedActivitiesDisclosureTextBlock_lbl1" xml:lang="en-US" id="us-gaap_RestructuringAndRelatedActivitiesDisclosureTextBlock_lbl1">Restructuring and Related Activities Disclosure [Text Block]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="RestructuringAndRelatedActivitiesDisclosureTextBlock" xlink:to="us-gaap_RestructuringAndRelatedActivitiesDisclosureTextBlock_lbl1" xlink:title="label: RestructuringAndRelatedActivitiesDisclosureTextBlock to us-gaap_RestructuringAndRelatedActivitiesDisclosureTextBlock_lbl1" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_RetainedEarningsMember" xlink:label="RetainedEarningsMember" xlink:title="RetainedEarningsMember" />
    <link:label xlink:type="resource" xlink:label="us-gaap_RetainedEarningsMember_lbl" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="us-gaap_RetainedEarningsMember_lbl" xml:lang="en-US" id="us-gaap_RetainedEarningsMember_lbl">Accumulated Deficit [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="RetainedEarningsMember" xlink:to="us-gaap_RetainedEarningsMember_lbl" xlink:title="label: RetainedEarningsMember to us-gaap_RetainedEarningsMember_lbl" />
    <link:label xlink:type="resource" xlink:label="us-gaap_RetainedEarningsMember_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_RetainedEarningsMember_lbl1" xml:lang="en-US" id="us-gaap_RetainedEarningsMember_lbl1">Retained Earnings [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="RetainedEarningsMember" xlink:to="us-gaap_RetainedEarningsMember_lbl1" xlink:title="label: RetainedEarningsMember to us-gaap_RetainedEarningsMember_lbl1" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_RetainedEarningsAccumulatedDeficit" xlink:label="RetainedEarningsAccumulatedDeficit" xlink:title="RetainedEarningsAccumulatedDeficit" />
    <link:label xlink:type="resource" xlink:label="us-gaap_RetainedEarningsAccumulatedDeficit_lbl" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="us-gaap_RetainedEarningsAccumulatedDeficit_lbl" xml:lang="en-US" id="us-gaap_RetainedEarningsAccumulatedDeficit_lbl">Accumulated deficit</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="RetainedEarningsAccumulatedDeficit" xlink:to="us-gaap_RetainedEarningsAccumulatedDeficit_lbl" xlink:title="label: RetainedEarningsAccumulatedDeficit to us-gaap_RetainedEarningsAccumulatedDeficit_lbl" />
    <link:label xlink:type="resource" xlink:label="us-gaap_RetainedEarningsAccumulatedDeficit_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_RetainedEarningsAccumulatedDeficit_lbl1" xml:lang="en-US" id="us-gaap_RetainedEarningsAccumulatedDeficit_lbl1">Retained Earnings (Accumulated Deficit)</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="RetainedEarningsAccumulatedDeficit" xlink:to="us-gaap_RetainedEarningsAccumulatedDeficit_lbl1" xlink:title="label: RetainedEarningsAccumulatedDeficit to us-gaap_RetainedEarningsAccumulatedDeficit_lbl1" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_RevenueFromContractWithCustomerMember" xlink:label="RevenueFromContractWithCustomerMember" xlink:title="RevenueFromContractWithCustomerMember" />
    <link:label xlink:type="resource" xlink:label="us-gaap_RevenueFromContractWithCustomerMember_lbl" xlink:role="http://www.xbrl.org/2003/role/verboseLabel" xlink:title="us-gaap_RevenueFromContractWithCustomerMember_lbl" xml:lang="en-US" id="us-gaap_RevenueFromContractWithCustomerMember_lbl">Revenue [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="RevenueFromContractWithCustomerMember" xlink:to="us-gaap_RevenueFromContractWithCustomerMember_lbl" xlink:title="label: RevenueFromContractWithCustomerMember to us-gaap_RevenueFromContractWithCustomerMember_lbl" />
    <link:label xlink:type="resource" xlink:label="us-gaap_RevenueFromContractWithCustomerMember_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_RevenueFromContractWithCustomerMember_lbl1" xml:lang="en-US" id="us-gaap_RevenueFromContractWithCustomerMember_lbl1">Revenue from Contract with Customer Benchmark [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="RevenueFromContractWithCustomerMember" xlink:to="us-gaap_RevenueFromContractWithCustomerMember_lbl1" xlink:title="label: RevenueFromContractWithCustomerMember to us-gaap_RevenueFromContractWithCustomerMember_lbl1" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_RevenueFromContractWithCustomerAbstract" xlink:label="RevenueFromContractWithCustomerAbstract" xlink:title="RevenueFromContractWithCustomerAbstract" />
    <link:label xlink:type="resource" xlink:label="us-gaap_RevenueFromContractWithCustomerAbstract_lbl" xlink:role="http://www.xbrl.org/2003/role/verboseLabel" xlink:title="us-gaap_RevenueFromContractWithCustomerAbstract_lbl" xml:lang="en-US" id="us-gaap_RevenueFromContractWithCustomerAbstract_lbl">Revenue Recognition [Abstract]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="RevenueFromContractWithCustomerAbstract" xlink:to="us-gaap_RevenueFromContractWithCustomerAbstract_lbl" xlink:title="label: RevenueFromContractWithCustomerAbstract to us-gaap_RevenueFromContractWithCustomerAbstract_lbl" />
    <link:label xlink:type="resource" xlink:label="us-gaap_RevenueFromContractWithCustomerAbstract_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_RevenueFromContractWithCustomerAbstract_lbl1" xml:lang="en-US" id="us-gaap_RevenueFromContractWithCustomerAbstract_lbl1">Revenue from Contract with Customer [Abstract]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="RevenueFromContractWithCustomerAbstract" xlink:to="us-gaap_RevenueFromContractWithCustomerAbstract_lbl1" xlink:title="label: RevenueFromContractWithCustomerAbstract to us-gaap_RevenueFromContractWithCustomerAbstract_lbl1" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_RevenueFromContractWithCustomerPolicyTextBlock" xlink:label="RevenueFromContractWithCustomerPolicyTextBlock" xlink:title="RevenueFromContractWithCustomerPolicyTextBlock" />
    <link:label xlink:type="resource" xlink:label="us-gaap_RevenueFromContractWithCustomerPolicyTextBlock_lbl" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="us-gaap_RevenueFromContractWithCustomerPolicyTextBlock_lbl" xml:lang="en-US" id="us-gaap_RevenueFromContractWithCustomerPolicyTextBlock_lbl">Revenue Recognition</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="RevenueFromContractWithCustomerPolicyTextBlock" xlink:to="us-gaap_RevenueFromContractWithCustomerPolicyTextBlock_lbl" xlink:title="label: RevenueFromContractWithCustomerPolicyTextBlock to us-gaap_RevenueFromContractWithCustomerPolicyTextBlock_lbl" />
    <link:label xlink:type="resource" xlink:label="us-gaap_RevenueFromContractWithCustomerPolicyTextBlock_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_RevenueFromContractWithCustomerPolicyTextBlock_lbl1" xml:lang="en-US" id="us-gaap_RevenueFromContractWithCustomerPolicyTextBlock_lbl1">Revenue from Contract with Customer [Policy Text Block]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="RevenueFromContractWithCustomerPolicyTextBlock" xlink:to="us-gaap_RevenueFromContractWithCustomerPolicyTextBlock_lbl1" xlink:title="label: RevenueFromContractWithCustomerPolicyTextBlock to us-gaap_RevenueFromContractWithCustomerPolicyTextBlock_lbl1" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax" xlink:label="RevenueFromContractWithCustomerExcludingAssessedTax" xlink:title="RevenueFromContractWithCustomerExcludingAssessedTax" />
    <link:label xlink:type="resource" xlink:label="us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax_lbl" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax_lbl" xml:lang="en-US" id="us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax_lbl">Revenue</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="RevenueFromContractWithCustomerExcludingAssessedTax" xlink:to="us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax_lbl" xlink:title="label: RevenueFromContractWithCustomerExcludingAssessedTax to us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax_lbl" />
    <link:label xlink:type="resource" xlink:label="us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax_lbl1" xml:lang="en-US" id="us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax_lbl1">Revenue from Contract with Customer, Excluding Assessed Tax</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="RevenueFromContractWithCustomerExcludingAssessedTax" xlink:to="us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax_lbl1" xlink:title="label: RevenueFromContractWithCustomerExcludingAssessedTax to us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax_lbl1" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_RevenueRecognitionPolicyTextBlock" xlink:label="RevenueRecognitionPolicyTextBlock" xlink:title="RevenueRecognitionPolicyTextBlock" />
    <link:label xlink:type="resource" xlink:label="us-gaap_RevenueRecognitionPolicyTextBlock_lbl" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="us-gaap_RevenueRecognitionPolicyTextBlock_lbl" xml:lang="en-US" id="us-gaap_RevenueRecognitionPolicyTextBlock_lbl">Deferred Revenue</link:label>
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    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsForfeituresAndExpirationsInPeriod" xlink:label="ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsForfeituresAndExpirationsInPeriod" xlink:title="ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsForfeituresAndExpirationsInPeriod" />
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    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardFairValueAssumptionsWeightedAverageVolatilityRate" xlink:label="ShareBasedCompensationArrangementByShareBasedPaymentAwardFairValueAssumptionsWeightedAverageVolatilityRate" xlink:title="ShareBasedCompensationArrangementByShareBasedPaymentAwardFairValueAssumptionsWeightedAverageVolatilityRate" />
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    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsOutstandingWeightedAverageExercisePrice" xlink:to="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsOutstandingWeightedAverageExercisePrice_lbl1" xlink:title="label: ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsOutstandingWeightedAverageExercisePrice to us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsOutstandingWeightedAverageExercisePrice_lbl1" />
    <link:label xlink:type="resource" xlink:label="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsOutstandingWeightedAverageExercisePrice_lbl2" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsOutstandingWeightedAverageExercisePrice_lbl2" xml:lang="en-US" id="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsOutstandingWeightedAverageExercisePrice_lbl2">Share-based Compensation Arrangement by Share-based Payment Award, Options, Outstanding, Weighted Average Exercise Price</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsOutstandingWeightedAverageExercisePrice" xlink:to="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsOutstandingWeightedAverageExercisePrice_lbl2" xlink:title="label: ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsOutstandingWeightedAverageExercisePrice to us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsOutstandingWeightedAverageExercisePrice_lbl2" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsOutstandingIntrinsicValue" xlink:label="ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsOutstandingIntrinsicValue" xlink:title="ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsOutstandingIntrinsicValue" />
    <link:label xlink:type="resource" xlink:label="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsOutstandingIntrinsicValue_lbl" xlink:role="http://www.xbrl.org/2003/role/periodEndLabel" xlink:title="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsOutstandingIntrinsicValue_lbl" xml:lang="en-US" id="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsOutstandingIntrinsicValue_lbl">Aggregate intrinsic value, outstanding at end of period</link:label>
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    <link:label xlink:type="resource" xlink:label="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsOutstandingIntrinsicValue_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsOutstandingIntrinsicValue_lbl1" xml:lang="en-US" id="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsOutstandingIntrinsicValue_lbl1">Share-based Compensation Arrangement by Share-based Payment Award, Options, Outstanding, Intrinsic Value</link:label>
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    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsGrantsInPeriodWeightedAverageGrantDateFairValue" xlink:label="ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsGrantsInPeriodWeightedAverageGrantDateFairValue" xlink:title="ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsGrantsInPeriodWeightedAverageGrantDateFairValue" />
    <link:label xlink:type="resource" xlink:label="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsGrantsInPeriodWeightedAverageGrantDateFairValue_lbl" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsGrantsInPeriodWeightedAverageGrantDateFairValue_lbl" xml:lang="en-US" id="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsGrantsInPeriodWeightedAverageGrantDateFairValue_lbl">Weighted average fair value of options granted (in dollars per share)</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsGrantsInPeriodWeightedAverageGrantDateFairValue" xlink:to="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsGrantsInPeriodWeightedAverageGrantDateFairValue_lbl" xlink:title="label: ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsGrantsInPeriodWeightedAverageGrantDateFairValue to us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsGrantsInPeriodWeightedAverageGrantDateFairValue_lbl" />
    <link:label xlink:type="resource" xlink:label="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsGrantsInPeriodWeightedAverageGrantDateFairValue_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsGrantsInPeriodWeightedAverageGrantDateFairValue_lbl1" xml:lang="en-US" id="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsGrantsInPeriodWeightedAverageGrantDateFairValue_lbl1">Weighted-average grant date fair value (in dollars per share)</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsGrantsInPeriodWeightedAverageGrantDateFairValue" xlink:to="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsGrantsInPeriodWeightedAverageGrantDateFairValue_lbl1" xlink:title="label: ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsGrantsInPeriodWeightedAverageGrantDateFairValue to us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsGrantsInPeriodWeightedAverageGrantDateFairValue_lbl1" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsOutstandingRollForward" xlink:label="ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsOutstandingRollForward" xlink:title="ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsOutstandingRollForward" />
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    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsOutstandingRollForward" xlink:to="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsOutstandingRollForward_lbl" xlink:title="label: ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsOutstandingRollForward to us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsOutstandingRollForward_lbl" />
    <link:label xlink:type="resource" xlink:label="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsOutstandingRollForward_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsOutstandingRollForward_lbl1" xml:lang="en-US" id="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsOutstandingRollForward_lbl1">Share-based Compensation Arrangement by Share-based Payment Award, Options, Outstanding [Roll Forward]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsOutstandingRollForward" xlink:to="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsOutstandingRollForward_lbl1" xlink:title="label: ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsOutstandingRollForward to us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsOutstandingRollForward_lbl1" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_ShareBasedCompensationArrangementsByShareBasedPaymentAwardAwardTypeAndPlanNameDomain" xlink:label="ShareBasedCompensationArrangementsByShareBasedPaymentAwardAwardTypeAndPlanNameDomain" xlink:title="ShareBasedCompensationArrangementsByShareBasedPaymentAwardAwardTypeAndPlanNameDomain" />
    <link:label xlink:type="resource" xlink:label="us-gaap_ShareBasedCompensationArrangementsByShareBasedPaymentAwardAwardTypeAndPlanNameDomain_lbl" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_ShareBasedCompensationArrangementsByShareBasedPaymentAwardAwardTypeAndPlanNameDomain_lbl" xml:lang="en-US" id="us-gaap_ShareBasedCompensationArrangementsByShareBasedPaymentAwardAwardTypeAndPlanNameDomain_lbl">Equity Award [Domain]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="ShareBasedCompensationArrangementsByShareBasedPaymentAwardAwardTypeAndPlanNameDomain" xlink:to="us-gaap_ShareBasedCompensationArrangementsByShareBasedPaymentAwardAwardTypeAndPlanNameDomain_lbl" xlink:title="label: ShareBasedCompensationArrangementsByShareBasedPaymentAwardAwardTypeAndPlanNameDomain to us-gaap_ShareBasedCompensationArrangementsByShareBasedPaymentAwardAwardTypeAndPlanNameDomain_lbl" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_ShareBasedCompensationOptionAndIncentivePlansPolicy" xlink:label="ShareBasedCompensationOptionAndIncentivePlansPolicy" xlink:title="ShareBasedCompensationOptionAndIncentivePlansPolicy" />
    <link:label xlink:type="resource" xlink:label="us-gaap_ShareBasedCompensationOptionAndIncentivePlansPolicy_lbl" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="us-gaap_ShareBasedCompensationOptionAndIncentivePlansPolicy_lbl" xml:lang="en-US" id="us-gaap_ShareBasedCompensationOptionAndIncentivePlansPolicy_lbl">Stock-Based Compensation Expense</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="ShareBasedCompensationOptionAndIncentivePlansPolicy" xlink:to="us-gaap_ShareBasedCompensationOptionAndIncentivePlansPolicy_lbl" xlink:title="label: ShareBasedCompensationOptionAndIncentivePlansPolicy to us-gaap_ShareBasedCompensationOptionAndIncentivePlansPolicy_lbl" />
    <link:label xlink:type="resource" xlink:label="us-gaap_ShareBasedCompensationOptionAndIncentivePlansPolicy_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_ShareBasedCompensationOptionAndIncentivePlansPolicy_lbl1" xml:lang="en-US" id="us-gaap_ShareBasedCompensationOptionAndIncentivePlansPolicy_lbl1">Share-based Payment Arrangement [Policy Text Block]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="ShareBasedCompensationOptionAndIncentivePlansPolicy" xlink:to="us-gaap_ShareBasedCompensationOptionAndIncentivePlansPolicy_lbl1" xlink:title="label: ShareBasedCompensationOptionAndIncentivePlansPolicy to us-gaap_ShareBasedCompensationOptionAndIncentivePlansPolicy_lbl1" />
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    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="SharesPaidForTaxWithholdingForShareBasedCompensation" xlink:to="us-gaap_SharesPaidForTaxWithholdingForShareBasedCompensation_lbl" xlink:title="label: SharesPaidForTaxWithholdingForShareBasedCompensation to us-gaap_SharesPaidForTaxWithholdingForShareBasedCompensation_lbl" />
    <link:label xlink:type="resource" xlink:label="us-gaap_SharesPaidForTaxWithholdingForShareBasedCompensation_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_SharesPaidForTaxWithholdingForShareBasedCompensation_lbl1" xml:lang="en-US" id="us-gaap_SharesPaidForTaxWithholdingForShareBasedCompensation_lbl1">Share-based Payment Arrangement, Shares Withheld for Tax Withholding Obligation</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="SharesPaidForTaxWithholdingForShareBasedCompensation" xlink:to="us-gaap_SharesPaidForTaxWithholdingForShareBasedCompensation_lbl1" xlink:title="label: SharesPaidForTaxWithholdingForShareBasedCompensation to us-gaap_SharesPaidForTaxWithholdingForShareBasedCompensation_lbl1" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_SharesIssued" xlink:label="SharesIssued" xlink:title="SharesIssued" />
    <link:label xlink:type="resource" xlink:label="us-gaap_SharesIssued_lbl" xlink:role="http://www.xbrl.org/2003/role/periodStartLabel" xlink:title="us-gaap_SharesIssued_lbl" xml:lang="en-US" id="us-gaap_SharesIssued_lbl">Balance (in shares)</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="SharesIssued" xlink:to="us-gaap_SharesIssued_lbl" xlink:title="label: SharesIssued to us-gaap_SharesIssued_lbl" />
    <link:label xlink:type="resource" xlink:label="us-gaap_SharesIssued_lbl1" xlink:role="http://www.xbrl.org/2003/role/periodEndLabel" xlink:title="us-gaap_SharesIssued_lbl1" xml:lang="en-US" id="us-gaap_SharesIssued_lbl1">Balance (in shares)</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="SharesIssued" xlink:to="us-gaap_SharesIssued_lbl1" xlink:title="label: SharesIssued to us-gaap_SharesIssued_lbl1" />
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    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="SharesIssued" xlink:to="us-gaap_SharesIssued_lbl2" xlink:title="label: SharesIssued to us-gaap_SharesIssued_lbl2" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_StatementOfFinancialPositionAbstract" xlink:label="StatementOfFinancialPositionAbstract" xlink:title="StatementOfFinancialPositionAbstract" />
    <link:label xlink:type="resource" xlink:label="us-gaap_StatementOfFinancialPositionAbstract_lbl" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_StatementOfFinancialPositionAbstract_lbl" xml:lang="en-US" id="us-gaap_StatementOfFinancialPositionAbstract_lbl">CONSOLIDATED BALANCE SHEETS [Abstract]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="StatementOfFinancialPositionAbstract" xlink:to="us-gaap_StatementOfFinancialPositionAbstract_lbl" xlink:title="label: StatementOfFinancialPositionAbstract to us-gaap_StatementOfFinancialPositionAbstract_lbl" />
    <link:label xlink:type="resource" xlink:label="us-gaap_StatementOfFinancialPositionAbstract_lbl1" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="us-gaap_StatementOfFinancialPositionAbstract_lbl1" xml:lang="en-US" id="us-gaap_StatementOfFinancialPositionAbstract_lbl1">Consolidated Balance Sheet [Abstract]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="StatementOfFinancialPositionAbstract" xlink:to="us-gaap_StatementOfFinancialPositionAbstract_lbl1" xlink:title="label: StatementOfFinancialPositionAbstract to us-gaap_StatementOfFinancialPositionAbstract_lbl1" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_StatementOfIncomeAndComprehensiveIncomeAbstract" xlink:label="StatementOfIncomeAndComprehensiveIncomeAbstract" xlink:title="StatementOfIncomeAndComprehensiveIncomeAbstract" />
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    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="StatementOfIncomeAndComprehensiveIncomeAbstract" xlink:to="us-gaap_StatementOfIncomeAndComprehensiveIncomeAbstract_lbl" xlink:title="label: StatementOfIncomeAndComprehensiveIncomeAbstract to us-gaap_StatementOfIncomeAndComprehensiveIncomeAbstract_lbl" />
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    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="StatementTable" xlink:to="us-gaap_StatementTable_lbl" xlink:title="label: StatementTable to us-gaap_StatementTable_lbl" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_StatementLineItems" xlink:label="StatementLineItems" xlink:title="StatementLineItems" />
    <link:label xlink:type="resource" xlink:label="us-gaap_StatementLineItems_lbl" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_StatementLineItems_lbl" xml:lang="en-US" id="us-gaap_StatementLineItems_lbl">Statement [Line Items]</link:label>
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    <link:label xlink:type="resource" xlink:label="us-gaap_ValuationAllowancesAndReservesPeriodIncreaseDecrease_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_ValuationAllowancesAndReservesPeriodIncreaseDecrease_lbl1" xml:lang="en-US" id="us-gaap_ValuationAllowancesAndReservesPeriodIncreaseDecrease_lbl1">SEC Schedule, 12-09, Valuation Allowances and Reserves, Period Increase (Decrease)</link:label>
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    <link:label xlink:type="resource" xlink:label="us-gaap_WeightedAverageNumberOfDilutedSharesOutstanding_lbl" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="us-gaap_WeightedAverageNumberOfDilutedSharesOutstanding_lbl" xml:lang="en-US" id="us-gaap_WeightedAverageNumberOfDilutedSharesOutstanding_lbl">Shares used in computing diluted net income (loss) per share (in shares)</link:label>
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    <link:label xlink:type="resource" xlink:label="us-gaap_WeightedAverageNumberOfDilutedSharesOutstanding_lbl1" xlink:role="http://www.xbrl.org/2003/role/totalLabel" xlink:title="us-gaap_WeightedAverageNumberOfDilutedSharesOutstanding_lbl1" xml:lang="en-US" id="us-gaap_WeightedAverageNumberOfDilutedSharesOutstanding_lbl1">Shares used in computing diluted net income per share (in shares)</link:label>
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    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_WeightedAverageNumberDilutedSharesOutstandingAdjustmentAbstract" xlink:label="WeightedAverageNumberDilutedSharesOutstandingAdjustmentAbstract" xlink:title="WeightedAverageNumberDilutedSharesOutstandingAdjustmentAbstract" />
    <link:label xlink:type="resource" xlink:label="us-gaap_WeightedAverageNumberDilutedSharesOutstandingAdjustmentAbstract_lbl" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_WeightedAverageNumberDilutedSharesOutstandingAdjustmentAbstract_lbl" xml:lang="en-US" id="us-gaap_WeightedAverageNumberDilutedSharesOutstandingAdjustmentAbstract_lbl">Effect of Diluted Securities [Abstract]</link:label>
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    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_WeightedAverageNumberOfSharesOutstandingDilutedDisclosureItemsAbstract" xlink:label="WeightedAverageNumberOfSharesOutstandingDilutedDisclosureItemsAbstract" xlink:title="WeightedAverageNumberOfSharesOutstandingDilutedDisclosureItemsAbstract" />
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    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/srt/2021/elts/srt-2021-01-31.xsd#srt_ChiefExecutiveOfficerMember" xlink:label="ChiefExecutiveOfficerMember" xlink:title="ChiefExecutiveOfficerMember" />
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    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="ChiefExecutiveOfficerMember" xlink:to="srt_ChiefExecutiveOfficerMember_lbl1" xlink:title="label: ChiefExecutiveOfficerMember to srt_ChiefExecutiveOfficerMember_lbl1" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/srt/2021/elts/srt-2021-01-31.xsd#srt_ConsolidatedEntitiesDomain" xlink:label="ConsolidatedEntitiesDomain" xlink:title="ConsolidatedEntitiesDomain" />
    <link:label xlink:type="resource" xlink:label="srt_ConsolidatedEntitiesDomain_lbl" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="srt_ConsolidatedEntitiesDomain_lbl" xml:lang="en-US" id="srt_ConsolidatedEntitiesDomain_lbl">Consolidated Entities [Domain]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="ConsolidatedEntitiesDomain" xlink:to="srt_ConsolidatedEntitiesDomain_lbl" xlink:title="label: ConsolidatedEntitiesDomain to srt_ConsolidatedEntitiesDomain_lbl" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/srt/2021/elts/srt-2021-01-31.xsd#srt_ConsolidatedEntitiesAxis" xlink:label="ConsolidatedEntitiesAxis" xlink:title="ConsolidatedEntitiesAxis" />
    <link:label xlink:type="resource" xlink:label="srt_ConsolidatedEntitiesAxis_lbl" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="srt_ConsolidatedEntitiesAxis_lbl" xml:lang="en-US" id="srt_ConsolidatedEntitiesAxis_lbl">Consolidated Entities [Axis]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="ConsolidatedEntitiesAxis" xlink:to="srt_ConsolidatedEntitiesAxis_lbl" xlink:title="label: ConsolidatedEntitiesAxis to srt_ConsolidatedEntitiesAxis_lbl" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/srt/2021/elts/srt-2021-01-31.xsd#srt_ContractualObligationFiscalYearMaturityScheduleTableTextBlock" xlink:label="ContractualObligationFiscalYearMaturityScheduleTableTextBlock" xlink:title="ContractualObligationFiscalYearMaturityScheduleTableTextBlock" />
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    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="ContractualObligationFiscalYearMaturityScheduleTableTextBlock" xlink:to="srt_ContractualObligationFiscalYearMaturityScheduleTableTextBlock_lbl1" xlink:title="label: ContractualObligationFiscalYearMaturityScheduleTableTextBlock to srt_ContractualObligationFiscalYearMaturityScheduleTableTextBlock_lbl1" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/srt/2021/elts/srt-2021-01-31.xsd#srt_EquityMethodInvesteeNameDomain" xlink:label="EquityMethodInvesteeNameDomain" xlink:title="EquityMethodInvesteeNameDomain" />
    <link:label xlink:type="resource" xlink:label="srt_EquityMethodInvesteeNameDomain_lbl" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="srt_EquityMethodInvesteeNameDomain_lbl" xml:lang="en-US" id="srt_EquityMethodInvesteeNameDomain_lbl">Investment, Name [Domain]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="EquityMethodInvesteeNameDomain" xlink:to="srt_EquityMethodInvesteeNameDomain_lbl" xlink:title="label: EquityMethodInvesteeNameDomain to srt_EquityMethodInvesteeNameDomain_lbl" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/srt/2021/elts/srt-2021-01-31.xsd#srt_LitigationCaseAxis" xlink:label="LitigationCaseAxis" xlink:title="LitigationCaseAxis" />
    <link:label xlink:type="resource" xlink:label="srt_LitigationCaseAxis_lbl" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="srt_LitigationCaseAxis_lbl" xml:lang="en-US" id="srt_LitigationCaseAxis_lbl">Litigation Case [Axis]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="LitigationCaseAxis" xlink:to="srt_LitigationCaseAxis_lbl" xlink:title="label: LitigationCaseAxis to srt_LitigationCaseAxis_lbl" />
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    <link:label xlink:type="resource" xlink:label="srt_LitigationCaseTypeDomain_lbl" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="srt_LitigationCaseTypeDomain_lbl" xml:lang="en-US" id="srt_LitigationCaseTypeDomain_lbl">Litigation Case [Domain]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="LitigationCaseTypeDomain" xlink:to="srt_LitigationCaseTypeDomain_lbl" xlink:title="label: LitigationCaseTypeDomain to srt_LitigationCaseTypeDomain_lbl" />
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    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="MajorCustomersAxis" xlink:to="srt_MajorCustomersAxis_lbl" xlink:title="label: MajorCustomersAxis to srt_MajorCustomersAxis_lbl" />
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    <link:label xlink:type="resource" xlink:label="srt_MaximumMember_lbl1" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="srt_MaximumMember_lbl1" xml:lang="en-US" id="srt_MaximumMember_lbl1">Maximum [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="MaximumMember" xlink:to="srt_MaximumMember_lbl1" xlink:title="label: MaximumMember to srt_MaximumMember_lbl1" />
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    <link:label xlink:type="resource" xlink:label="srt_OwnershipDomain_lbl" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="srt_OwnershipDomain_lbl" xml:lang="en-US" id="srt_OwnershipDomain_lbl">Ownership [Domain]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="OwnershipDomain" xlink:to="srt_OwnershipDomain_lbl" xlink:title="label: OwnershipDomain to srt_OwnershipDomain_lbl" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/srt/2021/elts/srt-2021-01-31.xsd#srt_OwnershipAxis" xlink:label="OwnershipAxis" xlink:title="OwnershipAxis" />
    <link:label xlink:type="resource" xlink:label="srt_OwnershipAxis_lbl" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="srt_OwnershipAxis_lbl" xml:lang="en-US" id="srt_OwnershipAxis_lbl">Ownership [Axis]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="OwnershipAxis" xlink:to="srt_OwnershipAxis_lbl" xlink:title="label: OwnershipAxis to srt_OwnershipAxis_lbl" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/srt/2021/elts/srt-2021-01-31.xsd#srt_ProductsAndServicesDomain" xlink:label="ProductsAndServicesDomain" xlink:title="ProductsAndServicesDomain" />
    <link:label xlink:type="resource" xlink:label="srt_ProductsAndServicesDomain_lbl" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="srt_ProductsAndServicesDomain_lbl" xml:lang="en-US" id="srt_ProductsAndServicesDomain_lbl">Products and Services [Domain]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="ProductsAndServicesDomain" xlink:to="srt_ProductsAndServicesDomain_lbl" xlink:title="label: ProductsAndServicesDomain to srt_ProductsAndServicesDomain_lbl" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/srt/2021/elts/srt-2021-01-31.xsd#srt_ProductOrServiceAxis" xlink:label="ProductOrServiceAxis" xlink:title="ProductOrServiceAxis" />
    <link:label xlink:type="resource" xlink:label="srt_ProductOrServiceAxis_lbl" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="srt_ProductOrServiceAxis_lbl" xml:lang="en-US" id="srt_ProductOrServiceAxis_lbl">Products and Services [Axis]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="ProductOrServiceAxis" xlink:to="srt_ProductOrServiceAxis_lbl" xlink:title="label: ProductOrServiceAxis to srt_ProductOrServiceAxis_lbl" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/srt/2021/elts/srt-2021-01-31.xsd#srt_RevisionOfPriorPeriodAccountingStandardsUpdateAdjustmentMember" xlink:label="RevisionOfPriorPeriodAccountingStandardsUpdateAdjustmentMember" xlink:title="RevisionOfPriorPeriodAccountingStandardsUpdateAdjustmentMember" />
    <link:label xlink:type="resource" xlink:label="srt_RevisionOfPriorPeriodAccountingStandardsUpdateAdjustmentMember_lbl" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="srt_RevisionOfPriorPeriodAccountingStandardsUpdateAdjustmentMember_lbl" xml:lang="en-US" id="srt_RevisionOfPriorPeriodAccountingStandardsUpdateAdjustmentMember_lbl">Adjustment [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="RevisionOfPriorPeriodAccountingStandardsUpdateAdjustmentMember" xlink:to="srt_RevisionOfPriorPeriodAccountingStandardsUpdateAdjustmentMember_lbl" xlink:title="label: RevisionOfPriorPeriodAccountingStandardsUpdateAdjustmentMember to srt_RevisionOfPriorPeriodAccountingStandardsUpdateAdjustmentMember_lbl" />
    <link:label xlink:type="resource" xlink:label="srt_RevisionOfPriorPeriodAccountingStandardsUpdateAdjustmentMember_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="srt_RevisionOfPriorPeriodAccountingStandardsUpdateAdjustmentMember_lbl1" xml:lang="en-US" id="srt_RevisionOfPriorPeriodAccountingStandardsUpdateAdjustmentMember_lbl1">Revision of Prior Period, Accounting Standards Update, Adjustment [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="RevisionOfPriorPeriodAccountingStandardsUpdateAdjustmentMember" xlink:to="srt_RevisionOfPriorPeriodAccountingStandardsUpdateAdjustmentMember_lbl1" xlink:title="label: RevisionOfPriorPeriodAccountingStandardsUpdateAdjustmentMember to srt_RevisionOfPriorPeriodAccountingStandardsUpdateAdjustmentMember_lbl1" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/srt/2021/elts/srt-2021-01-31.xsd#srt_RangeMember" xlink:label="RangeMember" xlink:title="RangeMember" />
    <link:label xlink:type="resource" xlink:label="srt_RangeMember_lbl" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="srt_RangeMember_lbl" xml:lang="en-US" id="srt_RangeMember_lbl">Statistical Measurement [Domain]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="RangeMember" xlink:to="srt_RangeMember_lbl" xlink:title="label: RangeMember to srt_RangeMember_lbl" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/srt/2021/elts/srt-2021-01-31.xsd#srt_RangeAxis" xlink:label="RangeAxis" xlink:title="RangeAxis" />
    <link:label xlink:type="resource" xlink:label="srt_RangeAxis_lbl" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="srt_RangeAxis_lbl" xml:lang="en-US" id="srt_RangeAxis_lbl">Statistical Measurement [Axis]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="RangeAxis" xlink:to="srt_RangeAxis_lbl" xlink:title="label: RangeAxis to srt_RangeAxis_lbl" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/srt/2021/elts/srt-2021-01-31.xsd#srt_RestatementDomain" xlink:label="RestatementDomain" xlink:title="RestatementDomain" />
    <link:label xlink:type="resource" xlink:label="srt_RestatementDomain_lbl" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="srt_RestatementDomain_lbl" xml:lang="en-US" id="srt_RestatementDomain_lbl">Revision of Prior Period [Domain]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="RestatementDomain" xlink:to="srt_RestatementDomain_lbl" xlink:title="label: RestatementDomain to srt_RestatementDomain_lbl" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/srt/2021/elts/srt-2021-01-31.xsd#srt_RestatementAxis" xlink:label="RestatementAxis" xlink:title="RestatementAxis" />
    <link:label xlink:type="resource" xlink:label="srt_RestatementAxis_lbl" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="srt_RestatementAxis_lbl" xml:lang="en-US" id="srt_RestatementAxis_lbl">Revision of Prior Period [Axis]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="RestatementAxis" xlink:to="srt_RestatementAxis_lbl" xlink:title="label: RestatementAxis to srt_RestatementAxis_lbl" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/srt/2021/elts/srt-2021-01-31.xsd#srt_ScenarioPreviouslyReportedMember" xlink:label="ScenarioPreviouslyReportedMember" xlink:title="ScenarioPreviouslyReportedMember" />
    <link:label xlink:type="resource" xlink:label="srt_ScenarioPreviouslyReportedMember_lbl" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="srt_ScenarioPreviouslyReportedMember_lbl" xml:lang="en-US" id="srt_ScenarioPreviouslyReportedMember_lbl">As Previously Reported [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="ScenarioPreviouslyReportedMember" xlink:to="srt_ScenarioPreviouslyReportedMember_lbl" xlink:title="label: ScenarioPreviouslyReportedMember to srt_ScenarioPreviouslyReportedMember_lbl" />
    <link:label xlink:type="resource" xlink:label="srt_ScenarioPreviouslyReportedMember_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="srt_ScenarioPreviouslyReportedMember_lbl1" xml:lang="en-US" id="srt_ScenarioPreviouslyReportedMember_lbl1">Previously Reported [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="ScenarioPreviouslyReportedMember" xlink:to="srt_ScenarioPreviouslyReportedMember_lbl1" xlink:title="label: ScenarioPreviouslyReportedMember to srt_ScenarioPreviouslyReportedMember_lbl1" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/srt/2021/elts/srt-2021-01-31.xsd#srt_ScheduleOfEquityMethodInvestmentEquityMethodInvesteeNameAxis" xlink:label="ScheduleOfEquityMethodInvestmentEquityMethodInvesteeNameAxis" xlink:title="ScheduleOfEquityMethodInvestmentEquityMethodInvesteeNameAxis" />
    <link:label xlink:type="resource" xlink:label="srt_ScheduleOfEquityMethodInvestmentEquityMethodInvesteeNameAxis_lbl" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="srt_ScheduleOfEquityMethodInvestmentEquityMethodInvesteeNameAxis_lbl" xml:lang="en-US" id="srt_ScheduleOfEquityMethodInvestmentEquityMethodInvesteeNameAxis_lbl">Investment, Name [Axis]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="ScheduleOfEquityMethodInvestmentEquityMethodInvesteeNameAxis" xlink:to="srt_ScheduleOfEquityMethodInvestmentEquityMethodInvesteeNameAxis_lbl" xlink:title="label: ScheduleOfEquityMethodInvestmentEquityMethodInvesteeNameAxis to srt_ScheduleOfEquityMethodInvestmentEquityMethodInvesteeNameAxis_lbl" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.sec.gov/dei/2021q4/dei-2021q4.xsd#dei_CoverAbstract" xlink:label="CoverAbstract" xlink:title="CoverAbstract" />
    <link:label xlink:type="resource" xlink:label="dei_CoverAbstract_lbl" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="dei_CoverAbstract_lbl" xml:lang="en-US" id="dei_CoverAbstract_lbl">Cover [Abstract]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="CoverAbstract" xlink:to="dei_CoverAbstract_lbl" xlink:title="label: CoverAbstract to dei_CoverAbstract_lbl" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.sec.gov/dei/2021q4/dei-2021q4.xsd#dei_DocumentType" xlink:label="DocumentType" xlink:title="DocumentType" />
    <link:label xlink:type="resource" xlink:label="dei_DocumentType_lbl" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="dei_DocumentType_lbl" xml:lang="en-US" id="dei_DocumentType_lbl">Document Type</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="DocumentType" xlink:to="dei_DocumentType_lbl" xlink:title="label: DocumentType to dei_DocumentType_lbl" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.sec.gov/dei/2021q4/dei-2021q4.xsd#dei_DocumentAnnualReport" xlink:label="DocumentAnnualReport" xlink:title="DocumentAnnualReport" />
    <link:label xlink:type="resource" xlink:label="dei_DocumentAnnualReport_lbl" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="dei_DocumentAnnualReport_lbl" xml:lang="en-US" id="dei_DocumentAnnualReport_lbl">Document Annual Report</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="DocumentAnnualReport" xlink:to="dei_DocumentAnnualReport_lbl" xlink:title="label: DocumentAnnualReport to dei_DocumentAnnualReport_lbl" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.sec.gov/dei/2021q4/dei-2021q4.xsd#dei_DocumentTransitionReport" xlink:label="DocumentTransitionReport" xlink:title="DocumentTransitionReport" />
    <link:label xlink:type="resource" xlink:label="dei_DocumentTransitionReport_lbl" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="dei_DocumentTransitionReport_lbl" xml:lang="en-US" id="dei_DocumentTransitionReport_lbl">Document Transition Report</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="DocumentTransitionReport" xlink:to="dei_DocumentTransitionReport_lbl" xlink:title="label: DocumentTransitionReport to dei_DocumentTransitionReport_lbl" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.sec.gov/dei/2021q4/dei-2021q4.xsd#dei_EntityInteractiveDataCurrent" xlink:label="EntityInteractiveDataCurrent" xlink:title="EntityInteractiveDataCurrent" />
    <link:label xlink:type="resource" xlink:label="dei_EntityInteractiveDataCurrent_lbl" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="dei_EntityInteractiveDataCurrent_lbl" xml:lang="en-US" id="dei_EntityInteractiveDataCurrent_lbl">Entity Interactive Data Current</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="EntityInteractiveDataCurrent" xlink:to="dei_EntityInteractiveDataCurrent_lbl" xlink:title="label: EntityInteractiveDataCurrent to dei_EntityInteractiveDataCurrent_lbl" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.sec.gov/dei/2021q4/dei-2021q4.xsd#dei_AmendmentFlag" xlink:label="AmendmentFlag" xlink:title="AmendmentFlag" />
    <link:label xlink:type="resource" xlink:label="dei_AmendmentFlag_lbl" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="dei_AmendmentFlag_lbl" xml:lang="en-US" id="dei_AmendmentFlag_lbl">Amendment Flag</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="AmendmentFlag" xlink:to="dei_AmendmentFlag_lbl" xlink:title="label: AmendmentFlag to dei_AmendmentFlag_lbl" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.sec.gov/dei/2021q4/dei-2021q4.xsd#dei_IcfrAuditorAttestationFlag" xlink:label="IcfrAuditorAttestationFlag" xlink:title="IcfrAuditorAttestationFlag" />
    <link:label xlink:type="resource" xlink:label="dei_IcfrAuditorAttestationFlag_lbl" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="dei_IcfrAuditorAttestationFlag_lbl" xml:lang="en-US" id="dei_IcfrAuditorAttestationFlag_lbl">ICFR Auditor Attestation Flag</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="IcfrAuditorAttestationFlag" xlink:to="dei_IcfrAuditorAttestationFlag_lbl" xlink:title="label: IcfrAuditorAttestationFlag to dei_IcfrAuditorAttestationFlag_lbl" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.sec.gov/dei/2021q4/dei-2021q4.xsd#dei_DocumentFiscalYearFocus" xlink:label="DocumentFiscalYearFocus" xlink:title="DocumentFiscalYearFocus" />
    <link:label xlink:type="resource" xlink:label="dei_DocumentFiscalYearFocus_lbl" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="dei_DocumentFiscalYearFocus_lbl" xml:lang="en-US" id="dei_DocumentFiscalYearFocus_lbl">Document Fiscal Year Focus</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="DocumentFiscalYearFocus" xlink:to="dei_DocumentFiscalYearFocus_lbl" xlink:title="label: DocumentFiscalYearFocus to dei_DocumentFiscalYearFocus_lbl" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.sec.gov/dei/2021q4/dei-2021q4.xsd#dei_DocumentFiscalPeriodFocus" xlink:label="DocumentFiscalPeriodFocus" xlink:title="DocumentFiscalPeriodFocus" />
    <link:label xlink:type="resource" xlink:label="dei_DocumentFiscalPeriodFocus_lbl" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="dei_DocumentFiscalPeriodFocus_lbl" xml:lang="en-US" id="dei_DocumentFiscalPeriodFocus_lbl">Document Fiscal Period Focus</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="DocumentFiscalPeriodFocus" xlink:to="dei_DocumentFiscalPeriodFocus_lbl" xlink:title="label: DocumentFiscalPeriodFocus to dei_DocumentFiscalPeriodFocus_lbl" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.sec.gov/dei/2021q4/dei-2021q4.xsd#dei_DocumentPeriodEndDate" xlink:label="DocumentPeriodEndDate" xlink:title="DocumentPeriodEndDate" />
    <link:label xlink:type="resource" xlink:label="dei_DocumentPeriodEndDate_lbl" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="dei_DocumentPeriodEndDate_lbl" xml:lang="en-US" id="dei_DocumentPeriodEndDate_lbl">Document Period End Date</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="DocumentPeriodEndDate" xlink:to="dei_DocumentPeriodEndDate_lbl" xlink:title="label: DocumentPeriodEndDate to dei_DocumentPeriodEndDate_lbl" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.sec.gov/dei/2021q4/dei-2021q4.xsd#dei_EntityRegistrantName" xlink:label="EntityRegistrantName" xlink:title="EntityRegistrantName" />
    <link:label xlink:type="resource" xlink:label="dei_EntityRegistrantName_lbl" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="dei_EntityRegistrantName_lbl" xml:lang="en-US" id="dei_EntityRegistrantName_lbl">Entity Registrant Name</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="EntityRegistrantName" xlink:to="dei_EntityRegistrantName_lbl" xlink:title="label: EntityRegistrantName to dei_EntityRegistrantName_lbl" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.sec.gov/dei/2021q4/dei-2021q4.xsd#dei_EntityCentralIndexKey" xlink:label="EntityCentralIndexKey" xlink:title="EntityCentralIndexKey" />
    <link:label xlink:type="resource" xlink:label="dei_EntityCentralIndexKey_lbl" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="dei_EntityCentralIndexKey_lbl" xml:lang="en-US" id="dei_EntityCentralIndexKey_lbl">Entity Central Index Key</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="EntityCentralIndexKey" xlink:to="dei_EntityCentralIndexKey_lbl" xlink:title="label: EntityCentralIndexKey to dei_EntityCentralIndexKey_lbl" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.sec.gov/dei/2021q4/dei-2021q4.xsd#dei_EntityFileNumber" xlink:label="EntityFileNumber" xlink:title="EntityFileNumber" />
    <link:label xlink:type="resource" xlink:label="dei_EntityFileNumber_lbl" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="dei_EntityFileNumber_lbl" xml:lang="en-US" id="dei_EntityFileNumber_lbl">Entity File Number</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="EntityFileNumber" xlink:to="dei_EntityFileNumber_lbl" xlink:title="label: EntityFileNumber to dei_EntityFileNumber_lbl" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.sec.gov/dei/2021q4/dei-2021q4.xsd#dei_EntityTaxIdentificationNumber" xlink:label="EntityTaxIdentificationNumber" xlink:title="EntityTaxIdentificationNumber" />
    <link:label xlink:type="resource" xlink:label="dei_EntityTaxIdentificationNumber_lbl" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="dei_EntityTaxIdentificationNumber_lbl" xml:lang="en-US" id="dei_EntityTaxIdentificationNumber_lbl">Entity Tax Identification Number</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="EntityTaxIdentificationNumber" xlink:to="dei_EntityTaxIdentificationNumber_lbl" xlink:title="label: EntityTaxIdentificationNumber to dei_EntityTaxIdentificationNumber_lbl" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.sec.gov/dei/2021q4/dei-2021q4.xsd#dei_EntityIncorporationStateCountryCode" xlink:label="EntityIncorporationStateCountryCode" xlink:title="EntityIncorporationStateCountryCode" />
    <link:label xlink:type="resource" xlink:label="dei_EntityIncorporationStateCountryCode_lbl" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="dei_EntityIncorporationStateCountryCode_lbl" xml:lang="en-US" id="dei_EntityIncorporationStateCountryCode_lbl">Entity Incorporation, State or Country Code</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="EntityIncorporationStateCountryCode" xlink:to="dei_EntityIncorporationStateCountryCode_lbl" xlink:title="label: EntityIncorporationStateCountryCode to dei_EntityIncorporationStateCountryCode_lbl" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.sec.gov/dei/2021q4/dei-2021q4.xsd#dei_CurrentFiscalYearEndDate" xlink:label="CurrentFiscalYearEndDate" xlink:title="CurrentFiscalYearEndDate" />
    <link:label xlink:type="resource" xlink:label="dei_CurrentFiscalYearEndDate_lbl" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="dei_CurrentFiscalYearEndDate_lbl" xml:lang="en-US" id="dei_CurrentFiscalYearEndDate_lbl">Current Fiscal Year End Date</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="CurrentFiscalYearEndDate" xlink:to="dei_CurrentFiscalYearEndDate_lbl" xlink:title="label: CurrentFiscalYearEndDate to dei_CurrentFiscalYearEndDate_lbl" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.sec.gov/dei/2021q4/dei-2021q4.xsd#dei_EntityWellKnownSeasonedIssuer" xlink:label="EntityWellKnownSeasonedIssuer" xlink:title="EntityWellKnownSeasonedIssuer" />
    <link:label xlink:type="resource" xlink:label="dei_EntityWellKnownSeasonedIssuer_lbl" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="dei_EntityWellKnownSeasonedIssuer_lbl" xml:lang="en-US" id="dei_EntityWellKnownSeasonedIssuer_lbl">Entity Well-known Seasoned Issuer</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="EntityWellKnownSeasonedIssuer" xlink:to="dei_EntityWellKnownSeasonedIssuer_lbl" xlink:title="label: EntityWellKnownSeasonedIssuer to dei_EntityWellKnownSeasonedIssuer_lbl" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.sec.gov/dei/2021q4/dei-2021q4.xsd#dei_EntityVoluntaryFilers" xlink:label="EntityVoluntaryFilers" xlink:title="EntityVoluntaryFilers" />
    <link:label xlink:type="resource" xlink:label="dei_EntityVoluntaryFilers_lbl" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="dei_EntityVoluntaryFilers_lbl" xml:lang="en-US" id="dei_EntityVoluntaryFilers_lbl">Entity Voluntary Filers</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="EntityVoluntaryFilers" xlink:to="dei_EntityVoluntaryFilers_lbl" xlink:title="label: EntityVoluntaryFilers to dei_EntityVoluntaryFilers_lbl" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.sec.gov/dei/2021q4/dei-2021q4.xsd#dei_EntityCurrentReportingStatus" xlink:label="EntityCurrentReportingStatus" xlink:title="EntityCurrentReportingStatus" />
    <link:label xlink:type="resource" xlink:label="dei_EntityCurrentReportingStatus_lbl" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="dei_EntityCurrentReportingStatus_lbl" xml:lang="en-US" id="dei_EntityCurrentReportingStatus_lbl">Entity Current Reporting Status</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="EntityCurrentReportingStatus" xlink:to="dei_EntityCurrentReportingStatus_lbl" xlink:title="label: EntityCurrentReportingStatus to dei_EntityCurrentReportingStatus_lbl" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.sec.gov/dei/2021q4/dei-2021q4.xsd#dei_EntityShellCompany" xlink:label="EntityShellCompany" xlink:title="EntityShellCompany" />
    <link:label xlink:type="resource" xlink:label="dei_EntityShellCompany_lbl" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="dei_EntityShellCompany_lbl" xml:lang="en-US" id="dei_EntityShellCompany_lbl">Entity Shell Company</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="EntityShellCompany" xlink:to="dei_EntityShellCompany_lbl" xlink:title="label: EntityShellCompany to dei_EntityShellCompany_lbl" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.sec.gov/dei/2021q4/dei-2021q4.xsd#dei_EntityFilerCategory" xlink:label="EntityFilerCategory" xlink:title="EntityFilerCategory" />
    <link:label xlink:type="resource" xlink:label="dei_EntityFilerCategory_lbl" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="dei_EntityFilerCategory_lbl" xml:lang="en-US" id="dei_EntityFilerCategory_lbl">Entity Filer Category</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="EntityFilerCategory" xlink:to="dei_EntityFilerCategory_lbl" xlink:title="label: EntityFilerCategory to dei_EntityFilerCategory_lbl" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.sec.gov/dei/2021q4/dei-2021q4.xsd#dei_EntitySmallBusiness" xlink:label="EntitySmallBusiness" xlink:title="EntitySmallBusiness" />
    <link:label xlink:type="resource" xlink:label="dei_EntitySmallBusiness_lbl" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="dei_EntitySmallBusiness_lbl" xml:lang="en-US" id="dei_EntitySmallBusiness_lbl">Entity Small Business</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="EntitySmallBusiness" xlink:to="dei_EntitySmallBusiness_lbl" xlink:title="label: EntitySmallBusiness to dei_EntitySmallBusiness_lbl" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.sec.gov/dei/2021q4/dei-2021q4.xsd#dei_EntityEmergingGrowthCompany" xlink:label="EntityEmergingGrowthCompany" xlink:title="EntityEmergingGrowthCompany" />
    <link:label xlink:type="resource" xlink:label="dei_EntityEmergingGrowthCompany_lbl" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="dei_EntityEmergingGrowthCompany_lbl" xml:lang="en-US" id="dei_EntityEmergingGrowthCompany_lbl">Entity Emerging Growth Company</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="EntityEmergingGrowthCompany" xlink:to="dei_EntityEmergingGrowthCompany_lbl" xlink:title="label: EntityEmergingGrowthCompany to dei_EntityEmergingGrowthCompany_lbl" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.sec.gov/dei/2021q4/dei-2021q4.xsd#dei_EntityPublicFloat" xlink:label="EntityPublicFloat" xlink:title="EntityPublicFloat" />
    <link:label xlink:type="resource" xlink:label="dei_EntityPublicFloat_lbl" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="dei_EntityPublicFloat_lbl" xml:lang="en-US" id="dei_EntityPublicFloat_lbl">Entity Public Float</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="EntityPublicFloat" xlink:to="dei_EntityPublicFloat_lbl" xlink:title="label: EntityPublicFloat to dei_EntityPublicFloat_lbl" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.sec.gov/dei/2021q4/dei-2021q4.xsd#dei_EntityAddressAddressLine1" xlink:label="EntityAddressAddressLine1" xlink:title="EntityAddressAddressLine1" />
    <link:label xlink:type="resource" xlink:label="dei_EntityAddressAddressLine1_lbl" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="dei_EntityAddressAddressLine1_lbl" xml:lang="en-US" id="dei_EntityAddressAddressLine1_lbl">Entity Address, Address Line One</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="EntityAddressAddressLine1" xlink:to="dei_EntityAddressAddressLine1_lbl" xlink:title="label: EntityAddressAddressLine1 to dei_EntityAddressAddressLine1_lbl" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.sec.gov/dei/2021q4/dei-2021q4.xsd#dei_EntityAddressCityOrTown" xlink:label="EntityAddressCityOrTown" xlink:title="EntityAddressCityOrTown" />
    <link:label xlink:type="resource" xlink:label="dei_EntityAddressCityOrTown_lbl" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="dei_EntityAddressCityOrTown_lbl" xml:lang="en-US" id="dei_EntityAddressCityOrTown_lbl">Entity Address, City or Town</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="EntityAddressCityOrTown" xlink:to="dei_EntityAddressCityOrTown_lbl" xlink:title="label: EntityAddressCityOrTown to dei_EntityAddressCityOrTown_lbl" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.sec.gov/dei/2021q4/dei-2021q4.xsd#dei_EntityAddressStateOrProvince" xlink:label="EntityAddressStateOrProvince" xlink:title="EntityAddressStateOrProvince" />
    <link:label xlink:type="resource" xlink:label="dei_EntityAddressStateOrProvince_lbl" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="dei_EntityAddressStateOrProvince_lbl" xml:lang="en-US" id="dei_EntityAddressStateOrProvince_lbl">Entity Address, State or Province</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="EntityAddressStateOrProvince" xlink:to="dei_EntityAddressStateOrProvince_lbl" xlink:title="label: EntityAddressStateOrProvince to dei_EntityAddressStateOrProvince_lbl" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.sec.gov/dei/2021q4/dei-2021q4.xsd#dei_EntityAddressPostalZipCode" xlink:label="EntityAddressPostalZipCode" xlink:title="EntityAddressPostalZipCode" />
    <link:label xlink:type="resource" xlink:label="dei_EntityAddressPostalZipCode_lbl" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="dei_EntityAddressPostalZipCode_lbl" xml:lang="en-US" id="dei_EntityAddressPostalZipCode_lbl">Entity Address, Postal Zip Code</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="EntityAddressPostalZipCode" xlink:to="dei_EntityAddressPostalZipCode_lbl" xlink:title="label: EntityAddressPostalZipCode to dei_EntityAddressPostalZipCode_lbl" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.sec.gov/dei/2021q4/dei-2021q4.xsd#dei_CityAreaCode" xlink:label="CityAreaCode" xlink:title="CityAreaCode" />
    <link:label xlink:type="resource" xlink:label="dei_CityAreaCode_lbl" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="dei_CityAreaCode_lbl" xml:lang="en-US" id="dei_CityAreaCode_lbl">City Area Code</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="CityAreaCode" xlink:to="dei_CityAreaCode_lbl" xlink:title="label: CityAreaCode to dei_CityAreaCode_lbl" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.sec.gov/dei/2021q4/dei-2021q4.xsd#dei_LocalPhoneNumber" xlink:label="LocalPhoneNumber" xlink:title="LocalPhoneNumber" />
    <link:label xlink:type="resource" xlink:label="dei_LocalPhoneNumber_lbl" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="dei_LocalPhoneNumber_lbl" xml:lang="en-US" id="dei_LocalPhoneNumber_lbl">Local Phone Number</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="LocalPhoneNumber" xlink:to="dei_LocalPhoneNumber_lbl" xlink:title="label: LocalPhoneNumber to dei_LocalPhoneNumber_lbl" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.sec.gov/dei/2021q4/dei-2021q4.xsd#dei_Security12bTitle" xlink:label="Security12bTitle" xlink:title="Security12bTitle" />
    <link:label xlink:type="resource" xlink:label="dei_Security12bTitle_lbl" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="dei_Security12bTitle_lbl" xml:lang="en-US" id="dei_Security12bTitle_lbl">Title of 12(b) Security</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="Security12bTitle" xlink:to="dei_Security12bTitle_lbl" xlink:title="label: Security12bTitle to dei_Security12bTitle_lbl" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.sec.gov/dei/2021q4/dei-2021q4.xsd#dei_TradingSymbol" xlink:label="TradingSymbol" xlink:title="TradingSymbol" />
    <link:label xlink:type="resource" xlink:label="dei_TradingSymbol_lbl" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="dei_TradingSymbol_lbl" xml:lang="en-US" id="dei_TradingSymbol_lbl">Trading Symbol</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="TradingSymbol" xlink:to="dei_TradingSymbol_lbl" xlink:title="label: TradingSymbol to dei_TradingSymbol_lbl" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.sec.gov/dei/2021q4/dei-2021q4.xsd#dei_SecurityExchangeName" xlink:label="SecurityExchangeName" xlink:title="SecurityExchangeName" />
    <link:label xlink:type="resource" xlink:label="dei_SecurityExchangeName_lbl" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="dei_SecurityExchangeName_lbl" xml:lang="en-US" id="dei_SecurityExchangeName_lbl">Security Exchange Name</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="SecurityExchangeName" xlink:to="dei_SecurityExchangeName_lbl" xlink:title="label: SecurityExchangeName to dei_SecurityExchangeName_lbl" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.sec.gov/dei/2021q4/dei-2021q4.xsd#dei_EntityCommonStockSharesOutstanding" xlink:label="EntityCommonStockSharesOutstanding" xlink:title="EntityCommonStockSharesOutstanding" />
    <link:label xlink:type="resource" xlink:label="dei_EntityCommonStockSharesOutstanding_lbl" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="dei_EntityCommonStockSharesOutstanding_lbl" xml:lang="en-US" id="dei_EntityCommonStockSharesOutstanding_lbl">Entity Common Stock, Shares Outstanding</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="EntityCommonStockSharesOutstanding" xlink:to="dei_EntityCommonStockSharesOutstanding_lbl" xlink:title="label: EntityCommonStockSharesOutstanding to dei_EntityCommonStockSharesOutstanding_lbl" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.sec.gov/dei/2021q4/dei-2021q4.xsd#dei_AuditorName" xlink:label="AuditorName" xlink:title="AuditorName" />
    <link:label xlink:type="resource" xlink:label="dei_AuditorName_lbl" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="dei_AuditorName_lbl" xml:lang="en-US" id="dei_AuditorName_lbl">Auditor Name</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="AuditorName" xlink:to="dei_AuditorName_lbl" xlink:title="label: AuditorName to dei_AuditorName_lbl" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.sec.gov/dei/2021q4/dei-2021q4.xsd#dei_AuditorLocation" xlink:label="AuditorLocation" xlink:title="AuditorLocation" />
    <link:label xlink:type="resource" xlink:label="dei_AuditorLocation_lbl" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="dei_AuditorLocation_lbl" xml:lang="en-US" id="dei_AuditorLocation_lbl">Auditor Location</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="AuditorLocation" xlink:to="dei_AuditorLocation_lbl" xlink:title="label: AuditorLocation to dei_AuditorLocation_lbl" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.sec.gov/dei/2021q4/dei-2021q4.xsd#dei_AuditorFirmId" xlink:label="AuditorFirmId" xlink:title="AuditorFirmId" />
    <link:label xlink:type="resource" xlink:label="dei_AuditorFirmId_lbl" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="dei_AuditorFirmId_lbl" xml:lang="en-US" id="dei_AuditorFirmId_lbl">Auditor Firm ID</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="AuditorFirmId" xlink:to="dei_AuditorFirmId_lbl" xlink:title="label: AuditorFirmId to dei_AuditorFirmId_lbl" />
    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_CollaborativeArrangementsAndLicensingAgreementsAbstract" xlink:label="CollaborativeArrangementsAndLicensingAgreementsAbstract" xlink:title="CollaborativeArrangementsAndLicensingAgreementsAbstract" />
    <link:label xlink:type="resource" xlink:label="ions_CollaborativeArrangementsAndLicensingAgreementsAbstract_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_CollaborativeArrangementsAndLicensingAgreementsAbstract_lbl1" xml:lang="en-US" id="ions_CollaborativeArrangementsAndLicensingAgreementsAbstract_lbl1">Collaborative Arrangements and Licensing Agreements [Abstract]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="CollaborativeArrangementsAndLicensingAgreementsAbstract" xlink:to="ions_CollaborativeArrangementsAndLicensingAgreementsAbstract_lbl1" xlink:title="label: CollaborativeArrangementsAndLicensingAgreementsAbstract to ions_CollaborativeArrangementsAndLicensingAgreementsAbstract_lbl1" />
    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_LongTermObligationsCurrent" xlink:label="LongTermObligationsCurrent" xlink:title="LongTermObligationsCurrent" />
    <link:label xlink:type="resource" xlink:label="ions_LongTermObligationsCurrent_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_LongTermObligationsCurrent_lbl" xml:lang="en-US" id="ions_LongTermObligationsCurrent_lbl">Amount of long-term debt and lease obligations, classified as current.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="LongTermObligationsCurrent" xlink:to="ions_LongTermObligationsCurrent_lbl" xlink:title="label: LongTermObligationsCurrent to ions_LongTermObligationsCurrent_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_LongTermObligationsCurrent_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_LongTermObligationsCurrent_lbl1" xml:lang="en-US" id="ions_LongTermObligationsCurrent_lbl1">Long-term Obligations, Current</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="LongTermObligationsCurrent" xlink:to="ions_LongTermObligationsCurrent_lbl1" xlink:title="label: LongTermObligationsCurrent to ions_LongTermObligationsCurrent_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_LongTermObligationsCurrent_lbl2" xlink:role="http://www.xbrl.org/2009/role/negatedLabel" xlink:title="ions_LongTermObligationsCurrent_lbl2" xml:lang="en-US" id="ions_LongTermObligationsCurrent_lbl2">Less: current portion</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="LongTermObligationsCurrent" xlink:to="ions_LongTermObligationsCurrent_lbl2" xlink:title="label: LongTermObligationsCurrent to ions_LongTermObligationsCurrent_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_LongTermObligationsNoncurrent" xlink:label="LongTermObligationsNoncurrent" xlink:title="LongTermObligationsNoncurrent" />
    <link:label xlink:type="resource" xlink:label="ions_LongTermObligationsNoncurrent_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_LongTermObligationsNoncurrent_lbl" xml:lang="en-US" id="ions_LongTermObligationsNoncurrent_lbl">Amount of long-term debt and lease obligations, classified as noncurrent.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="LongTermObligationsNoncurrent" xlink:to="ions_LongTermObligationsNoncurrent_lbl" xlink:title="label: LongTermObligationsNoncurrent to ions_LongTermObligationsNoncurrent_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_LongTermObligationsNoncurrent_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_LongTermObligationsNoncurrent_lbl1" xml:lang="en-US" id="ions_LongTermObligationsNoncurrent_lbl1">Long-term Obligations, Noncurrent</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="LongTermObligationsNoncurrent" xlink:to="ions_LongTermObligationsNoncurrent_lbl1" xlink:title="label: LongTermObligationsNoncurrent to ions_LongTermObligationsNoncurrent_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_LongTermObligationsNoncurrent_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_LongTermObligationsNoncurrent_lbl2" xml:lang="en-US" id="ions_LongTermObligationsNoncurrent_lbl2">Total Long-Term Obligations</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="LongTermObligationsNoncurrent" xlink:to="ions_LongTermObligationsNoncurrent_lbl2" xlink:title="label: LongTermObligationsNoncurrent to ions_LongTermObligationsNoncurrent_lbl2" />
    <link:label xlink:type="resource" xlink:label="ions_LongTermObligationsNoncurrent_lbl3" xlink:role="http://www.xbrl.org/2003/role/verboseLabel" xlink:title="ions_LongTermObligationsNoncurrent_lbl3" xml:lang="en-US" id="ions_LongTermObligationsNoncurrent_lbl3">Total long-term debt</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="LongTermObligationsNoncurrent" xlink:to="ions_LongTermObligationsNoncurrent_lbl3" xlink:title="label: LongTermObligationsNoncurrent to ions_LongTermObligationsNoncurrent_lbl3" />
    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_LongTermObligations" xlink:label="LongTermObligations" xlink:title="LongTermObligations" />
    <link:label xlink:type="resource" xlink:label="ions_LongTermObligations_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_LongTermObligations_lbl" xml:lang="en-US" id="ions_LongTermObligations_lbl">Including the current and noncurrent portions, amount of long-term debt and lease obligations.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="LongTermObligations" xlink:to="ions_LongTermObligations_lbl" xlink:title="label: LongTermObligations to ions_LongTermObligations_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_LongTermObligations_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_LongTermObligations_lbl1" xml:lang="en-US" id="ions_LongTermObligations_lbl1">Long-term Obligations</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="LongTermObligations" xlink:to="ions_LongTermObligations_lbl1" xlink:title="label: LongTermObligations to ions_LongTermObligations_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_LongTermObligations_lbl2" xlink:role="http://www.xbrl.org/2003/role/totalLabel" xlink:title="ions_LongTermObligations_lbl2" xml:lang="en-US" id="ions_LongTermObligations_lbl2">Total</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="LongTermObligations" xlink:to="ions_LongTermObligations_lbl2" xlink:title="label: LongTermObligations to ions_LongTermObligations_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_ConvertibleSeniorNotes1PercentMember" xlink:label="ConvertibleSeniorNotes1PercentMember" xlink:title="ConvertibleSeniorNotes1PercentMember" />
    <link:label xlink:type="resource" xlink:label="ions_ConvertibleSeniorNotes1PercentMember_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_ConvertibleSeniorNotes1PercentMember_lbl" xml:lang="en-US" id="ions_ConvertibleSeniorNotes1PercentMember_lbl">1 percent convertible senior notes due November 2021.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="ConvertibleSeniorNotes1PercentMember" xlink:to="ions_ConvertibleSeniorNotes1PercentMember_lbl" xlink:title="label: ConvertibleSeniorNotes1PercentMember to ions_ConvertibleSeniorNotes1PercentMember_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_ConvertibleSeniorNotes1PercentMember_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_ConvertibleSeniorNotes1PercentMember_lbl1" xml:lang="en-US" id="ions_ConvertibleSeniorNotes1PercentMember_lbl1">Convertible Senior Notes 1 Percent [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="ConvertibleSeniorNotes1PercentMember" xlink:to="ions_ConvertibleSeniorNotes1PercentMember_lbl1" xlink:title="label: ConvertibleSeniorNotes1PercentMember to ions_ConvertibleSeniorNotes1PercentMember_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_ConvertibleSeniorNotes1PercentMember_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_ConvertibleSeniorNotes1PercentMember_lbl2" xml:lang="en-US" id="ions_ConvertibleSeniorNotes1PercentMember_lbl2">1 Percent Convertible Senior Notes [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="ConvertibleSeniorNotes1PercentMember" xlink:to="ions_ConvertibleSeniorNotes1PercentMember_lbl2" xlink:title="label: ConvertibleSeniorNotes1PercentMember to ions_ConvertibleSeniorNotes1PercentMember_lbl2" />
    <link:label xlink:type="resource" xlink:label="ions_ConvertibleSeniorNotes1PercentMember_lbl3" xlink:role="http://www.xbrl.org/2003/role/verboseLabel" xlink:title="ions_ConvertibleSeniorNotes1PercentMember_lbl3" xml:lang="en-US" id="ions_ConvertibleSeniorNotes1PercentMember_lbl3">1% Notes [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="ConvertibleSeniorNotes1PercentMember" xlink:to="ions_ConvertibleSeniorNotes1PercentMember_lbl3" xlink:title="label: ConvertibleSeniorNotes1PercentMember to ions_ConvertibleSeniorNotes1PercentMember_lbl3" />
    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_LeasesAndOtherObligations" xlink:label="LeasesAndOtherObligations" xlink:title="LeasesAndOtherObligations" />
    <link:label xlink:type="resource" xlink:label="ions_LeasesAndOtherObligations_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_LeasesAndOtherObligations_lbl" xml:lang="en-US" id="ions_LeasesAndOtherObligations_lbl">Present value of lessee's discounted obligation for lease payments and the aggregate of other miscellaneous borrowings owed.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="LeasesAndOtherObligations" xlink:to="ions_LeasesAndOtherObligations_lbl" xlink:title="label: LeasesAndOtherObligations to ions_LeasesAndOtherObligations_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_LeasesAndOtherObligations_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_LeasesAndOtherObligations_lbl1" xml:lang="en-US" id="ions_LeasesAndOtherObligations_lbl1">Leases and Other Obligations</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="LeasesAndOtherObligations" xlink:to="ions_LeasesAndOtherObligations_lbl1" xlink:title="label: LeasesAndOtherObligations to ions_LeasesAndOtherObligations_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_LeasesAndOtherObligations_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_LeasesAndOtherObligations_lbl2" xml:lang="en-US" id="ions_LeasesAndOtherObligations_lbl2">Leases and other obligations</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="LeasesAndOtherObligations" xlink:to="ions_LeasesAndOtherObligations_lbl2" xlink:title="label: LeasesAndOtherObligations to ions_LeasesAndOtherObligations_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_ConvertibleSeniorNotes0125PercentMember" xlink:label="ConvertibleSeniorNotes0125PercentMember" xlink:title="ConvertibleSeniorNotes0125PercentMember" />
    <link:label xlink:type="resource" xlink:label="ions_ConvertibleSeniorNotes0125PercentMember_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_ConvertibleSeniorNotes0125PercentMember_lbl" xml:lang="en-US" id="ions_ConvertibleSeniorNotes0125PercentMember_lbl">0.125 percent convertible senior notes due December 2024.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="ConvertibleSeniorNotes0125PercentMember" xlink:to="ions_ConvertibleSeniorNotes0125PercentMember_lbl" xlink:title="label: ConvertibleSeniorNotes0125PercentMember to ions_ConvertibleSeniorNotes0125PercentMember_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_ConvertibleSeniorNotes0125PercentMember_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_ConvertibleSeniorNotes0125PercentMember_lbl1" xml:lang="en-US" id="ions_ConvertibleSeniorNotes0125PercentMember_lbl1">Convertible Senior Notes 0.125 Percent [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="ConvertibleSeniorNotes0125PercentMember" xlink:to="ions_ConvertibleSeniorNotes0125PercentMember_lbl1" xlink:title="label: ConvertibleSeniorNotes0125PercentMember to ions_ConvertibleSeniorNotes0125PercentMember_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_ConvertibleSeniorNotes0125PercentMember_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_ConvertibleSeniorNotes0125PercentMember_lbl2" xml:lang="en-US" id="ions_ConvertibleSeniorNotes0125PercentMember_lbl2">0.125 Percent Convertible Senior Notes [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="ConvertibleSeniorNotes0125PercentMember" xlink:to="ions_ConvertibleSeniorNotes0125PercentMember_lbl2" xlink:title="label: ConvertibleSeniorNotes0125PercentMember to ions_ConvertibleSeniorNotes0125PercentMember_lbl2" />
    <link:label xlink:type="resource" xlink:label="ions_ConvertibleSeniorNotes0125PercentMember_lbl3" xlink:role="http://www.xbrl.org/2003/role/verboseLabel" xlink:title="ions_ConvertibleSeniorNotes0125PercentMember_lbl3" xml:lang="en-US" id="ions_ConvertibleSeniorNotes0125PercentMember_lbl3">0.125% Notes [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="ConvertibleSeniorNotes0125PercentMember" xlink:to="ions_ConvertibleSeniorNotes0125PercentMember_lbl3" xlink:title="label: ConvertibleSeniorNotes0125PercentMember to ions_ConvertibleSeniorNotes0125PercentMember_lbl3" />
    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_ConvertibleSeniorNotes0PercentMember" xlink:label="ConvertibleSeniorNotes0PercentMember" xlink:title="ConvertibleSeniorNotes0PercentMember" />
    <link:label xlink:type="resource" xlink:label="ions_ConvertibleSeniorNotes0PercentMember_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_ConvertibleSeniorNotes0PercentMember_lbl" xml:lang="en-US" id="ions_ConvertibleSeniorNotes0PercentMember_lbl">0 percent convertible senior notes due April 2026.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="ConvertibleSeniorNotes0PercentMember" xlink:to="ions_ConvertibleSeniorNotes0PercentMember_lbl" xlink:title="label: ConvertibleSeniorNotes0PercentMember to ions_ConvertibleSeniorNotes0PercentMember_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_ConvertibleSeniorNotes0PercentMember_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_ConvertibleSeniorNotes0PercentMember_lbl1" xml:lang="en-US" id="ions_ConvertibleSeniorNotes0PercentMember_lbl1">Convertible Senior Notes 0 Percent [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="ConvertibleSeniorNotes0PercentMember" xlink:to="ions_ConvertibleSeniorNotes0PercentMember_lbl1" xlink:title="label: ConvertibleSeniorNotes0PercentMember to ions_ConvertibleSeniorNotes0PercentMember_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_ConvertibleSeniorNotes0PercentMember_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_ConvertibleSeniorNotes0PercentMember_lbl2" xml:lang="en-US" id="ions_ConvertibleSeniorNotes0PercentMember_lbl2">0 Percent Convertible Senior Notes [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="ConvertibleSeniorNotes0PercentMember" xlink:to="ions_ConvertibleSeniorNotes0PercentMember_lbl2" xlink:title="label: ConvertibleSeniorNotes0PercentMember to ions_ConvertibleSeniorNotes0PercentMember_lbl2" />
    <link:label xlink:type="resource" xlink:label="ions_ConvertibleSeniorNotes0PercentMember_lbl3" xlink:role="http://www.xbrl.org/2003/role/verboseLabel" xlink:title="ions_ConvertibleSeniorNotes0PercentMember_lbl3" xml:lang="en-US" id="ions_ConvertibleSeniorNotes0PercentMember_lbl3">0% Notes [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="ConvertibleSeniorNotes0PercentMember" xlink:to="ions_ConvertibleSeniorNotes0PercentMember_lbl3" xlink:title="label: ConvertibleSeniorNotes0PercentMember to ions_ConvertibleSeniorNotes0PercentMember_lbl3" />
    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_AkceaTherapeuticsIncMember" xlink:label="AkceaTherapeuticsIncMember" xlink:title="AkceaTherapeuticsIncMember" />
    <link:label xlink:type="resource" xlink:label="ions_AkceaTherapeuticsIncMember_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_AkceaTherapeuticsIncMember_lbl" xml:lang="en-US" id="ions_AkceaTherapeuticsIncMember_lbl">Akcea Therapeutics, Inc. is a subsidiary of the Company and was formed to develop and commercialize drugs for cardiometabolic disorders.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="AkceaTherapeuticsIncMember" xlink:to="ions_AkceaTherapeuticsIncMember_lbl" xlink:title="label: AkceaTherapeuticsIncMember to ions_AkceaTherapeuticsIncMember_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_AkceaTherapeuticsIncMember_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_AkceaTherapeuticsIncMember_lbl1" xml:lang="en-US" id="ions_AkceaTherapeuticsIncMember_lbl1">Akcea Therapeutics, Inc. [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="AkceaTherapeuticsIncMember" xlink:to="ions_AkceaTherapeuticsIncMember_lbl1" xlink:title="label: AkceaTherapeuticsIncMember to ions_AkceaTherapeuticsIncMember_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_AkceaTherapeuticsIncMember_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_AkceaTherapeuticsIncMember_lbl2" xml:lang="en-US" id="ions_AkceaTherapeuticsIncMember_lbl2">Akcea [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="AkceaTherapeuticsIncMember" xlink:to="ions_AkceaTherapeuticsIncMember_lbl2" xlink:title="label: AkceaTherapeuticsIncMember to ions_AkceaTherapeuticsIncMember_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_LessorOperatingLeasePeriodOfFreeRent" xlink:label="LessorOperatingLeasePeriodOfFreeRent" xlink:title="LessorOperatingLeasePeriodOfFreeRent" />
    <link:label xlink:type="resource" xlink:label="ions_LessorOperatingLeasePeriodOfFreeRent_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_LessorOperatingLeasePeriodOfFreeRent_lbl" xml:lang="en-US" id="ions_LessorOperatingLeasePeriodOfFreeRent_lbl">Period of time in which the lessor provides free rent under operating lease to the lessee, in 'PnYnMnDTnHnMnS' format, for example, 'P1Y5M13D' represents reported fact of one year, five months, and thirteen days.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="LessorOperatingLeasePeriodOfFreeRent" xlink:to="ions_LessorOperatingLeasePeriodOfFreeRent_lbl" xlink:title="label: LessorOperatingLeasePeriodOfFreeRent to ions_LessorOperatingLeasePeriodOfFreeRent_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_LessorOperatingLeasePeriodOfFreeRent_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_LessorOperatingLeasePeriodOfFreeRent_lbl1" xml:lang="en-US" id="ions_LessorOperatingLeasePeriodOfFreeRent_lbl1">Lessor, Operating Lease, Period of Free Rent</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="LessorOperatingLeasePeriodOfFreeRent" xlink:to="ions_LessorOperatingLeasePeriodOfFreeRent_lbl1" xlink:title="label: LessorOperatingLeasePeriodOfFreeRent to ions_LessorOperatingLeasePeriodOfFreeRent_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_LessorOperatingLeasePeriodOfFreeRent_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_LessorOperatingLeasePeriodOfFreeRent_lbl2" xml:lang="en-US" id="ions_LessorOperatingLeasePeriodOfFreeRent_lbl2">Period of free rent under sublease</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="LessorOperatingLeasePeriodOfFreeRent" xlink:to="ions_LessorOperatingLeasePeriodOfFreeRent_lbl2" xlink:title="label: LessorOperatingLeasePeriodOfFreeRent to ions_LessorOperatingLeasePeriodOfFreeRent_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_AnotherOfficeSpaceInBostonMember" xlink:label="AnotherOfficeSpaceInBostonMember" xlink:title="AnotherOfficeSpaceInBostonMember" />
    <link:label xlink:type="resource" xlink:label="ions_AnotherOfficeSpaceInBostonMember_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_AnotherOfficeSpaceInBostonMember_lbl" xml:lang="en-US" id="ions_AnotherOfficeSpaceInBostonMember_lbl">Another office space located in Boston, Massachusetts leased under non-cancelable operating lease entered into in September 2021.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="AnotherOfficeSpaceInBostonMember" xlink:to="ions_AnotherOfficeSpaceInBostonMember_lbl" xlink:title="label: AnotherOfficeSpaceInBostonMember to ions_AnotherOfficeSpaceInBostonMember_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_AnotherOfficeSpaceInBostonMember_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_AnotherOfficeSpaceInBostonMember_lbl1" xml:lang="en-US" id="ions_AnotherOfficeSpaceInBostonMember_lbl1">Another Office Space in Boston [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="AnotherOfficeSpaceInBostonMember" xlink:to="ions_AnotherOfficeSpaceInBostonMember_lbl1" xlink:title="label: AnotherOfficeSpaceInBostonMember to ions_AnotherOfficeSpaceInBostonMember_lbl1" />
    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_SubleasedOfficeSpaceInBostonMember" xlink:label="SubleasedOfficeSpaceInBostonMember" xlink:title="SubleasedOfficeSpaceInBostonMember" />
    <link:label xlink:type="resource" xlink:label="ions_SubleasedOfficeSpaceInBostonMember_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_SubleasedOfficeSpaceInBostonMember_lbl" xml:lang="en-US" id="ions_SubleasedOfficeSpaceInBostonMember_lbl">Sublease of office space located in Boston, Massachusetts leased under non-cancelable sublease operating lease entered into in January 2022.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="SubleasedOfficeSpaceInBostonMember" xlink:to="ions_SubleasedOfficeSpaceInBostonMember_lbl" xlink:title="label: SubleasedOfficeSpaceInBostonMember to ions_SubleasedOfficeSpaceInBostonMember_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_SubleasedOfficeSpaceInBostonMember_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_SubleasedOfficeSpaceInBostonMember_lbl1" xml:lang="en-US" id="ions_SubleasedOfficeSpaceInBostonMember_lbl1">Subleased Office Space in Boston [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="SubleasedOfficeSpaceInBostonMember" xlink:to="ions_SubleasedOfficeSpaceInBostonMember_lbl1" xlink:title="label: SubleasedOfficeSpaceInBostonMember to ions_SubleasedOfficeSpaceInBostonMember_lbl1" />
    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_CarlsbadOfficeSpacesMember" xlink:label="CarlsbadOfficeSpacesMember" xlink:title="CarlsbadOfficeSpacesMember" />
    <link:label xlink:type="resource" xlink:label="ions_CarlsbadOfficeSpacesMember_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_CarlsbadOfficeSpacesMember_lbl" xml:lang="en-US" id="ions_CarlsbadOfficeSpacesMember_lbl">Additional office spaces in Carlsbad, California leased under non-cancelable operating lease.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="CarlsbadOfficeSpacesMember" xlink:to="ions_CarlsbadOfficeSpacesMember_lbl" xlink:title="label: CarlsbadOfficeSpacesMember to ions_CarlsbadOfficeSpacesMember_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_CarlsbadOfficeSpacesMember_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_CarlsbadOfficeSpacesMember_lbl1" xml:lang="en-US" id="ions_CarlsbadOfficeSpacesMember_lbl1">Carlsbad Office Spaces [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="CarlsbadOfficeSpacesMember" xlink:to="ions_CarlsbadOfficeSpacesMember_lbl1" xlink:title="label: CarlsbadOfficeSpacesMember to ions_CarlsbadOfficeSpacesMember_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_CarlsbadOfficeSpacesMember_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_CarlsbadOfficeSpacesMember_lbl2" xml:lang="en-US" id="ions_CarlsbadOfficeSpacesMember_lbl2">Carlsbad Office Spaces [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="CarlsbadOfficeSpacesMember" xlink:to="ions_CarlsbadOfficeSpacesMember_lbl2" xlink:title="label: CarlsbadOfficeSpacesMember to ions_CarlsbadOfficeSpacesMember_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_LesseeOperatingLeasePeriodOfFreeRent" xlink:label="LesseeOperatingLeasePeriodOfFreeRent" xlink:title="LesseeOperatingLeasePeriodOfFreeRent" />
    <link:label xlink:type="resource" xlink:label="ions_LesseeOperatingLeasePeriodOfFreeRent_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_LesseeOperatingLeasePeriodOfFreeRent_lbl" xml:lang="en-US" id="ions_LesseeOperatingLeasePeriodOfFreeRent_lbl">Period of time in which the rent is free under operating lease, in 'PnYnMnDTnHnMnS' format, for example, 'P1Y5M13D' represents reported fact of one year, five months, and thirteen days.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="LesseeOperatingLeasePeriodOfFreeRent" xlink:to="ions_LesseeOperatingLeasePeriodOfFreeRent_lbl" xlink:title="label: LesseeOperatingLeasePeriodOfFreeRent to ions_LesseeOperatingLeasePeriodOfFreeRent_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_LesseeOperatingLeasePeriodOfFreeRent_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_LesseeOperatingLeasePeriodOfFreeRent_lbl1" xml:lang="en-US" id="ions_LesseeOperatingLeasePeriodOfFreeRent_lbl1">Lessee, Operating Lease, Period of Free Rent</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="LesseeOperatingLeasePeriodOfFreeRent" xlink:to="ions_LesseeOperatingLeasePeriodOfFreeRent_lbl1" xlink:title="label: LesseeOperatingLeasePeriodOfFreeRent to ions_LesseeOperatingLeasePeriodOfFreeRent_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_LesseeOperatingLeasePeriodOfFreeRent_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_LesseeOperatingLeasePeriodOfFreeRent_lbl2" xml:lang="en-US" id="ions_LesseeOperatingLeasePeriodOfFreeRent_lbl2">Period of free rent under lease</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="LesseeOperatingLeasePeriodOfFreeRent" xlink:to="ions_LesseeOperatingLeasePeriodOfFreeRent_lbl2" xlink:title="label: LesseeOperatingLeasePeriodOfFreeRent to ions_LesseeOperatingLeasePeriodOfFreeRent_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_LesseeOperatingLeaseAllowanceForTenantImprovements" xlink:label="LesseeOperatingLeaseAllowanceForTenantImprovements" xlink:title="LesseeOperatingLeaseAllowanceForTenantImprovements" />
    <link:label xlink:type="resource" xlink:label="ions_LesseeOperatingLeaseAllowanceForTenantImprovements_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_LesseeOperatingLeaseAllowanceForTenantImprovements_lbl" xml:lang="en-US" id="ions_LesseeOperatingLeaseAllowanceForTenantImprovements_lbl">Allowance for tenant improvements to the office space included in the lessee's operating lease.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="LesseeOperatingLeaseAllowanceForTenantImprovements" xlink:to="ions_LesseeOperatingLeaseAllowanceForTenantImprovements_lbl" xlink:title="label: LesseeOperatingLeaseAllowanceForTenantImprovements to ions_LesseeOperatingLeaseAllowanceForTenantImprovements_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_LesseeOperatingLeaseAllowanceForTenantImprovements_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_LesseeOperatingLeaseAllowanceForTenantImprovements_lbl1" xml:lang="en-US" id="ions_LesseeOperatingLeaseAllowanceForTenantImprovements_lbl1">Lessee, Operating Lease, Allowance for Tenant Improvements</link:label>
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    <link:label xlink:type="resource" xlink:label="ions_LesseeOperatingLeaseAllowanceForTenantImprovements_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_LesseeOperatingLeaseAllowanceForTenantImprovements_lbl2" xml:lang="en-US" id="ions_LesseeOperatingLeaseAllowanceForTenantImprovements_lbl2">Tenant improvement allowance</link:label>
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    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_BostonOfficeSpaceMember" xlink:label="BostonOfficeSpaceMember" xlink:title="BostonOfficeSpaceMember" />
    <link:label xlink:type="resource" xlink:label="ions_BostonOfficeSpaceMember_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_BostonOfficeSpaceMember_lbl" xml:lang="en-US" id="ions_BostonOfficeSpaceMember_lbl">Office space located in Boston, Massachusetts leased under non-cancelable operating lease entered into in the second quarter of 2018..</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="BostonOfficeSpaceMember" xlink:to="ions_BostonOfficeSpaceMember_lbl" xlink:title="label: BostonOfficeSpaceMember to ions_BostonOfficeSpaceMember_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_BostonOfficeSpaceMember_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_BostonOfficeSpaceMember_lbl1" xml:lang="en-US" id="ions_BostonOfficeSpaceMember_lbl1">Boston Office Space [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="BostonOfficeSpaceMember" xlink:to="ions_BostonOfficeSpaceMember_lbl1" xlink:title="label: BostonOfficeSpaceMember to ions_BostonOfficeSpaceMember_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_BostonOfficeSpaceMember_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_BostonOfficeSpaceMember_lbl2" xml:lang="en-US" id="ions_BostonOfficeSpaceMember_lbl2">Boston Office Space [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="BostonOfficeSpaceMember" xlink:to="ions_BostonOfficeSpaceMember_lbl2" xlink:title="label: BostonOfficeSpaceMember to ions_BostonOfficeSpaceMember_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_CarlsbadFacilityMember" xlink:label="CarlsbadFacilityMember" xlink:title="CarlsbadFacilityMember" />
    <link:label xlink:type="resource" xlink:label="ions_CarlsbadFacilityMember_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_CarlsbadFacilityMember_lbl" xml:lang="en-US" id="ions_CarlsbadFacilityMember_lbl">Office and laboratory space in a facility adjacent to the Company's manufacturing facility located in Carlsbad, California leased under non-cancelable operating lease.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="CarlsbadFacilityMember" xlink:to="ions_CarlsbadFacilityMember_lbl" xlink:title="label: CarlsbadFacilityMember to ions_CarlsbadFacilityMember_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_CarlsbadFacilityMember_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_CarlsbadFacilityMember_lbl1" xml:lang="en-US" id="ions_CarlsbadFacilityMember_lbl1">Carlsbad Facility [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="CarlsbadFacilityMember" xlink:to="ions_CarlsbadFacilityMember_lbl1" xlink:title="label: CarlsbadFacilityMember to ions_CarlsbadFacilityMember_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_CarlsbadFacilityMember_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_CarlsbadFacilityMember_lbl2" xml:lang="en-US" id="ions_CarlsbadFacilityMember_lbl2">Carlsbad Facility [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="CarlsbadFacilityMember" xlink:to="ions_CarlsbadFacilityMember_lbl2" xlink:title="label: CarlsbadFacilityMember to ions_CarlsbadFacilityMember_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_LesseeLeasingArrangementsOperatingLeasesNumberOfOptionsToExtendLease" xlink:label="LesseeLeasingArrangementsOperatingLeasesNumberOfOptionsToExtendLease" xlink:title="LesseeLeasingArrangementsOperatingLeasesNumberOfOptionsToExtendLease" />
    <link:label xlink:type="resource" xlink:label="ions_LesseeLeasingArrangementsOperatingLeasesNumberOfOptionsToExtendLease_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_LesseeLeasingArrangementsOperatingLeasesNumberOfOptionsToExtendLease_lbl" xml:lang="en-US" id="ions_LesseeLeasingArrangementsOperatingLeasesNumberOfOptionsToExtendLease_lbl">The number of options to extend the lease under the lessee's operating leasing arrangement.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="LesseeLeasingArrangementsOperatingLeasesNumberOfOptionsToExtendLease" xlink:to="ions_LesseeLeasingArrangementsOperatingLeasesNumberOfOptionsToExtendLease_lbl" xlink:title="label: LesseeLeasingArrangementsOperatingLeasesNumberOfOptionsToExtendLease to ions_LesseeLeasingArrangementsOperatingLeasesNumberOfOptionsToExtendLease_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_LesseeLeasingArrangementsOperatingLeasesNumberOfOptionsToExtendLease_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_LesseeLeasingArrangementsOperatingLeasesNumberOfOptionsToExtendLease_lbl1" xml:lang="en-US" id="ions_LesseeLeasingArrangementsOperatingLeasesNumberOfOptionsToExtendLease_lbl1">Lessee, Leasing Arrangements, Operating Leases, Number of options to extend lease</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="LesseeLeasingArrangementsOperatingLeasesNumberOfOptionsToExtendLease" xlink:to="ions_LesseeLeasingArrangementsOperatingLeasesNumberOfOptionsToExtendLease_lbl1" xlink:title="label: LesseeLeasingArrangementsOperatingLeasesNumberOfOptionsToExtendLease to ions_LesseeLeasingArrangementsOperatingLeasesNumberOfOptionsToExtendLease_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_LesseeLeasingArrangementsOperatingLeasesNumberOfOptionsToExtendLease_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_LesseeLeasingArrangementsOperatingLeasesNumberOfOptionsToExtendLease_lbl2" xml:lang="en-US" id="ions_LesseeLeasingArrangementsOperatingLeasesNumberOfOptionsToExtendLease_lbl2">Number of options to extend lease</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="LesseeLeasingArrangementsOperatingLeasesNumberOfOptionsToExtendLease" xlink:to="ions_LesseeLeasingArrangementsOperatingLeasesNumberOfOptionsToExtendLease_lbl2" xlink:title="label: LesseeLeasingArrangementsOperatingLeasesNumberOfOptionsToExtendLease to ions_LesseeLeasingArrangementsOperatingLeasesNumberOfOptionsToExtendLease_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_LongTermObligationsExcludingConvertibleDebtCurrent" xlink:label="LongTermObligationsExcludingConvertibleDebtCurrent" xlink:title="LongTermObligationsExcludingConvertibleDebtCurrent" />
    <link:label xlink:type="resource" xlink:label="ions_LongTermObligationsExcludingConvertibleDebtCurrent_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_LongTermObligationsExcludingConvertibleDebtCurrent_lbl" xml:lang="en-US" id="ions_LongTermObligationsExcludingConvertibleDebtCurrent_lbl">Amount of long-term debt and lease obligations, excluding convertible debt, classified as current.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="LongTermObligationsExcludingConvertibleDebtCurrent" xlink:to="ions_LongTermObligationsExcludingConvertibleDebtCurrent_lbl" xlink:title="label: LongTermObligationsExcludingConvertibleDebtCurrent to ions_LongTermObligationsExcludingConvertibleDebtCurrent_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_LongTermObligationsExcludingConvertibleDebtCurrent_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_LongTermObligationsExcludingConvertibleDebtCurrent_lbl1" xml:lang="en-US" id="ions_LongTermObligationsExcludingConvertibleDebtCurrent_lbl1">Long-term Obligations, Excluding Convertible Debt, Current</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="LongTermObligationsExcludingConvertibleDebtCurrent" xlink:to="ions_LongTermObligationsExcludingConvertibleDebtCurrent_lbl1" xlink:title="label: LongTermObligationsExcludingConvertibleDebtCurrent to ions_LongTermObligationsExcludingConvertibleDebtCurrent_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_LongTermObligationsExcludingConvertibleDebtCurrent_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_LongTermObligationsExcludingConvertibleDebtCurrent_lbl2" xml:lang="en-US" id="ions_LongTermObligationsExcludingConvertibleDebtCurrent_lbl2">Current portion of long-term obligations</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="LongTermObligationsExcludingConvertibleDebtCurrent" xlink:to="ions_LongTermObligationsExcludingConvertibleDebtCurrent_lbl2" xlink:title="label: LongTermObligationsExcludingConvertibleDebtCurrent to ions_LongTermObligationsExcludingConvertibleDebtCurrent_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_LongTermObligationsExcludingConvertibleDebtNoncurrent" xlink:label="LongTermObligationsExcludingConvertibleDebtNoncurrent" xlink:title="LongTermObligationsExcludingConvertibleDebtNoncurrent" />
    <link:label xlink:type="resource" xlink:label="ions_LongTermObligationsExcludingConvertibleDebtNoncurrent_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_LongTermObligationsExcludingConvertibleDebtNoncurrent_lbl" xml:lang="en-US" id="ions_LongTermObligationsExcludingConvertibleDebtNoncurrent_lbl">Amount of long-term debt and lease obligations, excluding convertible debt, classified as noncurrent.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="LongTermObligationsExcludingConvertibleDebtNoncurrent" xlink:to="ions_LongTermObligationsExcludingConvertibleDebtNoncurrent_lbl" xlink:title="label: LongTermObligationsExcludingConvertibleDebtNoncurrent to ions_LongTermObligationsExcludingConvertibleDebtNoncurrent_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_LongTermObligationsExcludingConvertibleDebtNoncurrent_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_LongTermObligationsExcludingConvertibleDebtNoncurrent_lbl1" xml:lang="en-US" id="ions_LongTermObligationsExcludingConvertibleDebtNoncurrent_lbl1">Long-term Obligations Excluding Convertible Debt, Noncurrent</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="LongTermObligationsExcludingConvertibleDebtNoncurrent" xlink:to="ions_LongTermObligationsExcludingConvertibleDebtNoncurrent_lbl1" xlink:title="label: LongTermObligationsExcludingConvertibleDebtNoncurrent to ions_LongTermObligationsExcludingConvertibleDebtNoncurrent_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_LongTermObligationsExcludingConvertibleDebtNoncurrent_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_LongTermObligationsExcludingConvertibleDebtNoncurrent_lbl2" xml:lang="en-US" id="ions_LongTermObligationsExcludingConvertibleDebtNoncurrent_lbl2">Long-term obligations, less current portion</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="LongTermObligationsExcludingConvertibleDebtNoncurrent" xlink:to="ions_LongTermObligationsExcludingConvertibleDebtNoncurrent_lbl2" xlink:title="label: LongTermObligationsExcludingConvertibleDebtNoncurrent to ions_LongTermObligationsExcludingConvertibleDebtNoncurrent_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_ConvertibleSeniorNotes0125PercentIssuedInExchangeFor1PercentNotesMember" xlink:label="ConvertibleSeniorNotes0125PercentIssuedInExchangeFor1PercentNotesMember" xlink:title="ConvertibleSeniorNotes0125PercentIssuedInExchangeFor1PercentNotesMember" />
    <link:label xlink:type="resource" xlink:label="ions_ConvertibleSeniorNotes0125PercentIssuedInExchangeFor1PercentNotesMember_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_ConvertibleSeniorNotes0125PercentIssuedInExchangeFor1PercentNotesMember_lbl" xml:lang="en-US" id="ions_ConvertibleSeniorNotes0125PercentIssuedInExchangeFor1PercentNotesMember_lbl">0.125 percent convertible senior notes due December 2024 that were issued in exchange for 1 percent notes in December 2019.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="ConvertibleSeniorNotes0125PercentIssuedInExchangeFor1PercentNotesMember" xlink:to="ions_ConvertibleSeniorNotes0125PercentIssuedInExchangeFor1PercentNotesMember_lbl" xlink:title="label: ConvertibleSeniorNotes0125PercentIssuedInExchangeFor1PercentNotesMember to ions_ConvertibleSeniorNotes0125PercentIssuedInExchangeFor1PercentNotesMember_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_ConvertibleSeniorNotes0125PercentIssuedInExchangeFor1PercentNotesMember_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_ConvertibleSeniorNotes0125PercentIssuedInExchangeFor1PercentNotesMember_lbl1" xml:lang="en-US" id="ions_ConvertibleSeniorNotes0125PercentIssuedInExchangeFor1PercentNotesMember_lbl1">Convertible Senior Notes 0.125 Percent, Issued in Exchange for 1 Percent Notes [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="ConvertibleSeniorNotes0125PercentIssuedInExchangeFor1PercentNotesMember" xlink:to="ions_ConvertibleSeniorNotes0125PercentIssuedInExchangeFor1PercentNotesMember_lbl1" xlink:title="label: ConvertibleSeniorNotes0125PercentIssuedInExchangeFor1PercentNotesMember to ions_ConvertibleSeniorNotes0125PercentIssuedInExchangeFor1PercentNotesMember_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_ConvertibleSeniorNotes0125PercentIssuedInExchangeFor1PercentNotesMember_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_ConvertibleSeniorNotes0125PercentIssuedInExchangeFor1PercentNotesMember_lbl2" xml:lang="en-US" id="ions_ConvertibleSeniorNotes0125PercentIssuedInExchangeFor1PercentNotesMember_lbl2">0.125% Convertible Senior Notes Issued in Exchange for 1 Percent Notes [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="ConvertibleSeniorNotes0125PercentIssuedInExchangeFor1PercentNotesMember" xlink:to="ions_ConvertibleSeniorNotes0125PercentIssuedInExchangeFor1PercentNotesMember_lbl2" xlink:title="label: ConvertibleSeniorNotes0125PercentIssuedInExchangeFor1PercentNotesMember to ions_ConvertibleSeniorNotes0125PercentIssuedInExchangeFor1PercentNotesMember_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_ConvertibleSeniorNotes275PercentMember" xlink:label="ConvertibleSeniorNotes275PercentMember" xlink:title="ConvertibleSeniorNotes275PercentMember" />
    <link:label xlink:type="resource" xlink:label="ions_ConvertibleSeniorNotes275PercentMember_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_ConvertibleSeniorNotes275PercentMember_lbl" xml:lang="en-US" id="ions_ConvertibleSeniorNotes275PercentMember_lbl">2 3/4 percent convertible senior notes due October 2019.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="ConvertibleSeniorNotes275PercentMember" xlink:to="ions_ConvertibleSeniorNotes275PercentMember_lbl" xlink:title="label: ConvertibleSeniorNotes275PercentMember to ions_ConvertibleSeniorNotes275PercentMember_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_ConvertibleSeniorNotes275PercentMember_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_ConvertibleSeniorNotes275PercentMember_lbl1" xml:lang="en-US" id="ions_ConvertibleSeniorNotes275PercentMember_lbl1">Convertible Senior Notes 2.75 Percent [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="ConvertibleSeniorNotes275PercentMember" xlink:to="ions_ConvertibleSeniorNotes275PercentMember_lbl1" xlink:title="label: ConvertibleSeniorNotes275PercentMember to ions_ConvertibleSeniorNotes275PercentMember_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_ConvertibleSeniorNotes275PercentMember_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_ConvertibleSeniorNotes275PercentMember_lbl2" xml:lang="en-US" id="ions_ConvertibleSeniorNotes275PercentMember_lbl2">2.75% Convertible Senior Notes [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="ConvertibleSeniorNotes275PercentMember" xlink:to="ions_ConvertibleSeniorNotes275PercentMember_lbl2" xlink:title="label: ConvertibleSeniorNotes275PercentMember to ions_ConvertibleSeniorNotes275PercentMember_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_ConvertibleSeniorNotes0125PercentIssuedUnderSubscriptionAgreementsMember" xlink:label="ConvertibleSeniorNotes0125PercentIssuedUnderSubscriptionAgreementsMember" xlink:title="ConvertibleSeniorNotes0125PercentIssuedUnderSubscriptionAgreementsMember" />
    <link:label xlink:type="resource" xlink:label="ions_ConvertibleSeniorNotes0125PercentIssuedUnderSubscriptionAgreementsMember_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_ConvertibleSeniorNotes0125PercentIssuedUnderSubscriptionAgreementsMember_lbl" xml:lang="en-US" id="ions_ConvertibleSeniorNotes0125PercentIssuedUnderSubscriptionAgreementsMember_lbl">0.125 percent convertible senior notes due December 2024 that were issued under subscription agreements in December 2019.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="ConvertibleSeniorNotes0125PercentIssuedUnderSubscriptionAgreementsMember" xlink:to="ions_ConvertibleSeniorNotes0125PercentIssuedUnderSubscriptionAgreementsMember_lbl" xlink:title="label: ConvertibleSeniorNotes0125PercentIssuedUnderSubscriptionAgreementsMember to ions_ConvertibleSeniorNotes0125PercentIssuedUnderSubscriptionAgreementsMember_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_ConvertibleSeniorNotes0125PercentIssuedUnderSubscriptionAgreementsMember_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_ConvertibleSeniorNotes0125PercentIssuedUnderSubscriptionAgreementsMember_lbl1" xml:lang="en-US" id="ions_ConvertibleSeniorNotes0125PercentIssuedUnderSubscriptionAgreementsMember_lbl1">Convertible Senior Notes 0.125 Percent, Issued under Subscription Agreements [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="ConvertibleSeniorNotes0125PercentIssuedUnderSubscriptionAgreementsMember" xlink:to="ions_ConvertibleSeniorNotes0125PercentIssuedUnderSubscriptionAgreementsMember_lbl1" xlink:title="label: ConvertibleSeniorNotes0125PercentIssuedUnderSubscriptionAgreementsMember to ions_ConvertibleSeniorNotes0125PercentIssuedUnderSubscriptionAgreementsMember_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_ConvertibleSeniorNotes0125PercentIssuedUnderSubscriptionAgreementsMember_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_ConvertibleSeniorNotes0125PercentIssuedUnderSubscriptionAgreementsMember_lbl2" xml:lang="en-US" id="ions_ConvertibleSeniorNotes0125PercentIssuedUnderSubscriptionAgreementsMember_lbl2">0.125% Convertible Senior Notes Issued under Subscription Agreements [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="ConvertibleSeniorNotes0125PercentIssuedUnderSubscriptionAgreementsMember" xlink:to="ions_ConvertibleSeniorNotes0125PercentIssuedUnderSubscriptionAgreementsMember_lbl2" xlink:title="label: ConvertibleSeniorNotes0125PercentIssuedUnderSubscriptionAgreementsMember to ions_ConvertibleSeniorNotes0125PercentIssuedUnderSubscriptionAgreementsMember_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_DebtInstrumentConvertibleSharesSubjectToConversion" xlink:label="DebtInstrumentConvertibleSharesSubjectToConversion" xlink:title="DebtInstrumentConvertibleSharesSubjectToConversion" />
    <link:label xlink:type="resource" xlink:label="ions_DebtInstrumentConvertibleSharesSubjectToConversion_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_DebtInstrumentConvertibleSharesSubjectToConversion_lbl" xml:lang="en-US" id="ions_DebtInstrumentConvertibleSharesSubjectToConversion_lbl">The number of shares of common stock subject to conversion if the debt was converted to equity.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="DebtInstrumentConvertibleSharesSubjectToConversion" xlink:to="ions_DebtInstrumentConvertibleSharesSubjectToConversion_lbl" xlink:title="label: DebtInstrumentConvertibleSharesSubjectToConversion to ions_DebtInstrumentConvertibleSharesSubjectToConversion_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_DebtInstrumentConvertibleSharesSubjectToConversion_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_DebtInstrumentConvertibleSharesSubjectToConversion_lbl1" xml:lang="en-US" id="ions_DebtInstrumentConvertibleSharesSubjectToConversion_lbl1">Debt Instrument, Convertible, Shares Subject to Conversion</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="DebtInstrumentConvertibleSharesSubjectToConversion" xlink:to="ions_DebtInstrumentConvertibleSharesSubjectToConversion_lbl1" xlink:title="label: DebtInstrumentConvertibleSharesSubjectToConversion to ions_DebtInstrumentConvertibleSharesSubjectToConversion_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_DebtInstrumentConvertibleSharesSubjectToConversion_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_DebtInstrumentConvertibleSharesSubjectToConversion_lbl2" xml:lang="en-US" id="ions_DebtInstrumentConvertibleSharesSubjectToConversion_lbl2">Total shares of common stock subject to conversion (in shares)</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="DebtInstrumentConvertibleSharesSubjectToConversion" xlink:to="ions_DebtInstrumentConvertibleSharesSubjectToConversion_lbl2" xlink:title="label: DebtInstrumentConvertibleSharesSubjectToConversion to ions_DebtInstrumentConvertibleSharesSubjectToConversion_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_DebtInstrumentConvertibleConversionPriceIncludingCallSpread" xlink:label="DebtInstrumentConvertibleConversionPriceIncludingCallSpread" xlink:title="DebtInstrumentConvertibleConversionPriceIncludingCallSpread" />
    <link:label xlink:type="resource" xlink:label="ions_DebtInstrumentConvertibleConversionPriceIncludingCallSpread_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_DebtInstrumentConvertibleConversionPriceIncludingCallSpread_lbl" xml:lang="en-US" id="ions_DebtInstrumentConvertibleConversionPriceIncludingCallSpread_lbl">The computed conversion price per share of the debt instrument based on the the conversion feature embedded in the debt instrument and the impact of the purchased hedges in the call spread transaction.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="DebtInstrumentConvertibleConversionPriceIncludingCallSpread" xlink:to="ions_DebtInstrumentConvertibleConversionPriceIncludingCallSpread_lbl" xlink:title="label: DebtInstrumentConvertibleConversionPriceIncludingCallSpread to ions_DebtInstrumentConvertibleConversionPriceIncludingCallSpread_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_DebtInstrumentConvertibleConversionPriceIncludingCallSpread_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_DebtInstrumentConvertibleConversionPriceIncludingCallSpread_lbl1" xml:lang="en-US" id="ions_DebtInstrumentConvertibleConversionPriceIncludingCallSpread_lbl1">Debt Instrument, Convertible, Conversion Price including call spread</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="DebtInstrumentConvertibleConversionPriceIncludingCallSpread" xlink:to="ions_DebtInstrumentConvertibleConversionPriceIncludingCallSpread_lbl1" xlink:title="label: DebtInstrumentConvertibleConversionPriceIncludingCallSpread to ions_DebtInstrumentConvertibleConversionPriceIncludingCallSpread_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_DebtInstrumentConvertibleConversionPriceIncludingCallSpread_lbl2" xlink:role="http://www.xbrl.org/2003/role/verboseLabel" xlink:title="ions_DebtInstrumentConvertibleConversionPriceIncludingCallSpread_lbl2" xml:lang="en-US" id="ions_DebtInstrumentConvertibleConversionPriceIncludingCallSpread_lbl2">Effective conversion price per share with call spread (in dollars per share)</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="DebtInstrumentConvertibleConversionPriceIncludingCallSpread" xlink:to="ions_DebtInstrumentConvertibleConversionPriceIncludingCallSpread_lbl2" xlink:title="label: DebtInstrumentConvertibleConversionPriceIncludingCallSpread to ions_DebtInstrumentConvertibleConversionPriceIncludingCallSpread_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_CallSpread" xlink:label="CallSpread" xlink:title="CallSpread" />
    <link:label xlink:type="resource" xlink:label="ions_CallSpread_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_CallSpread_lbl" xml:lang="en-US" id="ions_CallSpread_lbl">The net cash outflow from payments for hedge transactions and proceeds from the issuance of warrants. The call spread transaction was entered into to minimize the impact of potential economic dilution upon conversion of the 0.125% notes issued.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="CallSpread" xlink:to="ions_CallSpread_lbl" xlink:title="label: CallSpread to ions_CallSpread_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_CallSpread_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_CallSpread_lbl1" xml:lang="en-US" id="ions_CallSpread_lbl1">Call Spread</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="CallSpread" xlink:to="ions_CallSpread_lbl1" xlink:title="label: CallSpread to ions_CallSpread_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_CallSpread_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_CallSpread_lbl2" xml:lang="en-US" id="ions_CallSpread_lbl2">Cost of call spread</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="CallSpread" xlink:to="ions_CallSpread_lbl2" xlink:title="label: CallSpread to ions_CallSpread_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_DebtInstrumentConvertiblePercentageOfPrincipalAmountUsedAsPurchasePriceUponOccurrenceOfFundamentalChange" xlink:label="DebtInstrumentConvertiblePercentageOfPrincipalAmountUsedAsPurchasePriceUponOccurrenceOfFundamentalChange" xlink:title="DebtInstrumentConvertiblePercentageOfPrincipalAmountUsedAsPurchasePriceUponOccurrenceOfFundamentalChange" />
    <link:label xlink:type="resource" xlink:label="ions_DebtInstrumentConvertiblePercentageOfPrincipalAmountUsedAsPurchasePriceUponOccurrenceOfFundamentalChange_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_DebtInstrumentConvertiblePercentageOfPrincipalAmountUsedAsPurchasePriceUponOccurrenceOfFundamentalChange_lbl" xml:lang="en-US" id="ions_DebtInstrumentConvertiblePercentageOfPrincipalAmountUsedAsPurchasePriceUponOccurrenceOfFundamentalChange_lbl">The percentage of the principal amount of the notes to be purchased, plus accrued and unpaid interest, upon the occurrence of certain fundamental changes, as set forth in the indenture governing the convertible notes.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="DebtInstrumentConvertiblePercentageOfPrincipalAmountUsedAsPurchasePriceUponOccurrenceOfFundamentalChange" xlink:to="ions_DebtInstrumentConvertiblePercentageOfPrincipalAmountUsedAsPurchasePriceUponOccurrenceOfFundamentalChange_lbl" xlink:title="label: DebtInstrumentConvertiblePercentageOfPrincipalAmountUsedAsPurchasePriceUponOccurrenceOfFundamentalChange to ions_DebtInstrumentConvertiblePercentageOfPrincipalAmountUsedAsPurchasePriceUponOccurrenceOfFundamentalChange_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_DebtInstrumentConvertiblePercentageOfPrincipalAmountUsedAsPurchasePriceUponOccurrenceOfFundamentalChange_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_DebtInstrumentConvertiblePercentageOfPrincipalAmountUsedAsPurchasePriceUponOccurrenceOfFundamentalChange_lbl1" xml:lang="en-US" id="ions_DebtInstrumentConvertiblePercentageOfPrincipalAmountUsedAsPurchasePriceUponOccurrenceOfFundamentalChange_lbl1">Debt Instrument, Convertible, Percentage of principal amount used as purchase price upon occurrence of fundamental change</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="DebtInstrumentConvertiblePercentageOfPrincipalAmountUsedAsPurchasePriceUponOccurrenceOfFundamentalChange" xlink:to="ions_DebtInstrumentConvertiblePercentageOfPrincipalAmountUsedAsPurchasePriceUponOccurrenceOfFundamentalChange_lbl1" xlink:title="label: DebtInstrumentConvertiblePercentageOfPrincipalAmountUsedAsPurchasePriceUponOccurrenceOfFundamentalChange to ions_DebtInstrumentConvertiblePercentageOfPrincipalAmountUsedAsPurchasePriceUponOccurrenceOfFundamentalChange_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_DebtInstrumentConvertiblePercentageOfPrincipalAmountUsedAsPurchasePriceUponOccurrenceOfFundamentalChange_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_DebtInstrumentConvertiblePercentageOfPrincipalAmountUsedAsPurchasePriceUponOccurrenceOfFundamentalChange_lbl2" xml:lang="en-US" id="ions_DebtInstrumentConvertiblePercentageOfPrincipalAmountUsedAsPurchasePriceUponOccurrenceOfFundamentalChange_lbl2">Percentage of principal amount used as purchase price upon occurrence of fundamental change</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="DebtInstrumentConvertiblePercentageOfPrincipalAmountUsedAsPurchasePriceUponOccurrenceOfFundamentalChange" xlink:to="ions_DebtInstrumentConvertiblePercentageOfPrincipalAmountUsedAsPurchasePriceUponOccurrenceOfFundamentalChange_lbl2" xlink:title="label: DebtInstrumentConvertiblePercentageOfPrincipalAmountUsedAsPurchasePriceUponOccurrenceOfFundamentalChange to ions_DebtInstrumentConvertiblePercentageOfPrincipalAmountUsedAsPurchasePriceUponOccurrenceOfFundamentalChange_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_ResearchDevelopmentAndPatentExpense" xlink:label="ResearchDevelopmentAndPatentExpense" xlink:title="ResearchDevelopmentAndPatentExpense" />
    <link:label xlink:type="resource" xlink:label="ions_ResearchDevelopmentAndPatentExpense_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_ResearchDevelopmentAndPatentExpense_lbl" xml:lang="en-US" id="ions_ResearchDevelopmentAndPatentExpense_lbl">The aggregate costs incurred (1) in a planned search or critical investigation aimed at discovery of new knowledge with the hope that such knowledge will be useful in developing a new product or service, a new process or technique, or in bringing about a significant improvement to an existing product or process; or (2) to translate research findings or other knowledge into a plan or design for a new product or process or for a significant improvement to an existing product or process whether intended for sale or the entity's use, during the reporting period charged to research and development projects. Also includes charges for amortization and write-downs of capitalized patent costs, as well as legal fees for patent litigation and patent defense.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="ResearchDevelopmentAndPatentExpense" xlink:to="ions_ResearchDevelopmentAndPatentExpense_lbl" xlink:title="label: ResearchDevelopmentAndPatentExpense to ions_ResearchDevelopmentAndPatentExpense_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_ResearchDevelopmentAndPatentExpense_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_ResearchDevelopmentAndPatentExpense_lbl1" xml:lang="en-US" id="ions_ResearchDevelopmentAndPatentExpense_lbl1">Research, Development and Patent Expense</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="ResearchDevelopmentAndPatentExpense" xlink:to="ions_ResearchDevelopmentAndPatentExpense_lbl1" xlink:title="label: ResearchDevelopmentAndPatentExpense to ions_ResearchDevelopmentAndPatentExpense_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_ResearchDevelopmentAndPatentExpense_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_ResearchDevelopmentAndPatentExpense_lbl2" xml:lang="en-US" id="ions_ResearchDevelopmentAndPatentExpense_lbl2">Research, development and patent</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="ResearchDevelopmentAndPatentExpense" xlink:to="ions_ResearchDevelopmentAndPatentExpense_lbl2" xlink:title="label: ResearchDevelopmentAndPatentExpense to ions_ResearchDevelopmentAndPatentExpense_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_CommercialMember" xlink:label="CommercialMember" xlink:title="CommercialMember" />
    <link:label xlink:type="resource" xlink:label="ions_CommercialMember_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_CommercialMember_lbl1" xml:lang="en-US" id="ions_CommercialMember_lbl1">Commercial [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="CommercialMember" xlink:to="ions_CommercialMember_lbl1" xlink:title="label: CommercialMember to ions_CommercialMember_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_CommercialMember_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_CommercialMember_lbl2" xml:lang="en-US" id="ions_CommercialMember_lbl2">Commercial Revenue [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="CommercialMember" xlink:to="ions_CommercialMember_lbl2" xlink:title="label: CommercialMember to ions_CommercialMember_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_SpinrazaRoyaltiesMember" xlink:label="SpinrazaRoyaltiesMember" xlink:title="SpinrazaRoyaltiesMember" />
    <link:label xlink:type="resource" xlink:label="ions_SpinrazaRoyaltiesMember_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_SpinrazaRoyaltiesMember_lbl" xml:lang="en-US" id="ions_SpinrazaRoyaltiesMember_lbl">Royalty revenues from the sale of SPINRAZA (nusinersen).</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="SpinrazaRoyaltiesMember" xlink:to="ions_SpinrazaRoyaltiesMember_lbl" xlink:title="label: SpinrazaRoyaltiesMember to ions_SpinrazaRoyaltiesMember_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_SpinrazaRoyaltiesMember_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_SpinrazaRoyaltiesMember_lbl1" xml:lang="en-US" id="ions_SpinrazaRoyaltiesMember_lbl1">Spinraza Royalties [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="SpinrazaRoyaltiesMember" xlink:to="ions_SpinrazaRoyaltiesMember_lbl1" xlink:title="label: SpinrazaRoyaltiesMember to ions_SpinrazaRoyaltiesMember_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_SpinrazaRoyaltiesMember_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_SpinrazaRoyaltiesMember_lbl2" xml:lang="en-US" id="ions_SpinrazaRoyaltiesMember_lbl2">SPINRAZA Royalties [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="SpinrazaRoyaltiesMember" xlink:to="ions_SpinrazaRoyaltiesMember_lbl2" xlink:title="label: SpinrazaRoyaltiesMember to ions_SpinrazaRoyaltiesMember_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_LicensingAndOtherRoyaltiesMember" xlink:label="LicensingAndOtherRoyaltiesMember" xlink:title="LicensingAndOtherRoyaltiesMember" />
    <link:label xlink:type="resource" xlink:label="ions_LicensingAndOtherRoyaltiesMember_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_LicensingAndOtherRoyaltiesMember_lbl" xml:lang="en-US" id="ions_LicensingAndOtherRoyaltiesMember_lbl">Revenue from license fees and other royalties, excluding royalties from the sale of SPINRAZA.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="LicensingAndOtherRoyaltiesMember" xlink:to="ions_LicensingAndOtherRoyaltiesMember_lbl" xlink:title="label: LicensingAndOtherRoyaltiesMember to ions_LicensingAndOtherRoyaltiesMember_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_LicensingAndOtherRoyaltiesMember_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_LicensingAndOtherRoyaltiesMember_lbl1" xml:lang="en-US" id="ions_LicensingAndOtherRoyaltiesMember_lbl1">Licensing and Other Royalties [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="LicensingAndOtherRoyaltiesMember" xlink:to="ions_LicensingAndOtherRoyaltiesMember_lbl1" xlink:title="label: LicensingAndOtherRoyaltiesMember to ions_LicensingAndOtherRoyaltiesMember_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_LicensingAndOtherRoyaltiesMember_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_LicensingAndOtherRoyaltiesMember_lbl2" xml:lang="en-US" id="ions_LicensingAndOtherRoyaltiesMember_lbl2">Licensing and Other Royalties [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="LicensingAndOtherRoyaltiesMember" xlink:to="ions_LicensingAndOtherRoyaltiesMember_lbl2" xlink:title="label: LicensingAndOtherRoyaltiesMember to ions_LicensingAndOtherRoyaltiesMember_lbl2" />
    <link:label xlink:type="resource" xlink:label="ions_LicensingAndOtherRoyaltiesMember_lbl3" xlink:role="http://www.xbrl.org/2003/role/verboseLabel" xlink:title="ions_LicensingAndOtherRoyaltiesMember_lbl3" xml:lang="en-US" id="ions_LicensingAndOtherRoyaltiesMember_lbl3">Licensing and Other Royalty Revenue [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="LicensingAndOtherRoyaltiesMember" xlink:to="ions_LicensingAndOtherRoyaltiesMember_lbl3" xlink:title="label: LicensingAndOtherRoyaltiesMember to ions_LicensingAndOtherRoyaltiesMember_lbl3" />
    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_ResearchAndDevelopmentRevenueUnderCollaborativeAgreementsMember" xlink:label="ResearchAndDevelopmentRevenueUnderCollaborativeAgreementsMember" xlink:title="ResearchAndDevelopmentRevenueUnderCollaborativeAgreementsMember" />
    <link:label xlink:type="resource" xlink:label="ions_ResearchAndDevelopmentRevenueUnderCollaborativeAgreementsMember_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_ResearchAndDevelopmentRevenueUnderCollaborativeAgreementsMember_lbl" xml:lang="en-US" id="ions_ResearchAndDevelopmentRevenueUnderCollaborativeAgreementsMember_lbl">Revenue from research and development services performed under a collaboration agreement.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="ResearchAndDevelopmentRevenueUnderCollaborativeAgreementsMember" xlink:to="ions_ResearchAndDevelopmentRevenueUnderCollaborativeAgreementsMember_lbl" xlink:title="label: ResearchAndDevelopmentRevenueUnderCollaborativeAgreementsMember to ions_ResearchAndDevelopmentRevenueUnderCollaborativeAgreementsMember_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_ResearchAndDevelopmentRevenueUnderCollaborativeAgreementsMember_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_ResearchAndDevelopmentRevenueUnderCollaborativeAgreementsMember_lbl1" xml:lang="en-US" id="ions_ResearchAndDevelopmentRevenueUnderCollaborativeAgreementsMember_lbl1">Research and Development Revenue Under Collaborative Agreements [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="ResearchAndDevelopmentRevenueUnderCollaborativeAgreementsMember" xlink:to="ions_ResearchAndDevelopmentRevenueUnderCollaborativeAgreementsMember_lbl1" xlink:title="label: ResearchAndDevelopmentRevenueUnderCollaborativeAgreementsMember to ions_ResearchAndDevelopmentRevenueUnderCollaborativeAgreementsMember_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_ResearchAndDevelopmentRevenueUnderCollaborativeAgreementsMember_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_ResearchAndDevelopmentRevenueUnderCollaborativeAgreementsMember_lbl2" xml:lang="en-US" id="ions_ResearchAndDevelopmentRevenueUnderCollaborativeAgreementsMember_lbl2">R&amp;D Revenue [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="ResearchAndDevelopmentRevenueUnderCollaborativeAgreementsMember" xlink:to="ions_ResearchAndDevelopmentRevenueUnderCollaborativeAgreementsMember_lbl2" xlink:title="label: ResearchAndDevelopmentRevenueUnderCollaborativeAgreementsMember to ions_ResearchAndDevelopmentRevenueUnderCollaborativeAgreementsMember_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_PeriodAfterBillingWhenPaymentIsReceived" xlink:label="PeriodAfterBillingWhenPaymentIsReceived" xlink:title="PeriodAfterBillingWhenPaymentIsReceived" />
    <link:label xlink:type="resource" xlink:label="ions_PeriodAfterBillingWhenPaymentIsReceived_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_PeriodAfterBillingWhenPaymentIsReceived_lbl" xml:lang="en-US" id="ions_PeriodAfterBillingWhenPaymentIsReceived_lbl">The time period between billing a collaboration partner for goods delivered or services performed that are due unconditionally and payment is received from the collaboration partner, in 'PnYnMnDTnHnMnS' format, for example, 'P1Y5M13D' represents the reported fact of one year, five months, and thirteen days.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="PeriodAfterBillingWhenPaymentIsReceived" xlink:to="ions_PeriodAfterBillingWhenPaymentIsReceived_lbl" xlink:title="label: PeriodAfterBillingWhenPaymentIsReceived to ions_PeriodAfterBillingWhenPaymentIsReceived_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_PeriodAfterBillingWhenPaymentIsReceived_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_PeriodAfterBillingWhenPaymentIsReceived_lbl1" xml:lang="en-US" id="ions_PeriodAfterBillingWhenPaymentIsReceived_lbl1">Period after billing when payment is received</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="PeriodAfterBillingWhenPaymentIsReceived" xlink:to="ions_PeriodAfterBillingWhenPaymentIsReceived_lbl1" xlink:title="label: PeriodAfterBillingWhenPaymentIsReceived to ions_PeriodAfterBillingWhenPaymentIsReceived_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_PeriodAfterBillingWhenPaymentIsReceived_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_PeriodAfterBillingWhenPaymentIsReceived_lbl2" xml:lang="en-US" id="ions_PeriodAfterBillingWhenPaymentIsReceived_lbl2">Period of time after billing when payment is received</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="PeriodAfterBillingWhenPaymentIsReceived" xlink:to="ions_PeriodAfterBillingWhenPaymentIsReceived_lbl2" xlink:title="label: PeriodAfterBillingWhenPaymentIsReceived to ions_PeriodAfterBillingWhenPaymentIsReceived_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_SignificantPartnersAbstract" xlink:label="SignificantPartnersAbstract" xlink:title="SignificantPartnersAbstract" />
    <link:label xlink:type="resource" xlink:label="ions_SignificantPartnersAbstract_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_SignificantPartnersAbstract_lbl1" xml:lang="en-US" id="ions_SignificantPartnersAbstract_lbl1">Significant Partners [Abstract]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="SignificantPartnersAbstract" xlink:to="ions_SignificantPartnersAbstract_lbl1" xlink:title="label: SignificantPartnersAbstract to ions_SignificantPartnersAbstract_lbl1" />
    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_NumberOfSignificantCustomers" xlink:label="NumberOfSignificantCustomers" xlink:title="NumberOfSignificantCustomers" />
    <link:label xlink:type="resource" xlink:label="ions_NumberOfSignificantCustomers_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_NumberOfSignificantCustomers_lbl" xml:lang="en-US" id="ions_NumberOfSignificantCustomers_lbl">The number of significant customers with which the Company does business.</link:label>
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    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_EffectiveIncomeTaxRateReconciliationAcquisitionOfNoncontrollingInterestAmount" xlink:label="EffectiveIncomeTaxRateReconciliationAcquisitionOfNoncontrollingInterestAmount" xlink:title="EffectiveIncomeTaxRateReconciliationAcquisitionOfNoncontrollingInterestAmount" />
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    <link:label xlink:type="resource" xlink:label="ions_ShareBasedPaymentArrangementBoardOfDirectorMember_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_ShareBasedPaymentArrangementBoardOfDirectorMember_lbl2" xml:lang="en-US" id="ions_ShareBasedPaymentArrangementBoardOfDirectorMember_lbl2">Board of Directors [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="ShareBasedPaymentArrangementBoardOfDirectorMember" xlink:to="ions_ShareBasedPaymentArrangementBoardOfDirectorMember_lbl2" xlink:title="label: ShareBasedPaymentArrangementBoardOfDirectorMember to ions_ShareBasedPaymentArrangementBoardOfDirectorMember_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_GrantedPriorToJune2020Member" xlink:label="GrantedPriorToJune2020Member" xlink:title="GrantedPriorToJune2020Member" />
    <link:label xlink:type="resource" xlink:label="ions_GrantedPriorToJune2020Member_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_GrantedPriorToJune2020Member_lbl" xml:lang="en-US" id="ions_GrantedPriorToJune2020Member_lbl">Awards granted prior to June 2020.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="GrantedPriorToJune2020Member" xlink:to="ions_GrantedPriorToJune2020Member_lbl" xlink:title="label: GrantedPriorToJune2020Member to ions_GrantedPriorToJune2020Member_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_GrantedPriorToJune2020Member_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_GrantedPriorToJune2020Member_lbl1" xml:lang="en-US" id="ions_GrantedPriorToJune2020Member_lbl1">Granted Prior to June 2020 [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="GrantedPriorToJune2020Member" xlink:to="ions_GrantedPriorToJune2020Member_lbl1" xlink:title="label: GrantedPriorToJune2020Member to ions_GrantedPriorToJune2020Member_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_GrantedPriorToJune2020Member_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_GrantedPriorToJune2020Member_lbl2" xml:lang="en-US" id="ions_GrantedPriorToJune2020Member_lbl2">Granted Prior to June 2020 [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="GrantedPriorToJune2020Member" xlink:to="ions_GrantedPriorToJune2020Member_lbl2" xlink:title="label: GrantedPriorToJune2020Member to ions_GrantedPriorToJune2020Member_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_GrantedAfterJune2020Member" xlink:label="GrantedAfterJune2020Member" xlink:title="GrantedAfterJune2020Member" />
    <link:label xlink:type="resource" xlink:label="ions_GrantedAfterJune2020Member_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_GrantedAfterJune2020Member_lbl" xml:lang="en-US" id="ions_GrantedAfterJune2020Member_lbl">Awards granted after June 2020.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="GrantedAfterJune2020Member" xlink:to="ions_GrantedAfterJune2020Member_lbl" xlink:title="label: GrantedAfterJune2020Member to ions_GrantedAfterJune2020Member_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_GrantedAfterJune2020Member_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_GrantedAfterJune2020Member_lbl1" xml:lang="en-US" id="ions_GrantedAfterJune2020Member_lbl1">Granted After June 2020 [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="GrantedAfterJune2020Member" xlink:to="ions_GrantedAfterJune2020Member_lbl1" xlink:title="label: GrantedAfterJune2020Member to ions_GrantedAfterJune2020Member_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_GrantedAfterJune2020Member_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_GrantedAfterJune2020Member_lbl2" xml:lang="en-US" id="ions_GrantedAfterJune2020Member_lbl2">Granted After June 2020 [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="GrantedAfterJune2020Member" xlink:to="ions_GrantedAfterJune2020Member_lbl2" xlink:title="label: GrantedAfterJune2020Member to ions_GrantedAfterJune2020Member_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_ShareBasedCompensationArrangementByShareBasedPaymentAwardNumberOfPerformancePeriods" xlink:label="ShareBasedCompensationArrangementByShareBasedPaymentAwardNumberOfPerformancePeriods" xlink:title="ShareBasedCompensationArrangementByShareBasedPaymentAwardNumberOfPerformancePeriods" />
    <link:label xlink:type="resource" xlink:label="ions_ShareBasedCompensationArrangementByShareBasedPaymentAwardNumberOfPerformancePeriods_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_ShareBasedCompensationArrangementByShareBasedPaymentAwardNumberOfPerformancePeriods_lbl" xml:lang="en-US" id="ions_ShareBasedCompensationArrangementByShareBasedPaymentAwardNumberOfPerformancePeriods_lbl">Number of separate performance periods under share-based payment arrangement.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="ShareBasedCompensationArrangementByShareBasedPaymentAwardNumberOfPerformancePeriods" xlink:to="ions_ShareBasedCompensationArrangementByShareBasedPaymentAwardNumberOfPerformancePeriods_lbl" xlink:title="label: ShareBasedCompensationArrangementByShareBasedPaymentAwardNumberOfPerformancePeriods to ions_ShareBasedCompensationArrangementByShareBasedPaymentAwardNumberOfPerformancePeriods_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_ShareBasedCompensationArrangementByShareBasedPaymentAwardNumberOfPerformancePeriods_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_ShareBasedCompensationArrangementByShareBasedPaymentAwardNumberOfPerformancePeriods_lbl1" xml:lang="en-US" id="ions_ShareBasedCompensationArrangementByShareBasedPaymentAwardNumberOfPerformancePeriods_lbl1">Share-based Compensation Arrangement by Share-based Payment Award, Number of Performance Periods</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="ShareBasedCompensationArrangementByShareBasedPaymentAwardNumberOfPerformancePeriods" xlink:to="ions_ShareBasedCompensationArrangementByShareBasedPaymentAwardNumberOfPerformancePeriods_lbl1" xlink:title="label: ShareBasedCompensationArrangementByShareBasedPaymentAwardNumberOfPerformancePeriods to ions_ShareBasedCompensationArrangementByShareBasedPaymentAwardNumberOfPerformancePeriods_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_ShareBasedCompensationArrangementByShareBasedPaymentAwardNumberOfPerformancePeriods_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_ShareBasedCompensationArrangementByShareBasedPaymentAwardNumberOfPerformancePeriods_lbl2" xml:lang="en-US" id="ions_ShareBasedCompensationArrangementByShareBasedPaymentAwardNumberOfPerformancePeriods_lbl2">Number of performance periods</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="ShareBasedCompensationArrangementByShareBasedPaymentAwardNumberOfPerformancePeriods" xlink:to="ions_ShareBasedCompensationArrangementByShareBasedPaymentAwardNumberOfPerformancePeriods_lbl2" xlink:title="label: ShareBasedCompensationArrangementByShareBasedPaymentAwardNumberOfPerformancePeriods to ions_ShareBasedCompensationArrangementByShareBasedPaymentAwardNumberOfPerformancePeriods_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_ShareBasedCompensationArrangementByShareBasedPaymentAwardNumberOfUnitsGuaranteedToVest" xlink:label="ShareBasedCompensationArrangementByShareBasedPaymentAwardNumberOfUnitsGuaranteedToVest" xlink:title="ShareBasedCompensationArrangementByShareBasedPaymentAwardNumberOfUnitsGuaranteedToVest" />
    <link:label xlink:type="resource" xlink:label="ions_ShareBasedCompensationArrangementByShareBasedPaymentAwardNumberOfUnitsGuaranteedToVest_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_ShareBasedCompensationArrangementByShareBasedPaymentAwardNumberOfUnitsGuaranteedToVest_lbl" xml:lang="en-US" id="ions_ShareBasedCompensationArrangementByShareBasedPaymentAwardNumberOfUnitsGuaranteedToVest_lbl">Number of units guaranteed to vest under share-based payment arrangement.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="ShareBasedCompensationArrangementByShareBasedPaymentAwardNumberOfUnitsGuaranteedToVest" xlink:to="ions_ShareBasedCompensationArrangementByShareBasedPaymentAwardNumberOfUnitsGuaranteedToVest_lbl" xlink:title="label: ShareBasedCompensationArrangementByShareBasedPaymentAwardNumberOfUnitsGuaranteedToVest to ions_ShareBasedCompensationArrangementByShareBasedPaymentAwardNumberOfUnitsGuaranteedToVest_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_ShareBasedCompensationArrangementByShareBasedPaymentAwardNumberOfUnitsGuaranteedToVest_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_ShareBasedCompensationArrangementByShareBasedPaymentAwardNumberOfUnitsGuaranteedToVest_lbl1" xml:lang="en-US" id="ions_ShareBasedCompensationArrangementByShareBasedPaymentAwardNumberOfUnitsGuaranteedToVest_lbl1">Share-based Compensation Arrangement by Share-based Payment Award, Number of units guaranteed to vest</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="ShareBasedCompensationArrangementByShareBasedPaymentAwardNumberOfUnitsGuaranteedToVest" xlink:to="ions_ShareBasedCompensationArrangementByShareBasedPaymentAwardNumberOfUnitsGuaranteedToVest_lbl1" xlink:title="label: ShareBasedCompensationArrangementByShareBasedPaymentAwardNumberOfUnitsGuaranteedToVest to ions_ShareBasedCompensationArrangementByShareBasedPaymentAwardNumberOfUnitsGuaranteedToVest_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_ShareBasedCompensationArrangementByShareBasedPaymentAwardNumberOfUnitsGuaranteedToVest_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_ShareBasedCompensationArrangementByShareBasedPaymentAwardNumberOfUnitsGuaranteedToVest_lbl2" xml:lang="en-US" id="ions_ShareBasedCompensationArrangementByShareBasedPaymentAwardNumberOfUnitsGuaranteedToVest_lbl2">Number of units guaranteed to vest</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="ShareBasedCompensationArrangementByShareBasedPaymentAwardNumberOfUnitsGuaranteedToVest" xlink:to="ions_ShareBasedCompensationArrangementByShareBasedPaymentAwardNumberOfUnitsGuaranteedToVest_lbl2" xlink:title="label: ShareBasedCompensationArrangementByShareBasedPaymentAwardNumberOfUnitsGuaranteedToVest to ions_ShareBasedCompensationArrangementByShareBasedPaymentAwardNumberOfUnitsGuaranteedToVest_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_ShareBasedCompensationArrangementByShareBasedPaymentAwardPercentageOfUnitsGuaranteedToVest" xlink:label="ShareBasedCompensationArrangementByShareBasedPaymentAwardPercentageOfUnitsGuaranteedToVest" xlink:title="ShareBasedCompensationArrangementByShareBasedPaymentAwardPercentageOfUnitsGuaranteedToVest" />
    <link:label xlink:type="resource" xlink:label="ions_ShareBasedCompensationArrangementByShareBasedPaymentAwardPercentageOfUnitsGuaranteedToVest_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_ShareBasedCompensationArrangementByShareBasedPaymentAwardPercentageOfUnitsGuaranteedToVest_lbl" xml:lang="en-US" id="ions_ShareBasedCompensationArrangementByShareBasedPaymentAwardPercentageOfUnitsGuaranteedToVest_lbl">Percentage of units guaranteed to vest under share-based payment arrangement.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="ShareBasedCompensationArrangementByShareBasedPaymentAwardPercentageOfUnitsGuaranteedToVest" xlink:to="ions_ShareBasedCompensationArrangementByShareBasedPaymentAwardPercentageOfUnitsGuaranteedToVest_lbl" xlink:title="label: ShareBasedCompensationArrangementByShareBasedPaymentAwardPercentageOfUnitsGuaranteedToVest to ions_ShareBasedCompensationArrangementByShareBasedPaymentAwardPercentageOfUnitsGuaranteedToVest_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_ShareBasedCompensationArrangementByShareBasedPaymentAwardPercentageOfUnitsGuaranteedToVest_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_ShareBasedCompensationArrangementByShareBasedPaymentAwardPercentageOfUnitsGuaranteedToVest_lbl1" xml:lang="en-US" id="ions_ShareBasedCompensationArrangementByShareBasedPaymentAwardPercentageOfUnitsGuaranteedToVest_lbl1">Share-based Compensation Arrangement by Share-based Payment Award, Percentage of units guaranteed to vest</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="ShareBasedCompensationArrangementByShareBasedPaymentAwardPercentageOfUnitsGuaranteedToVest" xlink:to="ions_ShareBasedCompensationArrangementByShareBasedPaymentAwardPercentageOfUnitsGuaranteedToVest_lbl1" xlink:title="label: ShareBasedCompensationArrangementByShareBasedPaymentAwardPercentageOfUnitsGuaranteedToVest to ions_ShareBasedCompensationArrangementByShareBasedPaymentAwardPercentageOfUnitsGuaranteedToVest_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_ShareBasedCompensationArrangementByShareBasedPaymentAwardPercentageOfUnitsGuaranteedToVest_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_ShareBasedCompensationArrangementByShareBasedPaymentAwardPercentageOfUnitsGuaranteedToVest_lbl2" xml:lang="en-US" id="ions_ShareBasedCompensationArrangementByShareBasedPaymentAwardPercentageOfUnitsGuaranteedToVest_lbl2">Percentage of units guaranteed to vest</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="ShareBasedCompensationArrangementByShareBasedPaymentAwardPercentageOfUnitsGuaranteedToVest" xlink:to="ions_ShareBasedCompensationArrangementByShareBasedPaymentAwardPercentageOfUnitsGuaranteedToVest_lbl2" xlink:title="label: ShareBasedCompensationArrangementByShareBasedPaymentAwardPercentageOfUnitsGuaranteedToVest to ions_ShareBasedCompensationArrangementByShareBasedPaymentAwardPercentageOfUnitsGuaranteedToVest_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_PropertyPlantAndEquipmentExcludingLandMember" xlink:label="PropertyPlantAndEquipmentExcludingLandMember" xlink:title="PropertyPlantAndEquipmentExcludingLandMember" />
    <link:label xlink:type="resource" xlink:label="ions_PropertyPlantAndEquipmentExcludingLandMember_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_PropertyPlantAndEquipmentExcludingLandMember_lbl" xml:lang="en-US" id="ions_PropertyPlantAndEquipmentExcludingLandMember_lbl">Physical assets used in the normal conduct of business and not intended for resale, excluding land. Examples include, but are not limited to, buildings, land and leasehold improvements, machinery and equipment, office equipment, and furniture and fixtures.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="PropertyPlantAndEquipmentExcludingLandMember" xlink:to="ions_PropertyPlantAndEquipmentExcludingLandMember_lbl" xlink:title="label: PropertyPlantAndEquipmentExcludingLandMember to ions_PropertyPlantAndEquipmentExcludingLandMember_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_PropertyPlantAndEquipmentExcludingLandMember_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_PropertyPlantAndEquipmentExcludingLandMember_lbl1" xml:lang="en-US" id="ions_PropertyPlantAndEquipmentExcludingLandMember_lbl1">Property, Plant and Equipment, Excluding Land [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="PropertyPlantAndEquipmentExcludingLandMember" xlink:to="ions_PropertyPlantAndEquipmentExcludingLandMember_lbl1" xlink:title="label: PropertyPlantAndEquipmentExcludingLandMember to ions_PropertyPlantAndEquipmentExcludingLandMember_lbl1" />
    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_EquipmentAndComputerSoftwareMember" xlink:label="EquipmentAndComputerSoftwareMember" xlink:title="EquipmentAndComputerSoftwareMember" />
    <link:label xlink:type="resource" xlink:label="ions_EquipmentAndComputerSoftwareMember_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_EquipmentAndComputerSoftwareMember_lbl" xml:lang="en-US" id="ions_EquipmentAndComputerSoftwareMember_lbl">Long lived, depreciable assets that are used in the creation, maintenance and utilization of information systems and purchased software applications and internally developed software for long-term internal use. Includes other tangible personal property, nonconsumable in nature, with finite lives used to produce goods and services, such as laboratory, manufacturing and other equipment.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="EquipmentAndComputerSoftwareMember" xlink:to="ions_EquipmentAndComputerSoftwareMember_lbl" xlink:title="label: EquipmentAndComputerSoftwareMember to ions_EquipmentAndComputerSoftwareMember_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_EquipmentAndComputerSoftwareMember_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_EquipmentAndComputerSoftwareMember_lbl1" xml:lang="en-US" id="ions_EquipmentAndComputerSoftwareMember_lbl1">Equipment and Computer Software [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="EquipmentAndComputerSoftwareMember" xlink:to="ions_EquipmentAndComputerSoftwareMember_lbl1" xlink:title="label: EquipmentAndComputerSoftwareMember to ions_EquipmentAndComputerSoftwareMember_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_EquipmentAndComputerSoftwareMember_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_EquipmentAndComputerSoftwareMember_lbl2" xml:lang="en-US" id="ions_EquipmentAndComputerSoftwareMember_lbl2">Computer Software, Laboratory, Manufacturing and Other Equipment [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="EquipmentAndComputerSoftwareMember" xlink:to="ions_EquipmentAndComputerSoftwareMember_lbl2" xlink:title="label: EquipmentAndComputerSoftwareMember to ions_EquipmentAndComputerSoftwareMember_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_PeriodToMakeInterestOnlyPaymentsOnMortgageLoan" xlink:label="PeriodToMakeInterestOnlyPaymentsOnMortgageLoan" xlink:title="PeriodToMakeInterestOnlyPaymentsOnMortgageLoan" />
    <link:label xlink:type="resource" xlink:label="ions_PeriodToMakeInterestOnlyPaymentsOnMortgageLoan_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_PeriodToMakeInterestOnlyPaymentsOnMortgageLoan_lbl" xml:lang="en-US" id="ions_PeriodToMakeInterestOnlyPaymentsOnMortgageLoan_lbl">Period of time to make only payments of interest on the mortgage loan, in 'PnYnMnDTnHnMnS' format, for example, 'P1Y5M13D' represents the reported fact of one year, five months, and thirteen days.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="PeriodToMakeInterestOnlyPaymentsOnMortgageLoan" xlink:to="ions_PeriodToMakeInterestOnlyPaymentsOnMortgageLoan_lbl" xlink:title="label: PeriodToMakeInterestOnlyPaymentsOnMortgageLoan to ions_PeriodToMakeInterestOnlyPaymentsOnMortgageLoan_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_PeriodToMakeInterestOnlyPaymentsOnMortgageLoan_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_PeriodToMakeInterestOnlyPaymentsOnMortgageLoan_lbl1" xml:lang="en-US" id="ions_PeriodToMakeInterestOnlyPaymentsOnMortgageLoan_lbl1">Period to make interest only payments on mortgage loan</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="PeriodToMakeInterestOnlyPaymentsOnMortgageLoan" xlink:to="ions_PeriodToMakeInterestOnlyPaymentsOnMortgageLoan_lbl1" xlink:title="label: PeriodToMakeInterestOnlyPaymentsOnMortgageLoan to ions_PeriodToMakeInterestOnlyPaymentsOnMortgageLoan_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_PeriodToMakeInterestOnlyPaymentsOnMortgageLoan_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_PeriodToMakeInterestOnlyPaymentsOnMortgageLoan_lbl2" xml:lang="en-US" id="ions_PeriodToMakeInterestOnlyPaymentsOnMortgageLoan_lbl2">Period to make interest only payments on mortgage loan</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="PeriodToMakeInterestOnlyPaymentsOnMortgageLoan" xlink:to="ions_PeriodToMakeInterestOnlyPaymentsOnMortgageLoan_lbl2" xlink:title="label: PeriodToMakeInterestOnlyPaymentsOnMortgageLoan to ions_PeriodToMakeInterestOnlyPaymentsOnMortgageLoan_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_NumberOfPurchasedFacilitiesFinancedWithMortgageDebt" xlink:label="NumberOfPurchasedFacilitiesFinancedWithMortgageDebt" xlink:title="NumberOfPurchasedFacilitiesFinancedWithMortgageDebt" />
    <link:label xlink:type="resource" xlink:label="ions_NumberOfPurchasedFacilitiesFinancedWithMortgageDebt_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_NumberOfPurchasedFacilitiesFinancedWithMortgageDebt_lbl" xml:lang="en-US" id="ions_NumberOfPurchasedFacilitiesFinancedWithMortgageDebt_lbl">The number of purchased facilities financed with mortgage debt.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="NumberOfPurchasedFacilitiesFinancedWithMortgageDebt" xlink:to="ions_NumberOfPurchasedFacilitiesFinancedWithMortgageDebt_lbl" xlink:title="label: NumberOfPurchasedFacilitiesFinancedWithMortgageDebt to ions_NumberOfPurchasedFacilitiesFinancedWithMortgageDebt_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_NumberOfPurchasedFacilitiesFinancedWithMortgageDebt_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_NumberOfPurchasedFacilitiesFinancedWithMortgageDebt_lbl1" xml:lang="en-US" id="ions_NumberOfPurchasedFacilitiesFinancedWithMortgageDebt_lbl1">Number of purchased facilities financed with mortgage debt</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="NumberOfPurchasedFacilitiesFinancedWithMortgageDebt" xlink:to="ions_NumberOfPurchasedFacilitiesFinancedWithMortgageDebt_lbl1" xlink:title="label: NumberOfPurchasedFacilitiesFinancedWithMortgageDebt to ions_NumberOfPurchasedFacilitiesFinancedWithMortgageDebt_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_NumberOfPurchasedFacilitiesFinancedWithMortgageDebt_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_NumberOfPurchasedFacilitiesFinancedWithMortgageDebt_lbl2" xml:lang="en-US" id="ions_NumberOfPurchasedFacilitiesFinancedWithMortgageDebt_lbl2">Number of purchased facilities financed with mortgage debt</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="NumberOfPurchasedFacilitiesFinancedWithMortgageDebt" xlink:to="ions_NumberOfPurchasedFacilitiesFinancedWithMortgageDebt_lbl2" xlink:title="label: NumberOfPurchasedFacilitiesFinancedWithMortgageDebt to ions_NumberOfPurchasedFacilitiesFinancedWithMortgageDebt_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_LongTermMortgageDebtMember" xlink:label="LongTermMortgageDebtMember" xlink:title="LongTermMortgageDebtMember" />
    <link:label xlink:type="resource" xlink:label="ions_LongTermMortgageDebtMember_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_LongTermMortgageDebtMember_lbl" xml:lang="en-US" id="ions_LongTermMortgageDebtMember_lbl">Two loan agreements with UBS AG entered into on July 18, 2017 to partially finance the purchase of the Company's research and development and manufacturing facilities.</link:label>
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    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_PrimaryResearchAndDevelopmentFacilityMember" xlink:label="PrimaryResearchAndDevelopmentFacilityMember" xlink:title="PrimaryResearchAndDevelopmentFacilityMember" />
    <link:label xlink:type="resource" xlink:label="ions_PrimaryResearchAndDevelopmentFacilityMember_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_PrimaryResearchAndDevelopmentFacilityMember_lbl" xml:lang="en-US" id="ions_PrimaryResearchAndDevelopmentFacilityMember_lbl">Facility constructed for the entity's primary research and development activities under a lease agreement with an affiliate of BioMed Realty, L.P.</link:label>
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    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_BoardOfDirectorStockOptionMember" xlink:label="BoardOfDirectorStockOptionMember" xlink:title="BoardOfDirectorStockOptionMember" />
    <link:label xlink:type="resource" xlink:label="ions_BoardOfDirectorStockOptionMember_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_BoardOfDirectorStockOptionMember_lbl" xml:lang="en-US" id="ions_BoardOfDirectorStockOptionMember_lbl">An arrangement whereby a member of the Board of Directors is entitled to receive in the future, subject to vesting and other restrictions, a number of shares in the entity at a specified price, as defined in the agreement, as a form of compensation.</link:label>
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    <link:label xlink:type="resource" xlink:label="ions_BoardOfDirectorStockOptionMember_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_BoardOfDirectorStockOptionMember_lbl1" xml:lang="en-US" id="ions_BoardOfDirectorStockOptionMember_lbl1">Board of Director Stock Option [Member]</link:label>
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    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsExercisesInPeriodWeightedAverageFairValue" xlink:label="ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsExercisesInPeriodWeightedAverageFairValue" xlink:title="ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsExercisesInPeriodWeightedAverageFairValue" />
    <link:label xlink:type="resource" xlink:label="ions_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsExercisesInPeriodWeightedAverageFairValue_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsExercisesInPeriodWeightedAverageFairValue_lbl" xml:lang="en-US" id="ions_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsExercisesInPeriodWeightedAverageFairValue_lbl">The weighted average grant-date fair value of options exercised during the reporting period as calculated by applying the disclosed option pricing methodology.</link:label>
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    <link:label xlink:type="resource" xlink:label="ions_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsExercisesInPeriodWeightedAverageFairValue_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsExercisesInPeriodWeightedAverageFairValue_lbl1" xml:lang="en-US" id="ions_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsExercisesInPeriodWeightedAverageFairValue_lbl1">Share-based Compensation Arrangement by Share-based Payment Award, Options, Exercises in Period, Weighted Average Fair Value</link:label>
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    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_OtherComprehensiveIncomeLossAdjustmentsFromPurchaseOfNoncontrollingInterestOfSubsidiary" xlink:label="OtherComprehensiveIncomeLossAdjustmentsFromPurchaseOfNoncontrollingInterestOfSubsidiary" xlink:title="OtherComprehensiveIncomeLossAdjustmentsFromPurchaseOfNoncontrollingInterestOfSubsidiary" />
    <link:label xlink:type="resource" xlink:label="ions_OtherComprehensiveIncomeLossAdjustmentsFromPurchaseOfNoncontrollingInterestOfSubsidiary_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_OtherComprehensiveIncomeLossAdjustmentsFromPurchaseOfNoncontrollingInterestOfSubsidiary_lbl" xml:lang="en-US" id="ions_OtherComprehensiveIncomeLossAdjustmentsFromPurchaseOfNoncontrollingInterestOfSubsidiary_lbl">Adjustments to other comprehensive income (loss) from purchase of noncontrolling interest of subsidiary.</link:label>
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    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_IncreaseDecreaseInIncomeTaxesReceivablePayable" xlink:label="IncreaseDecreaseInIncomeTaxesReceivablePayable" xlink:title="IncreaseDecreaseInIncomeTaxesReceivablePayable" />
    <link:label xlink:type="resource" xlink:label="ions_IncreaseDecreaseInIncomeTaxesReceivablePayable_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_IncreaseDecreaseInIncomeTaxesReceivablePayable_lbl" xml:lang="en-US" id="ions_IncreaseDecreaseInIncomeTaxesReceivablePayable_lbl">The increase (decrease) during the reporting period in income taxes receivable (payable), which represents the amount due from tax authorities for refunds of overpayments or recoveries of income taxes paid or the amount due for taxes based on the reporting entity's earnings or attributable to the entity's income earning process (business presence) within a given jurisdiction.</link:label>
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    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="IncreaseDecreaseInIncomeTaxesReceivablePayable" xlink:to="ions_IncreaseDecreaseInIncomeTaxesReceivablePayable_lbl2" xlink:title="label: IncreaseDecreaseInIncomeTaxesReceivablePayable to ions_IncreaseDecreaseInIncomeTaxesReceivablePayable_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_EarlyRepaymentOfConvertibleDebt" xlink:label="EarlyRepaymentOfConvertibleDebt" xlink:title="EarlyRepaymentOfConvertibleDebt" />
    <link:label xlink:type="resource" xlink:label="ions_EarlyRepaymentOfConvertibleDebt_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_EarlyRepaymentOfConvertibleDebt_lbl" xml:lang="en-US" id="ions_EarlyRepaymentOfConvertibleDebt_lbl">The cash outflow from the extinguishment of a long-term debt instrument which can be exchanged for a specified amount of another security, typically the entity's common stock, at the option of the issuer or the holder.</link:label>
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    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_NonCashCapitalAndPatentExpenditures" xlink:label="NonCashCapitalAndPatentExpenditures" xlink:title="NonCashCapitalAndPatentExpenditures" />
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    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_IonisCoreMember" xlink:label="IonisCoreMember" xlink:title="IonisCoreMember" />
    <link:label xlink:type="resource" xlink:label="ions_IonisCoreMember_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_IonisCoreMember_lbl" xml:lang="en-US" id="ions_IonisCoreMember_lbl">Reportable segment in which the Company is exploiting a novel drug discovery platform created to generate a broad pipeline of first-in-class or best-in-class drugs for the Company and its partners. This segment generates revenue from a multifaceted partnering strategy. This strategy includes revenue from collaborations with preferred partners, traditional alliances and working with a consortium of companies that can exploit the Company's drugs and technology. Revenue from collaborations with preferred partners and traditional alliances may consist of upfront payments, milestone payments, licensing fees and royalties.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="IonisCoreMember" xlink:to="ions_IonisCoreMember_lbl" xlink:title="label: IonisCoreMember to ions_IonisCoreMember_lbl" />
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    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="IonisCoreMember" xlink:to="ions_IonisCoreMember_lbl1" xlink:title="label: IonisCoreMember to ions_IonisCoreMember_lbl1" />
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    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="IonisCoreMember" xlink:to="ions_IonisCoreMember_lbl2" xlink:title="label: IonisCoreMember to ions_IonisCoreMember_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_WeightedAverageNumberOfSharesOwnedInSubsidiary" xlink:label="WeightedAverageNumberOfSharesOwnedInSubsidiary" xlink:title="WeightedAverageNumberOfSharesOwnedInSubsidiary" />
    <link:label xlink:type="resource" xlink:label="ions_WeightedAverageNumberOfSharesOwnedInSubsidiary_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_WeightedAverageNumberOfSharesOwnedInSubsidiary_lbl" xml:lang="en-US" id="ions_WeightedAverageNumberOfSharesOwnedInSubsidiary_lbl">Number of shares owned in the subsidiary during the reporting period determined by relating the portion of time within a reporting period that shares have been owned to the total time in that period.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="WeightedAverageNumberOfSharesOwnedInSubsidiary" xlink:to="ions_WeightedAverageNumberOfSharesOwnedInSubsidiary_lbl" xlink:title="label: WeightedAverageNumberOfSharesOwnedInSubsidiary to ions_WeightedAverageNumberOfSharesOwnedInSubsidiary_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_WeightedAverageNumberOfSharesOwnedInSubsidiary_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_WeightedAverageNumberOfSharesOwnedInSubsidiary_lbl1" xml:lang="en-US" id="ions_WeightedAverageNumberOfSharesOwnedInSubsidiary_lbl1">Weighted average number of shares owned in subsidiary</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="WeightedAverageNumberOfSharesOwnedInSubsidiary" xlink:to="ions_WeightedAverageNumberOfSharesOwnedInSubsidiary_lbl1" xlink:title="label: WeightedAverageNumberOfSharesOwnedInSubsidiary to ions_WeightedAverageNumberOfSharesOwnedInSubsidiary_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_WeightedAverageNumberOfSharesOwnedInSubsidiary_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_WeightedAverageNumberOfSharesOwnedInSubsidiary_lbl2" xml:lang="en-US" id="ions_WeightedAverageNumberOfSharesOwnedInSubsidiary_lbl2">Weighted average shares owned in Akcea (in shares)</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="WeightedAverageNumberOfSharesOwnedInSubsidiary" xlink:to="ions_WeightedAverageNumberOfSharesOwnedInSubsidiary_lbl2" xlink:title="label: WeightedAverageNumberOfSharesOwnedInSubsidiary to ions_WeightedAverageNumberOfSharesOwnedInSubsidiary_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_ProqrTherapeuticsNVMember" xlink:label="ProqrTherapeuticsNVMember" xlink:title="ProqrTherapeuticsNVMember" />
    <link:label xlink:type="resource" xlink:label="ions_ProqrTherapeuticsNVMember_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_ProqrTherapeuticsNVMember_lbl" xml:lang="en-US" id="ions_ProqrTherapeuticsNVMember_lbl">ProQR Therapeutics N.V. is a clinical stage biotech company that discovers and develops unique Ribonucleic acid (RNA) therapies for severe genetic disorders, specialized in retinal diseases.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="ProqrTherapeuticsNVMember" xlink:to="ions_ProqrTherapeuticsNVMember_lbl" xlink:title="label: ProqrTherapeuticsNVMember to ions_ProqrTherapeuticsNVMember_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_ProqrTherapeuticsNVMember_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_ProqrTherapeuticsNVMember_lbl1" xml:lang="en-US" id="ions_ProqrTherapeuticsNVMember_lbl1">ProQR Therapeutics N.V. [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="ProqrTherapeuticsNVMember" xlink:to="ions_ProqrTherapeuticsNVMember_lbl1" xlink:title="label: ProqrTherapeuticsNVMember to ions_ProqrTherapeuticsNVMember_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_ProqrTherapeuticsNVMember_lbl2" xlink:role="http://www.xbrl.org/2003/role/verboseLabel" xlink:title="ions_ProqrTherapeuticsNVMember_lbl2" xml:lang="en-US" id="ions_ProqrTherapeuticsNVMember_lbl2">ProQR Therapeutics N.V. [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="ProqrTherapeuticsNVMember" xlink:to="ions_ProqrTherapeuticsNVMember_lbl2" xlink:title="label: ProqrTherapeuticsNVMember to ions_ProqrTherapeuticsNVMember_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_BicycleTherapeuticsPlcMember" xlink:label="BicycleTherapeuticsPlcMember" xlink:title="BicycleTherapeuticsPlcMember" />
    <link:label xlink:type="resource" xlink:label="ions_BicycleTherapeuticsPlcMember_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_BicycleTherapeuticsPlcMember_lbl" xml:lang="en-US" id="ions_BicycleTherapeuticsPlcMember_lbl">Bicycle Therapeutics plc is a clinical-stage biopharmaceutical company that is pioneering a unique class of chemically synthesized medicines based on its proprietary bicyclic peptide product platform to address therapeutic needs unreachable with existing treatment modalities.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="BicycleTherapeuticsPlcMember" xlink:to="ions_BicycleTherapeuticsPlcMember_lbl" xlink:title="label: BicycleTherapeuticsPlcMember to ions_BicycleTherapeuticsPlcMember_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_BicycleTherapeuticsPlcMember_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_BicycleTherapeuticsPlcMember_lbl1" xml:lang="en-US" id="ions_BicycleTherapeuticsPlcMember_lbl1">Bicycle Therapeutics plc [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="BicycleTherapeuticsPlcMember" xlink:to="ions_BicycleTherapeuticsPlcMember_lbl1" xlink:title="label: BicycleTherapeuticsPlcMember to ions_BicycleTherapeuticsPlcMember_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_BicycleTherapeuticsPlcMember_lbl2" xlink:role="http://www.xbrl.org/2003/role/verboseLabel" xlink:title="ions_BicycleTherapeuticsPlcMember_lbl2" xml:lang="en-US" id="ions_BicycleTherapeuticsPlcMember_lbl2">Bicycle Therapeutics plc [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="BicycleTherapeuticsPlcMember" xlink:to="ions_BicycleTherapeuticsPlcMember_lbl2" xlink:title="label: BicycleTherapeuticsPlcMember to ions_BicycleTherapeuticsPlcMember_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_ClinicalRawMaterialsMember" xlink:label="ClinicalRawMaterialsMember" xlink:title="ClinicalRawMaterialsMember" />
    <link:label xlink:type="resource" xlink:label="ions_ClinicalRawMaterialsMember_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_ClinicalRawMaterialsMember_lbl" xml:lang="en-US" id="ions_ClinicalRawMaterialsMember_lbl">Raw materials purchased for use in producing medicines that have alternative future uses until they are used.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="ClinicalRawMaterialsMember" xlink:to="ions_ClinicalRawMaterialsMember_lbl" xlink:title="label: ClinicalRawMaterialsMember to ions_ClinicalRawMaterialsMember_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_ClinicalRawMaterialsMember_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_ClinicalRawMaterialsMember_lbl1" xml:lang="en-US" id="ions_ClinicalRawMaterialsMember_lbl1">Clinical Raw Materials [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="ClinicalRawMaterialsMember" xlink:to="ions_ClinicalRawMaterialsMember_lbl1" xlink:title="label: ClinicalRawMaterialsMember to ions_ClinicalRawMaterialsMember_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_ClinicalRawMaterialsMember_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_ClinicalRawMaterialsMember_lbl2" xml:lang="en-US" id="ions_ClinicalRawMaterialsMember_lbl2">Clinical [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="ClinicalRawMaterialsMember" xlink:to="ions_ClinicalRawMaterialsMember_lbl2" xlink:title="label: ClinicalRawMaterialsMember to ions_ClinicalRawMaterialsMember_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_CommercialRawMaterialsMember" xlink:label="CommercialRawMaterialsMember" xlink:title="CommercialRawMaterialsMember" />
    <link:label xlink:type="resource" xlink:label="ions_CommercialRawMaterialsMember_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_CommercialRawMaterialsMember_lbl" xml:lang="en-US" id="ions_CommercialRawMaterialsMember_lbl">Raw materials purchased for manufacturing medicines for commercial production.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="CommercialRawMaterialsMember" xlink:to="ions_CommercialRawMaterialsMember_lbl" xlink:title="label: CommercialRawMaterialsMember to ions_CommercialRawMaterialsMember_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_CommercialRawMaterialsMember_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_CommercialRawMaterialsMember_lbl1" xml:lang="en-US" id="ions_CommercialRawMaterialsMember_lbl1">Commercial Raw Materials [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="CommercialRawMaterialsMember" xlink:to="ions_CommercialRawMaterialsMember_lbl1" xlink:title="label: CommercialRawMaterialsMember to ions_CommercialRawMaterialsMember_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_CommercialRawMaterialsMember_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_CommercialRawMaterialsMember_lbl2" xml:lang="en-US" id="ions_CommercialRawMaterialsMember_lbl2">Commercial [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="CommercialRawMaterialsMember" xlink:to="ions_CommercialRawMaterialsMember_lbl2" xlink:title="label: CommercialRawMaterialsMember to ions_CommercialRawMaterialsMember_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_LiabilityForClinicalDevelopmentCostsPolicyPolicyTextBlock" xlink:label="LiabilityForClinicalDevelopmentCostsPolicyPolicyTextBlock" xlink:title="LiabilityForClinicalDevelopmentCostsPolicyPolicyTextBlock" />
    <link:label xlink:type="resource" xlink:label="ions_LiabilityForClinicalDevelopmentCostsPolicyPolicyTextBlock_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_LiabilityForClinicalDevelopmentCostsPolicyPolicyTextBlock_lbl" xml:lang="en-US" id="ions_LiabilityForClinicalDevelopmentCostsPolicyPolicyTextBlock_lbl">Disclosure of accounting policy for estimating the liability for clinical development costs.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="LiabilityForClinicalDevelopmentCostsPolicyPolicyTextBlock" xlink:to="ions_LiabilityForClinicalDevelopmentCostsPolicyPolicyTextBlock_lbl" xlink:title="label: LiabilityForClinicalDevelopmentCostsPolicyPolicyTextBlock to ions_LiabilityForClinicalDevelopmentCostsPolicyPolicyTextBlock_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_LiabilityForClinicalDevelopmentCostsPolicyPolicyTextBlock_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_LiabilityForClinicalDevelopmentCostsPolicyPolicyTextBlock_lbl1" xml:lang="en-US" id="ions_LiabilityForClinicalDevelopmentCostsPolicyPolicyTextBlock_lbl1">Liability for Clinical Development Costs, Policy [Policy Text Block]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="LiabilityForClinicalDevelopmentCostsPolicyPolicyTextBlock" xlink:to="ions_LiabilityForClinicalDevelopmentCostsPolicyPolicyTextBlock_lbl1" xlink:title="label: LiabilityForClinicalDevelopmentCostsPolicyPolicyTextBlock to ions_LiabilityForClinicalDevelopmentCostsPolicyPolicyTextBlock_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_LiabilityForClinicalDevelopmentCostsPolicyPolicyTextBlock_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_LiabilityForClinicalDevelopmentCostsPolicyPolicyTextBlock_lbl2" xml:lang="en-US" id="ions_LiabilityForClinicalDevelopmentCostsPolicyPolicyTextBlock_lbl2">Estimated Liability for Clinical Development Costs</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="LiabilityForClinicalDevelopmentCostsPolicyPolicyTextBlock" xlink:to="ions_LiabilityForClinicalDevelopmentCostsPolicyPolicyTextBlock_lbl2" xlink:title="label: LiabilityForClinicalDevelopmentCostsPolicyPolicyTextBlock to ions_LiabilityForClinicalDevelopmentCostsPolicyPolicyTextBlock_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_ResearchDevelopmentAndPatentMember" xlink:label="ResearchDevelopmentAndPatentMember" xlink:title="ResearchDevelopmentAndPatentMember" />
    <link:label xlink:type="resource" xlink:label="ions_ResearchDevelopmentAndPatentMember_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_ResearchDevelopmentAndPatentMember_lbl" xml:lang="en-US" id="ions_ResearchDevelopmentAndPatentMember_lbl">Primary financial statement caption encompassing research, development and patent expenses.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="ResearchDevelopmentAndPatentMember" xlink:to="ions_ResearchDevelopmentAndPatentMember_lbl" xlink:title="label: ResearchDevelopmentAndPatentMember to ions_ResearchDevelopmentAndPatentMember_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_ResearchDevelopmentAndPatentMember_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_ResearchDevelopmentAndPatentMember_lbl1" xml:lang="en-US" id="ions_ResearchDevelopmentAndPatentMember_lbl1">Research, Development and Patent [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="ResearchDevelopmentAndPatentMember" xlink:to="ions_ResearchDevelopmentAndPatentMember_lbl1" xlink:title="label: ResearchDevelopmentAndPatentMember to ions_ResearchDevelopmentAndPatentMember_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_ResearchDevelopmentAndPatentMember_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_ResearchDevelopmentAndPatentMember_lbl2" xml:lang="en-US" id="ions_ResearchDevelopmentAndPatentMember_lbl2">Research, Development and Patent [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="ResearchDevelopmentAndPatentMember" xlink:to="ions_ResearchDevelopmentAndPatentMember_lbl2" xlink:title="label: ResearchDevelopmentAndPatentMember to ions_ResearchDevelopmentAndPatentMember_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_NumberOfExecutiveOfficersTerminatingEmployment" xlink:label="NumberOfExecutiveOfficersTerminatingEmployment" xlink:title="NumberOfExecutiveOfficersTerminatingEmployment" />
    <link:label xlink:type="resource" xlink:label="ions_NumberOfExecutiveOfficersTerminatingEmployment_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_NumberOfExecutiveOfficersTerminatingEmployment_lbl" xml:lang="en-US" id="ions_NumberOfExecutiveOfficersTerminatingEmployment_lbl">The number of executive officers terminating employment with the company.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="NumberOfExecutiveOfficersTerminatingEmployment" xlink:to="ions_NumberOfExecutiveOfficersTerminatingEmployment_lbl" xlink:title="label: NumberOfExecutiveOfficersTerminatingEmployment to ions_NumberOfExecutiveOfficersTerminatingEmployment_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_NumberOfExecutiveOfficersTerminatingEmployment_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_NumberOfExecutiveOfficersTerminatingEmployment_lbl1" xml:lang="en-US" id="ions_NumberOfExecutiveOfficersTerminatingEmployment_lbl1">Number of executive officers terminating employment</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="NumberOfExecutiveOfficersTerminatingEmployment" xlink:to="ions_NumberOfExecutiveOfficersTerminatingEmployment_lbl1" xlink:title="label: NumberOfExecutiveOfficersTerminatingEmployment to ions_NumberOfExecutiveOfficersTerminatingEmployment_lbl1" />
    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_IssuedAfterDecember312021Member" xlink:label="IssuedAfterDecember312021Member" xlink:title="IssuedAfterDecember312021Member" />
    <link:label xlink:type="resource" xlink:label="ions_IssuedAfterDecember312021Member_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_IssuedAfterDecember312021Member_lbl" xml:lang="en-US" id="ions_IssuedAfterDecember312021Member_lbl">Awards issued after December 31, 2021.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="IssuedAfterDecember312021Member" xlink:to="ions_IssuedAfterDecember312021Member_lbl" xlink:title="label: IssuedAfterDecember312021Member to ions_IssuedAfterDecember312021Member_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_IssuedAfterDecember312021Member_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_IssuedAfterDecember312021Member_lbl1" xml:lang="en-US" id="ions_IssuedAfterDecember312021Member_lbl1">Issued after December 31, 2021 [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="IssuedAfterDecember312021Member" xlink:to="ions_IssuedAfterDecember312021Member_lbl1" xlink:title="label: IssuedAfterDecember312021Member to ions_IssuedAfterDecember312021Member_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_IssuedAfterDecember312021Member_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_IssuedAfterDecember312021Member_lbl2" xml:lang="en-US" id="ions_IssuedAfterDecember312021Member_lbl2">Issued after December 31, 2021 [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="IssuedAfterDecember312021Member" xlink:to="ions_IssuedAfterDecember312021Member_lbl2" xlink:title="label: IssuedAfterDecember312021Member to ions_IssuedAfterDecember312021Member_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_NumberOfExecutiveOfficersTerminatedBeforeChangeInControlWhenVestingWillAccelerateForExecutiveOfficers" xlink:label="NumberOfExecutiveOfficersTerminatedBeforeChangeInControlWhenVestingWillAccelerateForExecutiveOfficers" xlink:title="NumberOfExecutiveOfficersTerminatedBeforeChangeInControlWhenVestingWillAccelerateForExecutiveOfficers" />
    <link:label xlink:type="resource" xlink:label="ions_NumberOfExecutiveOfficersTerminatedBeforeChangeInControlWhenVestingWillAccelerateForExecutiveOfficers_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_NumberOfExecutiveOfficersTerminatedBeforeChangeInControlWhenVestingWillAccelerateForExecutiveOfficers_lbl" xml:lang="en-US" id="ions_NumberOfExecutiveOfficersTerminatedBeforeChangeInControlWhenVestingWillAccelerateForExecutiveOfficers_lbl">The number of executive officers terminated by the Company during the period that begins three months before and ends twelve months following a change in control of the Company when vesting will accelerate for options and RSUs outstanding as of the termination date for executive officers</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="NumberOfExecutiveOfficersTerminatedBeforeChangeInControlWhenVestingWillAccelerateForExecutiveOfficers" xlink:to="ions_NumberOfExecutiveOfficersTerminatedBeforeChangeInControlWhenVestingWillAccelerateForExecutiveOfficers_lbl" xlink:title="label: NumberOfExecutiveOfficersTerminatedBeforeChangeInControlWhenVestingWillAccelerateForExecutiveOfficers to ions_NumberOfExecutiveOfficersTerminatedBeforeChangeInControlWhenVestingWillAccelerateForExecutiveOfficers_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_NumberOfExecutiveOfficersTerminatedBeforeChangeInControlWhenVestingWillAccelerateForExecutiveOfficers_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_NumberOfExecutiveOfficersTerminatedBeforeChangeInControlWhenVestingWillAccelerateForExecutiveOfficers_lbl1" xml:lang="en-US" id="ions_NumberOfExecutiveOfficersTerminatedBeforeChangeInControlWhenVestingWillAccelerateForExecutiveOfficers_lbl1">Number of executive officers terminated before change in control when vesting will accelerate for executive officers</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="NumberOfExecutiveOfficersTerminatedBeforeChangeInControlWhenVestingWillAccelerateForExecutiveOfficers" xlink:to="ions_NumberOfExecutiveOfficersTerminatedBeforeChangeInControlWhenVestingWillAccelerateForExecutiveOfficers_lbl1" xlink:title="label: NumberOfExecutiveOfficersTerminatedBeforeChangeInControlWhenVestingWillAccelerateForExecutiveOfficers to ions_NumberOfExecutiveOfficersTerminatedBeforeChangeInControlWhenVestingWillAccelerateForExecutiveOfficers_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_NumberOfExecutiveOfficersTerminatedBeforeChangeInControlWhenVestingWillAccelerateForExecutiveOfficers_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_NumberOfExecutiveOfficersTerminatedBeforeChangeInControlWhenVestingWillAccelerateForExecutiveOfficers_lbl2" xml:lang="en-US" id="ions_NumberOfExecutiveOfficersTerminatedBeforeChangeInControlWhenVestingWillAccelerateForExecutiveOfficers_lbl2">Number of executive officers terminated before change in control when vesting will accelerate for executive officers</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="NumberOfExecutiveOfficersTerminatedBeforeChangeInControlWhenVestingWillAccelerateForExecutiveOfficers" xlink:to="ions_NumberOfExecutiveOfficersTerminatedBeforeChangeInControlWhenVestingWillAccelerateForExecutiveOfficers_lbl2" xlink:title="label: NumberOfExecutiveOfficersTerminatedBeforeChangeInControlWhenVestingWillAccelerateForExecutiveOfficers to ions_NumberOfExecutiveOfficersTerminatedBeforeChangeInControlWhenVestingWillAccelerateForExecutiveOfficers_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_PeriodBeforeChangeInControlWhenVestingWillAccelerateForExecutiveOfficers" xlink:label="PeriodBeforeChangeInControlWhenVestingWillAccelerateForExecutiveOfficers" xlink:title="PeriodBeforeChangeInControlWhenVestingWillAccelerateForExecutiveOfficers" />
    <link:label xlink:type="resource" xlink:label="ions_PeriodBeforeChangeInControlWhenVestingWillAccelerateForExecutiveOfficers_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_PeriodBeforeChangeInControlWhenVestingWillAccelerateForExecutiveOfficers_lbl" xml:lang="en-US" id="ions_PeriodBeforeChangeInControlWhenVestingWillAccelerateForExecutiveOfficers_lbl">Period of time before a change in control of the Company when vesting will accelerate for options and RSUs outstanding as of the termination date for executive officers, in 'PnYnMnDTnHnMnS' format, for example, 'P1Y5M13D' represents the reported fact of one year, five months, and thirteen days.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="PeriodBeforeChangeInControlWhenVestingWillAccelerateForExecutiveOfficers" xlink:to="ions_PeriodBeforeChangeInControlWhenVestingWillAccelerateForExecutiveOfficers_lbl" xlink:title="label: PeriodBeforeChangeInControlWhenVestingWillAccelerateForExecutiveOfficers to ions_PeriodBeforeChangeInControlWhenVestingWillAccelerateForExecutiveOfficers_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_PeriodBeforeChangeInControlWhenVestingWillAccelerateForExecutiveOfficers_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_PeriodBeforeChangeInControlWhenVestingWillAccelerateForExecutiveOfficers_lbl1" xml:lang="en-US" id="ions_PeriodBeforeChangeInControlWhenVestingWillAccelerateForExecutiveOfficers_lbl1">Period before change in control when vesting will accelerate for executive officers</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="PeriodBeforeChangeInControlWhenVestingWillAccelerateForExecutiveOfficers" xlink:to="ions_PeriodBeforeChangeInControlWhenVestingWillAccelerateForExecutiveOfficers_lbl1" xlink:title="label: PeriodBeforeChangeInControlWhenVestingWillAccelerateForExecutiveOfficers to ions_PeriodBeforeChangeInControlWhenVestingWillAccelerateForExecutiveOfficers_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_PeriodBeforeChangeInControlWhenVestingWillAccelerateForExecutiveOfficers_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_PeriodBeforeChangeInControlWhenVestingWillAccelerateForExecutiveOfficers_lbl2" xml:lang="en-US" id="ions_PeriodBeforeChangeInControlWhenVestingWillAccelerateForExecutiveOfficers_lbl2">Period before change in control when vesting will accelerate for executive officers</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="PeriodBeforeChangeInControlWhenVestingWillAccelerateForExecutiveOfficers" xlink:to="ions_PeriodBeforeChangeInControlWhenVestingWillAccelerateForExecutiveOfficers_lbl2" xlink:title="label: PeriodBeforeChangeInControlWhenVestingWillAccelerateForExecutiveOfficers to ions_PeriodBeforeChangeInControlWhenVestingWillAccelerateForExecutiveOfficers_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_PeriodAfterChangeInControlWhenVestingWillAccelerateForExecutiveOfficers" xlink:label="PeriodAfterChangeInControlWhenVestingWillAccelerateForExecutiveOfficers" xlink:title="PeriodAfterChangeInControlWhenVestingWillAccelerateForExecutiveOfficers" />
    <link:label xlink:type="resource" xlink:label="ions_PeriodAfterChangeInControlWhenVestingWillAccelerateForExecutiveOfficers_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_PeriodAfterChangeInControlWhenVestingWillAccelerateForExecutiveOfficers_lbl" xml:lang="en-US" id="ions_PeriodAfterChangeInControlWhenVestingWillAccelerateForExecutiveOfficers_lbl">Period of time after a change in control of the Company when vesting will accelerate for options and RSUs outstanding as of the termination date for executive officers, in 'PnYnMnDTnHnMnS' format, for example, 'P1Y5M13D' represents the reported fact of one year, five months, and thirteen days.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="PeriodAfterChangeInControlWhenVestingWillAccelerateForExecutiveOfficers" xlink:to="ions_PeriodAfterChangeInControlWhenVestingWillAccelerateForExecutiveOfficers_lbl" xlink:title="label: PeriodAfterChangeInControlWhenVestingWillAccelerateForExecutiveOfficers to ions_PeriodAfterChangeInControlWhenVestingWillAccelerateForExecutiveOfficers_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_PeriodAfterChangeInControlWhenVestingWillAccelerateForExecutiveOfficers_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_PeriodAfterChangeInControlWhenVestingWillAccelerateForExecutiveOfficers_lbl1" xml:lang="en-US" id="ions_PeriodAfterChangeInControlWhenVestingWillAccelerateForExecutiveOfficers_lbl1">Period after change in control when vesting will accelerate for executive officers</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="PeriodAfterChangeInControlWhenVestingWillAccelerateForExecutiveOfficers" xlink:to="ions_PeriodAfterChangeInControlWhenVestingWillAccelerateForExecutiveOfficers_lbl1" xlink:title="label: PeriodAfterChangeInControlWhenVestingWillAccelerateForExecutiveOfficers to ions_PeriodAfterChangeInControlWhenVestingWillAccelerateForExecutiveOfficers_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_PeriodAfterChangeInControlWhenVestingWillAccelerateForExecutiveOfficers_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_PeriodAfterChangeInControlWhenVestingWillAccelerateForExecutiveOfficers_lbl2" xml:lang="en-US" id="ions_PeriodAfterChangeInControlWhenVestingWillAccelerateForExecutiveOfficers_lbl2">Period after change in control when vesting will accelerate for executive officers</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="PeriodAfterChangeInControlWhenVestingWillAccelerateForExecutiveOfficers" xlink:to="ions_PeriodAfterChangeInControlWhenVestingWillAccelerateForExecutiveOfficers_lbl2" xlink:title="label: PeriodAfterChangeInControlWhenVestingWillAccelerateForExecutiveOfficers to ions_PeriodAfterChangeInControlWhenVestingWillAccelerateForExecutiveOfficers_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_EquityIncentivePlan2020Member" xlink:label="EquityIncentivePlan2020Member" xlink:title="EquityIncentivePlan2020Member" />
    <link:label xlink:type="resource" xlink:label="ions_EquityIncentivePlan2020Member_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_EquityIncentivePlan2020Member_lbl" xml:lang="en-US" id="ions_EquityIncentivePlan2020Member_lbl">In December 2020, the Company amended and restated the Akcea 2015 Equity Incentive Plan, including renaming the plan as the Ionis Pharmaceuticals, Inc. 2020 Equity Incentive Plan, or 2020 Plan. The 2020 Plan provided for the issuance of up to 2.6 million shares of Common Stock to employees, directors and consultants who were employees of Akcea prior to the Akcea Acquisition.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="EquityIncentivePlan2020Member" xlink:to="ions_EquityIncentivePlan2020Member_lbl" xlink:title="label: EquityIncentivePlan2020Member to ions_EquityIncentivePlan2020Member_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_EquityIncentivePlan2020Member_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_EquityIncentivePlan2020Member_lbl1" xml:lang="en-US" id="ions_EquityIncentivePlan2020Member_lbl1">Equity Incentive Plan 2020 [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="EquityIncentivePlan2020Member" xlink:to="ions_EquityIncentivePlan2020Member_lbl1" xlink:title="label: EquityIncentivePlan2020Member to ions_EquityIncentivePlan2020Member_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_EquityIncentivePlan2020Member_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_EquityIncentivePlan2020Member_lbl2" xml:lang="en-US" id="ions_EquityIncentivePlan2020Member_lbl2">2020 Equity Incentive Plan [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="EquityIncentivePlan2020Member" xlink:to="ions_EquityIncentivePlan2020Member_lbl2" xlink:title="label: EquityIncentivePlan2020Member to ions_EquityIncentivePlan2020Member_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_ShareBasedCompensationArrangementByShareBasedPaymentAwardHoldingPeriod" xlink:label="ShareBasedCompensationArrangementByShareBasedPaymentAwardHoldingPeriod" xlink:title="ShareBasedCompensationArrangementByShareBasedPaymentAwardHoldingPeriod" />
    <link:label xlink:type="resource" xlink:label="ions_ShareBasedCompensationArrangementByShareBasedPaymentAwardHoldingPeriod_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_ShareBasedCompensationArrangementByShareBasedPaymentAwardHoldingPeriod_lbl" xml:lang="en-US" id="ions_ShareBasedCompensationArrangementByShareBasedPaymentAwardHoldingPeriod_lbl">Represents the holding period from the date of purchase for stock purchased under the plan.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="ShareBasedCompensationArrangementByShareBasedPaymentAwardHoldingPeriod" xlink:to="ions_ShareBasedCompensationArrangementByShareBasedPaymentAwardHoldingPeriod_lbl" xlink:title="label: ShareBasedCompensationArrangementByShareBasedPaymentAwardHoldingPeriod to ions_ShareBasedCompensationArrangementByShareBasedPaymentAwardHoldingPeriod_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_ShareBasedCompensationArrangementByShareBasedPaymentAwardHoldingPeriod_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_ShareBasedCompensationArrangementByShareBasedPaymentAwardHoldingPeriod_lbl1" xml:lang="en-US" id="ions_ShareBasedCompensationArrangementByShareBasedPaymentAwardHoldingPeriod_lbl1">Share-based Compensation Arrangement by Share-based Payment Award, Holding Period</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="ShareBasedCompensationArrangementByShareBasedPaymentAwardHoldingPeriod" xlink:to="ions_ShareBasedCompensationArrangementByShareBasedPaymentAwardHoldingPeriod_lbl1" xlink:title="label: ShareBasedCompensationArrangementByShareBasedPaymentAwardHoldingPeriod to ions_ShareBasedCompensationArrangementByShareBasedPaymentAwardHoldingPeriod_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_ShareBasedCompensationArrangementByShareBasedPaymentAwardHoldingPeriod_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_ShareBasedCompensationArrangementByShareBasedPaymentAwardHoldingPeriod_lbl2" xml:lang="en-US" id="ions_ShareBasedCompensationArrangementByShareBasedPaymentAwardHoldingPeriod_lbl2">Holding period for purchased stock</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="ShareBasedCompensationArrangementByShareBasedPaymentAwardHoldingPeriod" xlink:to="ions_ShareBasedCompensationArrangementByShareBasedPaymentAwardHoldingPeriod_lbl2" xlink:title="label: ShareBasedCompensationArrangementByShareBasedPaymentAwardHoldingPeriod to ions_ShareBasedCompensationArrangementByShareBasedPaymentAwardHoldingPeriod_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_EmployeeStockPurchasePlanWeightedAverageSalesPriceOfSharesPurchased" xlink:label="EmployeeStockPurchasePlanWeightedAverageSalesPriceOfSharesPurchased" xlink:title="EmployeeStockPurchasePlanWeightedAverageSalesPriceOfSharesPurchased" />
    <link:label xlink:type="resource" xlink:label="ions_EmployeeStockPurchasePlanWeightedAverageSalesPriceOfSharesPurchased_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_EmployeeStockPurchasePlanWeightedAverageSalesPriceOfSharesPurchased_lbl" xml:lang="en-US" id="ions_EmployeeStockPurchasePlanWeightedAverageSalesPriceOfSharesPurchased_lbl">Weighted average sales price of shares purchased through an employee stock purchase plan.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="EmployeeStockPurchasePlanWeightedAverageSalesPriceOfSharesPurchased" xlink:to="ions_EmployeeStockPurchasePlanWeightedAverageSalesPriceOfSharesPurchased_lbl" xlink:title="label: EmployeeStockPurchasePlanWeightedAverageSalesPriceOfSharesPurchased to ions_EmployeeStockPurchasePlanWeightedAverageSalesPriceOfSharesPurchased_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_EmployeeStockPurchasePlanWeightedAverageSalesPriceOfSharesPurchased_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_EmployeeStockPurchasePlanWeightedAverageSalesPriceOfSharesPurchased_lbl1" xml:lang="en-US" id="ions_EmployeeStockPurchasePlanWeightedAverageSalesPriceOfSharesPurchased_lbl1">Employee Stock Purchase Plan, Weighted Average Sales Price of Shares Purchased</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="EmployeeStockPurchasePlanWeightedAverageSalesPriceOfSharesPurchased" xlink:to="ions_EmployeeStockPurchasePlanWeightedAverageSalesPriceOfSharesPurchased_lbl1" xlink:title="label: EmployeeStockPurchasePlanWeightedAverageSalesPriceOfSharesPurchased to ions_EmployeeStockPurchasePlanWeightedAverageSalesPriceOfSharesPurchased_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_EmployeeStockPurchasePlanWeightedAverageSalesPriceOfSharesPurchased_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_EmployeeStockPurchasePlanWeightedAverageSalesPriceOfSharesPurchased_lbl2" xml:lang="en-US" id="ions_EmployeeStockPurchasePlanWeightedAverageSalesPriceOfSharesPurchased_lbl2">Weighted average purchase price (in dollars per share)</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="EmployeeStockPurchasePlanWeightedAverageSalesPriceOfSharesPurchased" xlink:to="ions_EmployeeStockPurchasePlanWeightedAverageSalesPriceOfSharesPurchased_lbl2" xlink:title="label: EmployeeStockPurchasePlanWeightedAverageSalesPriceOfSharesPurchased to ions_EmployeeStockPurchasePlanWeightedAverageSalesPriceOfSharesPurchased_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_EmployeeStockPurchasePlanSharesAvailableForPurchase" xlink:label="EmployeeStockPurchasePlanSharesAvailableForPurchase" xlink:title="EmployeeStockPurchasePlanSharesAvailableForPurchase" />
    <link:label xlink:type="resource" xlink:label="ions_EmployeeStockPurchasePlanSharesAvailableForPurchase_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_EmployeeStockPurchasePlanSharesAvailableForPurchase_lbl" xml:lang="en-US" id="ions_EmployeeStockPurchasePlanSharesAvailableForPurchase_lbl">The number of shares available for purchase under an employee stock purchase plan.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="EmployeeStockPurchasePlanSharesAvailableForPurchase" xlink:to="ions_EmployeeStockPurchasePlanSharesAvailableForPurchase_lbl" xlink:title="label: EmployeeStockPurchasePlanSharesAvailableForPurchase to ions_EmployeeStockPurchasePlanSharesAvailableForPurchase_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_EmployeeStockPurchasePlanSharesAvailableForPurchase_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_EmployeeStockPurchasePlanSharesAvailableForPurchase_lbl1" xml:lang="en-US" id="ions_EmployeeStockPurchasePlanSharesAvailableForPurchase_lbl1">Employee Stock Purchase Plan, Shares Available for Purchase</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="EmployeeStockPurchasePlanSharesAvailableForPurchase" xlink:to="ions_EmployeeStockPurchasePlanSharesAvailableForPurchase_lbl1" xlink:title="label: EmployeeStockPurchasePlanSharesAvailableForPurchase to ions_EmployeeStockPurchasePlanSharesAvailableForPurchase_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_EmployeeStockPurchasePlanSharesAvailableForPurchase_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_EmployeeStockPurchasePlanSharesAvailableForPurchase_lbl2" xml:lang="en-US" id="ions_EmployeeStockPurchasePlanSharesAvailableForPurchase_lbl2">Shares available for purchase under ESPP (in shares)</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="EmployeeStockPurchasePlanSharesAvailableForPurchase" xlink:to="ions_EmployeeStockPurchasePlanSharesAvailableForPurchase_lbl2" xlink:title="label: EmployeeStockPurchasePlanSharesAvailableForPurchase to ions_EmployeeStockPurchasePlanSharesAvailableForPurchase_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_NonemployeeDirectorsStockOptionPlan2002Member" xlink:label="NonemployeeDirectorsStockOptionPlan2002Member" xlink:title="NonemployeeDirectorsStockOptionPlan2002Member" />
    <link:label xlink:type="resource" xlink:label="ions_NonemployeeDirectorsStockOptionPlan2002Member_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_NonemployeeDirectorsStockOptionPlan2002Member_lbl" xml:lang="en-US" id="ions_NonemployeeDirectorsStockOptionPlan2002Member_lbl">Represents the 2002 Non-Employee Directors Stock Option Plan, which provided for the issuance of stock options to the entity's non-employee directors for the purchase of common stock.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="NonemployeeDirectorsStockOptionPlan2002Member" xlink:to="ions_NonemployeeDirectorsStockOptionPlan2002Member_lbl" xlink:title="label: NonemployeeDirectorsStockOptionPlan2002Member to ions_NonemployeeDirectorsStockOptionPlan2002Member_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_NonemployeeDirectorsStockOptionPlan2002Member_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_NonemployeeDirectorsStockOptionPlan2002Member_lbl1" xml:lang="en-US" id="ions_NonemployeeDirectorsStockOptionPlan2002Member_lbl1">Nonemployee Directors' Stock Option Plan 2002 [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="NonemployeeDirectorsStockOptionPlan2002Member" xlink:to="ions_NonemployeeDirectorsStockOptionPlan2002Member_lbl1" xlink:title="label: NonemployeeDirectorsStockOptionPlan2002Member to ions_NonemployeeDirectorsStockOptionPlan2002Member_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_NonemployeeDirectorsStockOptionPlan2002Member_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_NonemployeeDirectorsStockOptionPlan2002Member_lbl2" xml:lang="en-US" id="ions_NonemployeeDirectorsStockOptionPlan2002Member_lbl2">2002 Non-Employee Directors' Stock Option Plan [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="NonemployeeDirectorsStockOptionPlan2002Member" xlink:to="ions_NonemployeeDirectorsStockOptionPlan2002Member_lbl2" xlink:title="label: NonemployeeDirectorsStockOptionPlan2002Member to ions_NonemployeeDirectorsStockOptionPlan2002Member_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_EquityIncentivePlan2011Member" xlink:label="EquityIncentivePlan2011Member" xlink:title="EquityIncentivePlan2011Member" />
    <link:label xlink:type="resource" xlink:label="ions_EquityIncentivePlan2011Member_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_EquityIncentivePlan2011Member_lbl" xml:lang="en-US" id="ions_EquityIncentivePlan2011Member_lbl">Represents the stock option plan that provides for the issuance of stock options, stock appreciation rights, restricted stock awards, restricted stock unit awards, and performance cash awards to employees, directors, and consultants.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="EquityIncentivePlan2011Member" xlink:to="ions_EquityIncentivePlan2011Member_lbl" xlink:title="label: EquityIncentivePlan2011Member to ions_EquityIncentivePlan2011Member_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_EquityIncentivePlan2011Member_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_EquityIncentivePlan2011Member_lbl1" xml:lang="en-US" id="ions_EquityIncentivePlan2011Member_lbl1">Equity Incentive Plan 2011 [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="EquityIncentivePlan2011Member" xlink:to="ions_EquityIncentivePlan2011Member_lbl1" xlink:title="label: EquityIncentivePlan2011Member to ions_EquityIncentivePlan2011Member_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_EquityIncentivePlan2011Member_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_EquityIncentivePlan2011Member_lbl2" xml:lang="en-US" id="ions_EquityIncentivePlan2011Member_lbl2">2011 Equity Incentive Plan [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="EquityIncentivePlan2011Member" xlink:to="ions_EquityIncentivePlan2011Member_lbl2" xlink:title="label: EquityIncentivePlan2011Member to ions_EquityIncentivePlan2011Member_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_StockOptionPlan1989Member" xlink:label="StockOptionPlan1989Member" xlink:title="StockOptionPlan1989Member" />
    <link:label xlink:type="resource" xlink:label="ions_StockOptionPlan1989Member_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_StockOptionPlan1989Member_lbl" xml:lang="en-US" id="ions_StockOptionPlan1989Member_lbl">Represents the 1989 Stock Option Plan, which provides the issuance of non-qualified and incentive stock options for the purchase of common stock to the entity's employees, directors and consultants.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="StockOptionPlan1989Member" xlink:to="ions_StockOptionPlan1989Member_lbl" xlink:title="label: StockOptionPlan1989Member to ions_StockOptionPlan1989Member_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_StockOptionPlan1989Member_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_StockOptionPlan1989Member_lbl1" xml:lang="en-US" id="ions_StockOptionPlan1989Member_lbl1">Stock Option Plan 1989 [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="StockOptionPlan1989Member" xlink:to="ions_StockOptionPlan1989Member_lbl1" xlink:title="label: StockOptionPlan1989Member to ions_StockOptionPlan1989Member_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_StockOptionPlan1989Member_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_StockOptionPlan1989Member_lbl2" xml:lang="en-US" id="ions_StockOptionPlan1989Member_lbl2">1989 Stock Option Plan [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="StockOptionPlan1989Member" xlink:to="ions_StockOptionPlan1989Member_lbl2" xlink:title="label: StockOptionPlan1989Member to ions_StockOptionPlan1989Member_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_EmployeeStockPurchasePlanMember" xlink:label="EmployeeStockPurchasePlanMember" xlink:title="EmployeeStockPurchasePlanMember" />
    <link:label xlink:type="resource" xlink:label="ions_EmployeeStockPurchasePlanMember_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_EmployeeStockPurchasePlanMember_lbl" xml:lang="en-US" id="ions_EmployeeStockPurchasePlanMember_lbl">Represents the 2009 Employee Stock Purchase Plan, as amended and restated, which permits full-time employees to purchase common stock through payroll deductions at a percentage of the fair market value.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="EmployeeStockPurchasePlanMember" xlink:to="ions_EmployeeStockPurchasePlanMember_lbl" xlink:title="label: EmployeeStockPurchasePlanMember to ions_EmployeeStockPurchasePlanMember_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_EmployeeStockPurchasePlanMember_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_EmployeeStockPurchasePlanMember_lbl1" xml:lang="en-US" id="ions_EmployeeStockPurchasePlanMember_lbl1">Employee Stock Purchase Plan [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="EmployeeStockPurchasePlanMember" xlink:to="ions_EmployeeStockPurchasePlanMember_lbl1" xlink:title="label: EmployeeStockPurchasePlanMember to ions_EmployeeStockPurchasePlanMember_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_EmployeeStockPurchasePlanMember_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_EmployeeStockPurchasePlanMember_lbl2" xml:lang="en-US" id="ions_EmployeeStockPurchasePlanMember_lbl2">Employee Stock Purchase Plan [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="EmployeeStockPurchasePlanMember" xlink:to="ions_EmployeeStockPurchasePlanMember_lbl2" xlink:title="label: EmployeeStockPurchasePlanMember to ions_EmployeeStockPurchasePlanMember_lbl2" />
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    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_IncreaseDecreaseInFungibleShareReserveForEachShareReturningFromFullValueAward" xlink:label="IncreaseDecreaseInFungibleShareReserveForEachShareReturningFromFullValueAward" xlink:title="IncreaseDecreaseInFungibleShareReserveForEachShareReturningFromFullValueAward" />
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    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_LesseeOperatingLeaseInformationTableTextBlock" xlink:label="LesseeOperatingLeaseInformationTableTextBlock" xlink:title="LesseeOperatingLeaseInformationTableTextBlock" />
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    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="LesseeOperatingLeaseInformationTableTextBlock" xlink:to="ions_LesseeOperatingLeaseInformationTableTextBlock_lbl" xlink:title="label: LesseeOperatingLeaseInformationTableTextBlock to ions_LesseeOperatingLeaseInformationTableTextBlock_lbl" />
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    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_ConvertibleNotesDisclosureTable" xlink:label="ConvertibleNotesDisclosureTable" xlink:title="ConvertibleNotesDisclosureTable" />
    <link:label xlink:type="resource" xlink:label="ions_ConvertibleNotesDisclosureTable_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_ConvertibleNotesDisclosureTable_lbl" xml:lang="en-US" id="ions_ConvertibleNotesDisclosureTable_lbl">Disclosure of information about income taxes.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="ConvertibleNotesDisclosureTable" xlink:to="ions_ConvertibleNotesDisclosureTable_lbl" xlink:title="label: ConvertibleNotesDisclosureTable to ions_ConvertibleNotesDisclosureTable_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_ConvertibleNotesDisclosureTable_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_ConvertibleNotesDisclosureTable_lbl1" xml:lang="en-US" id="ions_ConvertibleNotesDisclosureTable_lbl1">Convertible Notes Disclosure [Table]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="ConvertibleNotesDisclosureTable" xlink:to="ions_ConvertibleNotesDisclosureTable_lbl1" xlink:title="label: ConvertibleNotesDisclosureTable to ions_ConvertibleNotesDisclosureTable_lbl1" />
    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_ConvertibleNotesDisclosureLineItems" xlink:label="ConvertibleNotesDisclosureLineItems" xlink:title="ConvertibleNotesDisclosureLineItems" />
    <link:label xlink:type="resource" xlink:label="ions_ConvertibleNotesDisclosureLineItems_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_ConvertibleNotesDisclosureLineItems_lbl" xml:lang="en-US" id="ions_ConvertibleNotesDisclosureLineItems_lbl">Line items represent financial concepts included in a table. These concepts are used to disclose reportable information associated with domain members defined in one or many axes to the table.</link:label>
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    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="ConvertibleNotesDisclosureLineItems" xlink:to="ions_ConvertibleNotesDisclosureLineItems_lbl2" xlink:title="label: ConvertibleNotesDisclosureLineItems to ions_ConvertibleNotesDisclosureLineItems_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_AdjustmentsToAdditionalPaidInCapitalDeferredTaxLiabilityAdjustment" xlink:label="AdjustmentsToAdditionalPaidInCapitalDeferredTaxLiabilityAdjustment" xlink:title="AdjustmentsToAdditionalPaidInCapitalDeferredTaxLiabilityAdjustment" />
    <link:label xlink:type="resource" xlink:label="ions_AdjustmentsToAdditionalPaidInCapitalDeferredTaxLiabilityAdjustment_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_AdjustmentsToAdditionalPaidInCapitalDeferredTaxLiabilityAdjustment_lbl" xml:lang="en-US" id="ions_AdjustmentsToAdditionalPaidInCapitalDeferredTaxLiabilityAdjustment_lbl">Amount of increase (decrease) in additional paid in capital (APIC) due to deferred tax liability adjustment associated with the purchase of noncontrolling interest of Akcea Therapeutics, Inc.</link:label>
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    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_SecuritiesWithMaturityOfOneYearOrLessMember" xlink:label="SecuritiesWithMaturityOfOneYearOrLessMember" xlink:title="SecuritiesWithMaturityOfOneYearOrLessMember" />
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    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_SecuritiesWithMaturityOfMoreThanOneYearMember" xlink:label="SecuritiesWithMaturityOfMoreThanOneYearMember" xlink:title="SecuritiesWithMaturityOfMoreThanOneYearMember" />
    <link:label xlink:type="resource" xlink:label="ions_SecuritiesWithMaturityOfMoreThanOneYearMember_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_SecuritiesWithMaturityOfMoreThanOneYearMember_lbl" xml:lang="en-US" id="ions_SecuritiesWithMaturityOfMoreThanOneYearMember_lbl">Represents investment securities with an expected maturity of more than one year.</link:label>
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    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_DebtSecuritiesAvailableForSaleAndEquitySecuritiesFvNiGrossUnrealizedGain" xlink:label="DebtSecuritiesAvailableForSaleAndEquitySecuritiesFvNiGrossUnrealizedGain" xlink:title="DebtSecuritiesAvailableForSaleAndEquitySecuritiesFvNiGrossUnrealizedGain" />
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    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_DebtSecuritiesAvailableForSaleAndEquitySecuritiesFvNiCost" xlink:label="DebtSecuritiesAvailableForSaleAndEquitySecuritiesFvNiCost" xlink:title="DebtSecuritiesAvailableForSaleAndEquitySecuritiesFvNiCost" />
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    <link:label xlink:type="resource" xlink:label="ions_DebtSecuritiesAvailableForSaleAndEquitySecuritiesFvNiCost_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_DebtSecuritiesAvailableForSaleAndEquitySecuritiesFvNiCost_lbl1" xml:lang="en-US" id="ions_DebtSecuritiesAvailableForSaleAndEquitySecuritiesFvNiCost_lbl1">Debt Securities, Available-for-sale and Equity Securities, FV-NI, Cost</link:label>
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    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_DebtSecuritiesAvailableForSaleAndEquitySecuritiesFvNiGrossUnrealizedLoss" xlink:label="DebtSecuritiesAvailableForSaleAndEquitySecuritiesFvNiGrossUnrealizedLoss" xlink:title="DebtSecuritiesAvailableForSaleAndEquitySecuritiesFvNiGrossUnrealizedLoss" />
    <link:label xlink:type="resource" xlink:label="ions_DebtSecuritiesAvailableForSaleAndEquitySecuritiesFvNiGrossUnrealizedLoss_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_DebtSecuritiesAvailableForSaleAndEquitySecuritiesFvNiGrossUnrealizedLoss_lbl" xml:lang="en-US" id="ions_DebtSecuritiesAvailableForSaleAndEquitySecuritiesFvNiGrossUnrealizedLoss_lbl">Total of (1) unrealized loss in accumulated other comprehensive income (AOCI) on investment in debt security measured at fair value with change in fair value recognized in other comprehensive income (available-for-sale) and (2) unrealized loss on investment in equity security measured at fair value with change in fair value recognized in net income (FV-NI).</link:label>
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    <link:label xlink:type="resource" xlink:label="ions_DebtSecuritiesAvailableForSaleAndEquitySecuritiesFvNiGrossUnrealizedLoss_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_DebtSecuritiesAvailableForSaleAndEquitySecuritiesFvNiGrossUnrealizedLoss_lbl1" xml:lang="en-US" id="ions_DebtSecuritiesAvailableForSaleAndEquitySecuritiesFvNiGrossUnrealizedLoss_lbl1">Debt Securities, Available-for-sale and Equity Securities, FV-NI, Gross Unrealized Loss</link:label>
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    <link:label xlink:type="resource" xlink:label="ions_DebtSecuritiesAvailableForSaleAndEquitySecuritiesFvNiGrossUnrealizedLoss_lbl2" xlink:role="http://www.xbrl.org/2009/role/negatedLabel" xlink:title="ions_DebtSecuritiesAvailableForSaleAndEquitySecuritiesFvNiGrossUnrealizedLoss_lbl2" xml:lang="en-US" id="ions_DebtSecuritiesAvailableForSaleAndEquitySecuritiesFvNiGrossUnrealizedLoss_lbl2">Gross unrealized losses</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="DebtSecuritiesAvailableForSaleAndEquitySecuritiesFvNiGrossUnrealizedLoss" xlink:to="ions_DebtSecuritiesAvailableForSaleAndEquitySecuritiesFvNiGrossUnrealizedLoss_lbl2" xlink:title="label: DebtSecuritiesAvailableForSaleAndEquitySecuritiesFvNiGrossUnrealizedLoss to ions_DebtSecuritiesAvailableForSaleAndEquitySecuritiesFvNiGrossUnrealizedLoss_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_DebtSecuritiesAvailableForSaleAndEquitySecuritiesFvNi" xlink:label="DebtSecuritiesAvailableForSaleAndEquitySecuritiesFvNi" xlink:title="DebtSecuritiesAvailableForSaleAndEquitySecuritiesFvNi" />
    <link:label xlink:type="resource" xlink:label="ions_DebtSecuritiesAvailableForSaleAndEquitySecuritiesFvNi_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_DebtSecuritiesAvailableForSaleAndEquitySecuritiesFvNi_lbl" xml:lang="en-US" id="ions_DebtSecuritiesAvailableForSaleAndEquitySecuritiesFvNi_lbl">Total of (1) investment in debt security measured at fair value with change in fair value recognized in other comprehensive income (available-for-sale) and (2) amount of investment in equity security measured at fair value with change in fair value recognized in net income (FV-NI).</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="DebtSecuritiesAvailableForSaleAndEquitySecuritiesFvNi" xlink:to="ions_DebtSecuritiesAvailableForSaleAndEquitySecuritiesFvNi_lbl" xlink:title="label: DebtSecuritiesAvailableForSaleAndEquitySecuritiesFvNi to ions_DebtSecuritiesAvailableForSaleAndEquitySecuritiesFvNi_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_DebtSecuritiesAvailableForSaleAndEquitySecuritiesFvNi_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_DebtSecuritiesAvailableForSaleAndEquitySecuritiesFvNi_lbl1" xml:lang="en-US" id="ions_DebtSecuritiesAvailableForSaleAndEquitySecuritiesFvNi_lbl1">Debt Securities, Available-for-sale and Equity Securities, FV-NI</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="DebtSecuritiesAvailableForSaleAndEquitySecuritiesFvNi" xlink:to="ions_DebtSecuritiesAvailableForSaleAndEquitySecuritiesFvNi_lbl1" xlink:title="label: DebtSecuritiesAvailableForSaleAndEquitySecuritiesFvNi to ions_DebtSecuritiesAvailableForSaleAndEquitySecuritiesFvNi_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_DebtSecuritiesAvailableForSaleAndEquitySecuritiesFvNi_lbl2" xlink:role="http://www.xbrl.org/2003/role/totalLabel" xlink:title="ions_DebtSecuritiesAvailableForSaleAndEquitySecuritiesFvNi_lbl2" xml:lang="en-US" id="ions_DebtSecuritiesAvailableForSaleAndEquitySecuritiesFvNi_lbl2">Estimated fair value</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="DebtSecuritiesAvailableForSaleAndEquitySecuritiesFvNi" xlink:to="ions_DebtSecuritiesAvailableForSaleAndEquitySecuritiesFvNi_lbl2" xlink:title="label: DebtSecuritiesAvailableForSaleAndEquitySecuritiesFvNi to ions_DebtSecuritiesAvailableForSaleAndEquitySecuritiesFvNi_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_EquitySecuritiesPubliclyTradedCompaniesMember" xlink:label="EquitySecuritiesPubliclyTradedCompaniesMember" xlink:title="EquitySecuritiesPubliclyTradedCompaniesMember" />
    <link:label xlink:type="resource" xlink:label="ions_EquitySecuritiesPubliclyTradedCompaniesMember_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_EquitySecuritiesPubliclyTradedCompaniesMember_lbl" xml:lang="en-US" id="ions_EquitySecuritiesPubliclyTradedCompaniesMember_lbl">Ownership interest or right to acquire or dispose of ownership interest in publicly traded corporations and other legal entities for which ownership interest is represented by shares of common or preferred stock, convertible securities, stock rights, or stock warrants.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="EquitySecuritiesPubliclyTradedCompaniesMember" xlink:to="ions_EquitySecuritiesPubliclyTradedCompaniesMember_lbl" xlink:title="label: EquitySecuritiesPubliclyTradedCompaniesMember to ions_EquitySecuritiesPubliclyTradedCompaniesMember_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_EquitySecuritiesPubliclyTradedCompaniesMember_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_EquitySecuritiesPubliclyTradedCompaniesMember_lbl1" xml:lang="en-US" id="ions_EquitySecuritiesPubliclyTradedCompaniesMember_lbl1">Equity Securities, Publicly Traded Companies [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="EquitySecuritiesPubliclyTradedCompaniesMember" xlink:to="ions_EquitySecuritiesPubliclyTradedCompaniesMember_lbl1" xlink:title="label: EquitySecuritiesPubliclyTradedCompaniesMember to ions_EquitySecuritiesPubliclyTradedCompaniesMember_lbl1" />
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    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_EquitySecuritiesPrivateCompaniesMember" xlink:label="EquitySecuritiesPrivateCompaniesMember" xlink:title="EquitySecuritiesPrivateCompaniesMember" />
    <link:label xlink:type="resource" xlink:label="ions_EquitySecuritiesPrivateCompaniesMember_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_EquitySecuritiesPrivateCompaniesMember_lbl" xml:lang="en-US" id="ions_EquitySecuritiesPrivateCompaniesMember_lbl">Ownership interest or right to acquire or dispose of ownership interest in private corporations and other legal entities for which ownership interest is represented by shares of common or preferred stock, convertible securities, stock rights, or stock warrants.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="EquitySecuritiesPrivateCompaniesMember" xlink:to="ions_EquitySecuritiesPrivateCompaniesMember_lbl" xlink:title="label: EquitySecuritiesPrivateCompaniesMember to ions_EquitySecuritiesPrivateCompaniesMember_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_EquitySecuritiesPrivateCompaniesMember_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_EquitySecuritiesPrivateCompaniesMember_lbl1" xml:lang="en-US" id="ions_EquitySecuritiesPrivateCompaniesMember_lbl1">Equity Securities, Private Companies [Member]</link:label>
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    <link:label xlink:type="resource" xlink:label="ions_EquitySecuritiesPrivateCompaniesMember_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_EquitySecuritiesPrivateCompaniesMember_lbl2" xml:lang="en-US" id="ions_EquitySecuritiesPrivateCompaniesMember_lbl2">Equity Securities in Private Companies [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="EquitySecuritiesPrivateCompaniesMember" xlink:to="ions_EquitySecuritiesPrivateCompaniesMember_lbl2" xlink:title="label: EquitySecuritiesPrivateCompaniesMember to ions_EquitySecuritiesPrivateCompaniesMember_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_MaximumContractMaturityPeriodRange2" xlink:label="MaximumContractMaturityPeriodRange2" xlink:title="MaximumContractMaturityPeriodRange2" />
    <link:label xlink:type="resource" xlink:label="ions_MaximumContractMaturityPeriodRange2_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_MaximumContractMaturityPeriodRange2_lbl" xml:lang="en-US" id="ions_MaximumContractMaturityPeriodRange2_lbl">The maximum contract maturity period for the second range of available-for-sale securities, in 'PnYnMnDTnHnMnS' format, for example, 'P1Y5M13D' represents the reported fact of one year, five months, and thirteen days.</link:label>
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    <link:label xlink:type="resource" xlink:label="ions_MaximumContractMaturityPeriodRange2_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_MaximumContractMaturityPeriodRange2_lbl1" xml:lang="en-US" id="ions_MaximumContractMaturityPeriodRange2_lbl1">Maximum contract maturity period, range 2</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="MaximumContractMaturityPeriodRange2" xlink:to="ions_MaximumContractMaturityPeriodRange2_lbl1" xlink:title="label: MaximumContractMaturityPeriodRange2 to ions_MaximumContractMaturityPeriodRange2_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_MaximumContractMaturityPeriodRange2_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_MaximumContractMaturityPeriodRange2_lbl2" xml:lang="en-US" id="ions_MaximumContractMaturityPeriodRange2_lbl2">Maximum contract maturity period, range 2</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="MaximumContractMaturityPeriodRange2" xlink:to="ions_MaximumContractMaturityPeriodRange2_lbl2" xlink:title="label: MaximumContractMaturityPeriodRange2 to ions_MaximumContractMaturityPeriodRange2_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_MaximumContractMaturityPeriodRange1" xlink:label="MaximumContractMaturityPeriodRange1" xlink:title="MaximumContractMaturityPeriodRange1" />
    <link:label xlink:type="resource" xlink:label="ions_MaximumContractMaturityPeriodRange1_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_MaximumContractMaturityPeriodRange1_lbl" xml:lang="en-US" id="ions_MaximumContractMaturityPeriodRange1_lbl">The maximum contract maturity period for the first range of available-for-sale securities, in 'PnYnMnDTnHnMnS' format, for example, 'P1Y5M13D' represents the reported fact of one year, five months, and thirteen days.</link:label>
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    <link:label xlink:type="resource" xlink:label="ions_MaximumContractMaturityPeriodRange1_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_MaximumContractMaturityPeriodRange1_lbl1" xml:lang="en-US" id="ions_MaximumContractMaturityPeriodRange1_lbl1">Maximum contract maturity period, range 1</link:label>
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    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_MaximumContractMaturityPeriodRange3" xlink:label="MaximumContractMaturityPeriodRange3" xlink:title="MaximumContractMaturityPeriodRange3" />
    <link:label xlink:type="resource" xlink:label="ions_MaximumContractMaturityPeriodRange3_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_MaximumContractMaturityPeriodRange3_lbl" xml:lang="en-US" id="ions_MaximumContractMaturityPeriodRange3_lbl">The maximum contract maturity period for the third range of available-for-sale securities, in 'PnYnMnDTnHnMnS' format, for example, 'P1Y5M13D' represents the reported fact of one year, five months, and thirteen days.</link:label>
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    <link:label xlink:type="resource" xlink:label="ions_MaximumContractMaturityPeriodRange3_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_MaximumContractMaturityPeriodRange3_lbl1" xml:lang="en-US" id="ions_MaximumContractMaturityPeriodRange3_lbl1">Maximum contract maturity period, range 3</link:label>
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    <link:label xlink:type="resource" xlink:label="ions_MaximumContractMaturityPeriodRange3_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_MaximumContractMaturityPeriodRange3_lbl2" xml:lang="en-US" id="ions_MaximumContractMaturityPeriodRange3_lbl2">Maximum contract maturity period, range 3</link:label>
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    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_AvailableForSaleSecuritiesDebtMaturitiesAfterTwoThroughThreeAndOneHalfYearsPercentage" xlink:label="AvailableForSaleSecuritiesDebtMaturitiesAfterTwoThroughThreeAndOneHalfYearsPercentage" xlink:title="AvailableForSaleSecuritiesDebtMaturitiesAfterTwoThroughThreeAndOneHalfYearsPercentage" />
    <link:label xlink:type="resource" xlink:label="ions_AvailableForSaleSecuritiesDebtMaturitiesAfterTwoThroughThreeAndOneHalfYearsPercentage_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_AvailableForSaleSecuritiesDebtMaturitiesAfterTwoThroughThreeAndOneHalfYearsPercentage_lbl" xml:lang="en-US" id="ions_AvailableForSaleSecuritiesDebtMaturitiesAfterTwoThroughThreeAndOneHalfYearsPercentage_lbl">The percentage of available-for-sale debt securities that mature beyond two years but within three and one-half years of the balance sheet date.</link:label>
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    <link:label xlink:type="resource" xlink:label="ions_AvailableForSaleSecuritiesDebtMaturitiesAfterTwoThroughThreeAndOneHalfYearsPercentage_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_AvailableForSaleSecuritiesDebtMaturitiesAfterTwoThroughThreeAndOneHalfYearsPercentage_lbl1" xml:lang="en-US" id="ions_AvailableForSaleSecuritiesDebtMaturitiesAfterTwoThroughThreeAndOneHalfYearsPercentage_lbl1">Available-for-sale Securities, Debt Maturities, after Two Through Three and One Half Years, Percentage</link:label>
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    <link:label xlink:type="resource" xlink:label="ions_AvailableForSaleSecuritiesDebtMaturitiesAfterTwoThroughThreeAndOneHalfYearsPercentage_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_AvailableForSaleSecuritiesDebtMaturitiesAfterTwoThroughThreeAndOneHalfYearsPercentage_lbl2" xml:lang="en-US" id="ions_AvailableForSaleSecuritiesDebtMaturitiesAfterTwoThroughThreeAndOneHalfYearsPercentage_lbl2">After two years but within three and a half years</link:label>
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    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_AvailableForSaleSecuritiesDebtMaturitiesAfterOneThroughTwoYearsPercentage" xlink:label="AvailableForSaleSecuritiesDebtMaturitiesAfterOneThroughTwoYearsPercentage" xlink:title="AvailableForSaleSecuritiesDebtMaturitiesAfterOneThroughTwoYearsPercentage" />
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    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_SuzhouRiboLifeScienceCoLtdMember" xlink:label="SuzhouRiboLifeScienceCoLtdMember" xlink:title="SuzhouRiboLifeScienceCoLtdMember" />
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    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_AroBiotherapeuticsMember" xlink:label="AroBiotherapeuticsMember" xlink:title="AroBiotherapeuticsMember" />
    <link:label xlink:type="resource" xlink:label="ions_AroBiotherapeuticsMember_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_AroBiotherapeuticsMember_lbl" xml:lang="en-US" id="ions_AroBiotherapeuticsMember_lbl">Aro Biotherapeutics is a biotechnology company pioneering the development of tissue-targeted genetic medicines with a platform based on a proprietary protein technology called Centyrins.</link:label>
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    <link:label xlink:type="resource" xlink:label="ions_AroBiotherapeuticsMember_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_AroBiotherapeuticsMember_lbl1" xml:lang="en-US" id="ions_AroBiotherapeuticsMember_lbl1">Aro Biotherapeutics [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="AroBiotherapeuticsMember" xlink:to="ions_AroBiotherapeuticsMember_lbl1" xlink:title="label: AroBiotherapeuticsMember to ions_AroBiotherapeuticsMember_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_AroBiotherapeuticsMember_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_AroBiotherapeuticsMember_lbl2" xml:lang="en-US" id="ions_AroBiotherapeuticsMember_lbl2">Aro Biotherapeutics [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="AroBiotherapeuticsMember" xlink:to="ions_AroBiotherapeuticsMember_lbl2" xlink:title="label: AroBiotherapeuticsMember to ions_AroBiotherapeuticsMember_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_NumberOfInvestmentsInPrivatelyHeldCompaniesThatWereRevalued" xlink:label="NumberOfInvestmentsInPrivatelyHeldCompaniesThatWereRevalued" xlink:title="NumberOfInvestmentsInPrivatelyHeldCompaniesThatWereRevalued" />
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    <link:label xlink:type="resource" xlink:label="ions_NumberOfInvestmentsInPrivatelyHeldCompaniesThatWereRevalued_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_NumberOfInvestmentsInPrivatelyHeldCompaniesThatWereRevalued_lbl1" xml:lang="en-US" id="ions_NumberOfInvestmentsInPrivatelyHeldCompaniesThatWereRevalued_lbl1">Number of investments in privately-held companies that were revalued</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="NumberOfInvestmentsInPrivatelyHeldCompaniesThatWereRevalued" xlink:to="ions_NumberOfInvestmentsInPrivatelyHeldCompaniesThatWereRevalued_lbl1" xlink:title="label: NumberOfInvestmentsInPrivatelyHeldCompaniesThatWereRevalued to ions_NumberOfInvestmentsInPrivatelyHeldCompaniesThatWereRevalued_lbl1" />
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    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="NumberOfInvestmentsInPrivatelyHeldCompaniesThatWereRevalued" xlink:to="ions_NumberOfInvestmentsInPrivatelyHeldCompaniesThatWereRevalued_lbl2" xlink:title="label: NumberOfInvestmentsInPrivatelyHeldCompaniesThatWereRevalued to ions_NumberOfInvestmentsInPrivatelyHeldCompaniesThatWereRevalued_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_AccruedCommercialExpensesCurrent" xlink:label="AccruedCommercialExpensesCurrent" xlink:title="AccruedCommercialExpensesCurrent" />
    <link:label xlink:type="resource" xlink:label="ions_AccruedCommercialExpensesCurrent_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_AccruedCommercialExpensesCurrent_lbl" xml:lang="en-US" id="ions_AccruedCommercialExpensesCurrent_lbl">Carrying value as of the balance sheet date of obligations incurred through that date and payable for commercial expenses. Used to reflect the current portion of the liabilities (due within one year or within the normal operating cycle if longer).</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="AccruedCommercialExpensesCurrent" xlink:to="ions_AccruedCommercialExpensesCurrent_lbl" xlink:title="label: AccruedCommercialExpensesCurrent to ions_AccruedCommercialExpensesCurrent_lbl" />
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    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="AccruedCommercialExpensesCurrent" xlink:to="ions_AccruedCommercialExpensesCurrent_lbl1" xlink:title="label: AccruedCommercialExpensesCurrent to ions_AccruedCommercialExpensesCurrent_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_AccruedCommercialExpensesCurrent_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_AccruedCommercialExpensesCurrent_lbl2" xml:lang="en-US" id="ions_AccruedCommercialExpensesCurrent_lbl2">Commercial expenses</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="AccruedCommercialExpensesCurrent" xlink:to="ions_AccruedCommercialExpensesCurrent_lbl2" xlink:title="label: AccruedCommercialExpensesCurrent to ions_AccruedCommercialExpensesCurrent_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_AccruedClinicalExpenses" xlink:label="AccruedClinicalExpenses" xlink:title="AccruedClinicalExpenses" />
    <link:label xlink:type="resource" xlink:label="ions_AccruedClinicalExpenses_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_AccruedClinicalExpenses_lbl" xml:lang="en-US" id="ions_AccruedClinicalExpenses_lbl">Carrying value as of the balance sheet date of obligations incurred through that date and payable for clinical expenses. Used to reflect the current portion of the liabilities (due within one year or within the normal operating cycle if longer).</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="AccruedClinicalExpenses" xlink:to="ions_AccruedClinicalExpenses_lbl" xlink:title="label: AccruedClinicalExpenses to ions_AccruedClinicalExpenses_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_AccruedClinicalExpenses_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_AccruedClinicalExpenses_lbl1" xml:lang="en-US" id="ions_AccruedClinicalExpenses_lbl1">Accrued clinical expenses</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="AccruedClinicalExpenses" xlink:to="ions_AccruedClinicalExpenses_lbl1" xlink:title="label: AccruedClinicalExpenses to ions_AccruedClinicalExpenses_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_AccruedClinicalExpenses_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_AccruedClinicalExpenses_lbl2" xml:lang="en-US" id="ions_AccruedClinicalExpenses_lbl2">Clincial expenses</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="AccruedClinicalExpenses" xlink:to="ions_AccruedClinicalExpenses_lbl2" xlink:title="label: AccruedClinicalExpenses to ions_AccruedClinicalExpenses_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_AccruedInLicensingFeesCurrent" xlink:label="AccruedInLicensingFeesCurrent" xlink:title="AccruedInLicensingFeesCurrent" />
    <link:label xlink:type="resource" xlink:label="ions_AccruedInLicensingFeesCurrent_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_AccruedInLicensingFeesCurrent_lbl" xml:lang="en-US" id="ions_AccruedInLicensingFeesCurrent_lbl">Carrying value as of the balance sheet date of obligations incurred through that date and payable for in-licensing fees under collaboration agreements. Used to reflect the current portion of the liabilities (due within one year or within the normal operating cycle if longer).</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="AccruedInLicensingFeesCurrent" xlink:to="ions_AccruedInLicensingFeesCurrent_lbl" xlink:title="label: AccruedInLicensingFeesCurrent to ions_AccruedInLicensingFeesCurrent_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_AccruedInLicensingFeesCurrent_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_AccruedInLicensingFeesCurrent_lbl1" xml:lang="en-US" id="ions_AccruedInLicensingFeesCurrent_lbl1">Accrued in-licensing fees, Current</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="AccruedInLicensingFeesCurrent" xlink:to="ions_AccruedInLicensingFeesCurrent_lbl1" xlink:title="label: AccruedInLicensingFeesCurrent to ions_AccruedInLicensingFeesCurrent_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_AccruedInLicensingFeesCurrent_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_AccruedInLicensingFeesCurrent_lbl2" xml:lang="en-US" id="ions_AccruedInLicensingFeesCurrent_lbl2">In-licensing expenses</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="AccruedInLicensingFeesCurrent" xlink:to="ions_AccruedInLicensingFeesCurrent_lbl2" xlink:title="label: AccruedInLicensingFeesCurrent to ions_AccruedInLicensingFeesCurrent_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_AlnylamPharmaceuticalsIncMember" xlink:label="AlnylamPharmaceuticalsIncMember" xlink:title="AlnylamPharmaceuticalsIncMember" />
    <link:label xlink:type="resource" xlink:label="ions_AlnylamPharmaceuticalsIncMember_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_AlnylamPharmaceuticalsIncMember_lbl" xml:lang="en-US" id="ions_AlnylamPharmaceuticalsIncMember_lbl">Represents activity related to Alnylam Pharmaceuticals, Inc..</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="AlnylamPharmaceuticalsIncMember" xlink:to="ions_AlnylamPharmaceuticalsIncMember_lbl" xlink:title="label: AlnylamPharmaceuticalsIncMember to ions_AlnylamPharmaceuticalsIncMember_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_AlnylamPharmaceuticalsIncMember_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_AlnylamPharmaceuticalsIncMember_lbl1" xml:lang="en-US" id="ions_AlnylamPharmaceuticalsIncMember_lbl1">Alnylam Pharmaceuticals, Inc. [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="AlnylamPharmaceuticalsIncMember" xlink:to="ions_AlnylamPharmaceuticalsIncMember_lbl1" xlink:title="label: AlnylamPharmaceuticalsIncMember to ions_AlnylamPharmaceuticalsIncMember_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_AlnylamPharmaceuticalsIncMember_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_AlnylamPharmaceuticalsIncMember_lbl2" xml:lang="en-US" id="ions_AlnylamPharmaceuticalsIncMember_lbl2">Alnylam [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="AlnylamPharmaceuticalsIncMember" xlink:to="ions_AlnylamPharmaceuticalsIncMember_lbl2" xlink:title="label: AlnylamPharmaceuticalsIncMember to ions_AlnylamPharmaceuticalsIncMember_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_CollaborativeArrangementsAndNonCollaborativeArrangementTransactionsDisclosureTable" xlink:label="CollaborativeArrangementsAndNonCollaborativeArrangementTransactionsDisclosureTable" xlink:title="CollaborativeArrangementsAndNonCollaborativeArrangementTransactionsDisclosureTable" />
    <link:label xlink:type="resource" xlink:label="ions_CollaborativeArrangementsAndNonCollaborativeArrangementTransactionsDisclosureTable_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_CollaborativeArrangementsAndNonCollaborativeArrangementTransactionsDisclosureTable_lbl" xml:lang="en-US" id="ions_CollaborativeArrangementsAndNonCollaborativeArrangementTransactionsDisclosureTable_lbl">Disclosure of information about collaborative arrangements and non-collaborative arrangement transactions.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="CollaborativeArrangementsAndNonCollaborativeArrangementTransactionsDisclosureTable" xlink:to="ions_CollaborativeArrangementsAndNonCollaborativeArrangementTransactionsDisclosureTable_lbl" xlink:title="label: CollaborativeArrangementsAndNonCollaborativeArrangementTransactionsDisclosureTable to ions_CollaborativeArrangementsAndNonCollaborativeArrangementTransactionsDisclosureTable_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_CollaborativeArrangementsAndNonCollaborativeArrangementTransactionsDisclosureTable_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_CollaborativeArrangementsAndNonCollaborativeArrangementTransactionsDisclosureTable_lbl1" xml:lang="en-US" id="ions_CollaborativeArrangementsAndNonCollaborativeArrangementTransactionsDisclosureTable_lbl1">Collaborative Arrangements and Non-collaborative Arrangement Transactions Disclosure [Table]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="CollaborativeArrangementsAndNonCollaborativeArrangementTransactionsDisclosureTable" xlink:to="ions_CollaborativeArrangementsAndNonCollaborativeArrangementTransactionsDisclosureTable_lbl1" xlink:title="label: CollaborativeArrangementsAndNonCollaborativeArrangementTransactionsDisclosureTable to ions_CollaborativeArrangementsAndNonCollaborativeArrangementTransactionsDisclosureTable_lbl1" />
    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_CollaborativeArrangementsAndNonCollaborativeArrangementTransactionsDisclosureLineItems" xlink:label="CollaborativeArrangementsAndNonCollaborativeArrangementTransactionsDisclosureLineItems" xlink:title="CollaborativeArrangementsAndNonCollaborativeArrangementTransactionsDisclosureLineItems" />
    <link:label xlink:type="resource" xlink:label="ions_CollaborativeArrangementsAndNonCollaborativeArrangementTransactionsDisclosureLineItems_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_CollaborativeArrangementsAndNonCollaborativeArrangementTransactionsDisclosureLineItems_lbl" xml:lang="en-US" id="ions_CollaborativeArrangementsAndNonCollaborativeArrangementTransactionsDisclosureLineItems_lbl">Line items represent financial concepts included in a table. These concepts are used to disclose reportable information associated with domain members defined in one or many axes to the table.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="CollaborativeArrangementsAndNonCollaborativeArrangementTransactionsDisclosureLineItems" xlink:to="ions_CollaborativeArrangementsAndNonCollaborativeArrangementTransactionsDisclosureLineItems_lbl" xlink:title="label: CollaborativeArrangementsAndNonCollaborativeArrangementTransactionsDisclosureLineItems to ions_CollaborativeArrangementsAndNonCollaborativeArrangementTransactionsDisclosureLineItems_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_CollaborativeArrangementsAndNonCollaborativeArrangementTransactionsDisclosureLineItems_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_CollaborativeArrangementsAndNonCollaborativeArrangementTransactionsDisclosureLineItems_lbl1" xml:lang="en-US" id="ions_CollaborativeArrangementsAndNonCollaborativeArrangementTransactionsDisclosureLineItems_lbl1">Collaborative Arrangements and Non-collaborative Arrangement Transactions Disclosure [Line Items]</link:label>
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    <link:label xlink:type="resource" xlink:label="ions_CollaborativeArrangementsAndNonCollaborativeArrangementTransactionsDisclosureLineItems_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_CollaborativeArrangementsAndNonCollaborativeArrangementTransactionsDisclosureLineItems_lbl2" xml:lang="en-US" id="ions_CollaborativeArrangementsAndNonCollaborativeArrangementTransactionsDisclosureLineItems_lbl2">Collaborative Arrangements and Licensing Agreements [Abstract]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="CollaborativeArrangementsAndNonCollaborativeArrangementTransactionsDisclosureLineItems" xlink:to="ions_CollaborativeArrangementsAndNonCollaborativeArrangementTransactionsDisclosureLineItems_lbl2" xlink:title="label: CollaborativeArrangementsAndNonCollaborativeArrangementTransactionsDisclosureLineItems to ions_CollaborativeArrangementsAndNonCollaborativeArrangementTransactionsDisclosureLineItems_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_NovartisCollaborationMember" xlink:label="NovartisCollaborationMember" xlink:title="NovartisCollaborationMember" />
    <link:label xlink:type="resource" xlink:label="ions_NovartisCollaborationMember_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_NovartisCollaborationMember_lbl" xml:lang="en-US" id="ions_NovartisCollaborationMember_lbl">Collaboration agreement entered into with Novartis International AG (Novartis) in January 2017 to develop and commercialize pelacarsen and olezarsen.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="NovartisCollaborationMember" xlink:to="ions_NovartisCollaborationMember_lbl" xlink:title="label: NovartisCollaborationMember to ions_NovartisCollaborationMember_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_NovartisCollaborationMember_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_NovartisCollaborationMember_lbl1" xml:lang="en-US" id="ions_NovartisCollaborationMember_lbl1">Novartis Collaboration [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="NovartisCollaborationMember" xlink:to="ions_NovartisCollaborationMember_lbl1" xlink:title="label: NovartisCollaborationMember to ions_NovartisCollaborationMember_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_NovartisCollaborationMember_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_NovartisCollaborationMember_lbl2" xml:lang="en-US" id="ions_NovartisCollaborationMember_lbl2">Novartis [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="NovartisCollaborationMember" xlink:to="ions_NovartisCollaborationMember_lbl2" xlink:title="label: NovartisCollaborationMember to ions_NovartisCollaborationMember_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_GlaxoSmithKlineCollaborationMember" xlink:label="GlaxoSmithKlineCollaborationMember" xlink:title="GlaxoSmithKlineCollaborationMember" />
    <link:label xlink:type="resource" xlink:label="ions_GlaxoSmithKlineCollaborationMember_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_GlaxoSmithKlineCollaborationMember_lbl" xml:lang="en-US" id="ions_GlaxoSmithKlineCollaborationMember_lbl">Collaboration agreement entered into with GlaxoSmithKline (GSK) in March 2010 to discover and develop new medicines against targets for rare and serious diseases, including infectious diseases and some conditions causing blindness.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="GlaxoSmithKlineCollaborationMember" xlink:to="ions_GlaxoSmithKlineCollaborationMember_lbl" xlink:title="label: GlaxoSmithKlineCollaborationMember to ions_GlaxoSmithKlineCollaborationMember_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_GlaxoSmithKlineCollaborationMember_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_GlaxoSmithKlineCollaborationMember_lbl1" xml:lang="en-US" id="ions_GlaxoSmithKlineCollaborationMember_lbl1">Glaxo Smith Kline Collaboration [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="GlaxoSmithKlineCollaborationMember" xlink:to="ions_GlaxoSmithKlineCollaborationMember_lbl1" xlink:title="label: GlaxoSmithKlineCollaborationMember to ions_GlaxoSmithKlineCollaborationMember_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_GlaxoSmithKlineCollaborationMember_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_GlaxoSmithKlineCollaborationMember_lbl2" xml:lang="en-US" id="ions_GlaxoSmithKlineCollaborationMember_lbl2">GSK [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="GlaxoSmithKlineCollaborationMember" xlink:to="ions_GlaxoSmithKlineCollaborationMember_lbl2" xlink:title="label: GlaxoSmithKlineCollaborationMember to ions_GlaxoSmithKlineCollaborationMember_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_RocheCollaborationMember" xlink:label="RocheCollaborationMember" xlink:title="RocheCollaborationMember" />
    <link:label xlink:type="resource" xlink:label="ions_RocheCollaborationMember_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_RocheCollaborationMember_lbl" xml:lang="en-US" id="ions_RocheCollaborationMember_lbl">Collaboration agreements entered into with Hoffman-La Roche Inc. and F. Hoffmann-La Roche Ltd., collectively Roche.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="RocheCollaborationMember" xlink:to="ions_RocheCollaborationMember_lbl" xlink:title="label: RocheCollaborationMember to ions_RocheCollaborationMember_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_RocheCollaborationMember_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_RocheCollaborationMember_lbl1" xml:lang="en-US" id="ions_RocheCollaborationMember_lbl1">Roche Collaboration [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="RocheCollaborationMember" xlink:to="ions_RocheCollaborationMember_lbl1" xlink:title="label: RocheCollaborationMember to ions_RocheCollaborationMember_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_RocheCollaborationMember_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_RocheCollaborationMember_lbl2" xml:lang="en-US" id="ions_RocheCollaborationMember_lbl2">Roche [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="RocheCollaborationMember" xlink:to="ions_RocheCollaborationMember_lbl2" xlink:title="label: RocheCollaborationMember to ions_RocheCollaborationMember_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_BayerCollaborationsMember" xlink:label="BayerCollaborationsMember" xlink:title="BayerCollaborationsMember" />
    <link:label xlink:type="resource" xlink:label="ions_BayerCollaborationsMember_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_BayerCollaborationsMember_lbl" xml:lang="en-US" id="ions_BayerCollaborationsMember_lbl">Collaboration agreements entered into with Bayer HealthCare.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="BayerCollaborationsMember" xlink:to="ions_BayerCollaborationsMember_lbl" xlink:title="label: BayerCollaborationsMember to ions_BayerCollaborationsMember_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_BayerCollaborationsMember_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_BayerCollaborationsMember_lbl1" xml:lang="en-US" id="ions_BayerCollaborationsMember_lbl1">Bayer Collaborations [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="BayerCollaborationsMember" xlink:to="ions_BayerCollaborationsMember_lbl1" xlink:title="label: BayerCollaborationsMember to ions_BayerCollaborationsMember_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_BayerCollaborationsMember_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_BayerCollaborationsMember_lbl2" xml:lang="en-US" id="ions_BayerCollaborationsMember_lbl2">Bayer [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="BayerCollaborationsMember" xlink:to="ions_BayerCollaborationsMember_lbl2" xlink:title="label: BayerCollaborationsMember to ions_BayerCollaborationsMember_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_BiogenCollaborationsMember" xlink:label="BiogenCollaborationsMember" xlink:title="BiogenCollaborationsMember" />
    <link:label xlink:type="resource" xlink:label="ions_BiogenCollaborationsMember_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_BiogenCollaborationsMember_lbl" xml:lang="en-US" id="ions_BiogenCollaborationsMember_lbl">Collaboration agreements entered into with Biogen Inc.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="BiogenCollaborationsMember" xlink:to="ions_BiogenCollaborationsMember_lbl" xlink:title="label: BiogenCollaborationsMember to ions_BiogenCollaborationsMember_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_BiogenCollaborationsMember_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_BiogenCollaborationsMember_lbl1" xml:lang="en-US" id="ions_BiogenCollaborationsMember_lbl1">Biogen Collaborations [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="BiogenCollaborationsMember" xlink:to="ions_BiogenCollaborationsMember_lbl1" xlink:title="label: BiogenCollaborationsMember to ions_BiogenCollaborationsMember_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_BiogenCollaborationsMember_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_BiogenCollaborationsMember_lbl2" xml:lang="en-US" id="ions_BiogenCollaborationsMember_lbl2">Biogen [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="BiogenCollaborationsMember" xlink:to="ions_BiogenCollaborationsMember_lbl2" xlink:title="label: BiogenCollaborationsMember to ions_BiogenCollaborationsMember_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_AstrazenecaCollaborationsMember" xlink:label="AstrazenecaCollaborationsMember" xlink:title="AstrazenecaCollaborationsMember" />
    <link:label xlink:type="resource" xlink:label="ions_AstrazenecaCollaborationsMember_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_AstrazenecaCollaborationsMember_lbl" xml:lang="en-US" id="ions_AstrazenecaCollaborationsMember_lbl">Collaboration agreements entered into with AstraZeneca PLC.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="AstrazenecaCollaborationsMember" xlink:to="ions_AstrazenecaCollaborationsMember_lbl" xlink:title="label: AstrazenecaCollaborationsMember to ions_AstrazenecaCollaborationsMember_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_AstrazenecaCollaborationsMember_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_AstrazenecaCollaborationsMember_lbl1" xml:lang="en-US" id="ions_AstrazenecaCollaborationsMember_lbl1">AstraZeneca Collaborations [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="AstrazenecaCollaborationsMember" xlink:to="ions_AstrazenecaCollaborationsMember_lbl1" xlink:title="label: AstrazenecaCollaborationsMember to ions_AstrazenecaCollaborationsMember_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_AstrazenecaCollaborationsMember_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_AstrazenecaCollaborationsMember_lbl2" xml:lang="en-US" id="ions_AstrazenecaCollaborationsMember_lbl2">AstraZeneca [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="AstrazenecaCollaborationsMember" xlink:to="ions_AstrazenecaCollaborationsMember_lbl2" xlink:title="label: AstrazenecaCollaborationsMember to ions_AstrazenecaCollaborationsMember_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_MinimumAmountOfPaymentsReceivableForLicenseFeesAndMilestonePayments" xlink:label="MinimumAmountOfPaymentsReceivableForLicenseFeesAndMilestonePayments" xlink:title="MinimumAmountOfPaymentsReceivableForLicenseFeesAndMilestonePayments" />
    <link:label xlink:type="resource" xlink:label="ions_MinimumAmountOfPaymentsReceivableForLicenseFeesAndMilestonePayments_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_MinimumAmountOfPaymentsReceivableForLicenseFeesAndMilestonePayments_lbl" xml:lang="en-US" id="ions_MinimumAmountOfPaymentsReceivableForLicenseFeesAndMilestonePayments_lbl">The minimum amount of payments receivable for license fees and milestone payments under the collaboration agreement.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="MinimumAmountOfPaymentsReceivableForLicenseFeesAndMilestonePayments" xlink:to="ions_MinimumAmountOfPaymentsReceivableForLicenseFeesAndMilestonePayments_lbl" xlink:title="label: MinimumAmountOfPaymentsReceivableForLicenseFeesAndMilestonePayments to ions_MinimumAmountOfPaymentsReceivableForLicenseFeesAndMilestonePayments_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_MinimumAmountOfPaymentsReceivableForLicenseFeesAndMilestonePayments_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_MinimumAmountOfPaymentsReceivableForLicenseFeesAndMilestonePayments_lbl1" xml:lang="en-US" id="ions_MinimumAmountOfPaymentsReceivableForLicenseFeesAndMilestonePayments_lbl1">Minimum amount of payments receivable for license fees and milestone payments</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="MinimumAmountOfPaymentsReceivableForLicenseFeesAndMilestonePayments" xlink:to="ions_MinimumAmountOfPaymentsReceivableForLicenseFeesAndMilestonePayments_lbl1" xlink:title="label: MinimumAmountOfPaymentsReceivableForLicenseFeesAndMilestonePayments to ions_MinimumAmountOfPaymentsReceivableForLicenseFeesAndMilestonePayments_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_MinimumAmountOfPaymentsReceivableForLicenseFeesAndMilestonePayments_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_MinimumAmountOfPaymentsReceivableForLicenseFeesAndMilestonePayments_lbl2" xml:lang="en-US" id="ions_MinimumAmountOfPaymentsReceivableForLicenseFeesAndMilestonePayments_lbl2">Minimum amount of payments receivable for license fees and milestones</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="MinimumAmountOfPaymentsReceivableForLicenseFeesAndMilestonePayments" xlink:to="ions_MinimumAmountOfPaymentsReceivableForLicenseFeesAndMilestonePayments_lbl2" xlink:title="label: MinimumAmountOfPaymentsReceivableForLicenseFeesAndMilestonePayments to ions_MinimumAmountOfPaymentsReceivableForLicenseFeesAndMilestonePayments_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_NumberOfDiseaseIndications" xlink:label="NumberOfDiseaseIndications" xlink:title="NumberOfDiseaseIndications" />
    <link:label xlink:type="resource" xlink:label="ions_NumberOfDiseaseIndications_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_NumberOfDiseaseIndications_lbl" xml:lang="en-US" id="ions_NumberOfDiseaseIndications_lbl">Number of disease indications for which studies are currently being conducted under the collaboration agreement.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="NumberOfDiseaseIndications" xlink:to="ions_NumberOfDiseaseIndications_lbl" xlink:title="label: NumberOfDiseaseIndications to ions_NumberOfDiseaseIndications_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_NumberOfDiseaseIndications_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_NumberOfDiseaseIndications_lbl1" xml:lang="en-US" id="ions_NumberOfDiseaseIndications_lbl1">Number of disease indications</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="NumberOfDiseaseIndications" xlink:to="ions_NumberOfDiseaseIndications_lbl1" xlink:title="label: NumberOfDiseaseIndications to ions_NumberOfDiseaseIndications_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_NumberOfDiseaseIndications_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_NumberOfDiseaseIndications_lbl2" xml:lang="en-US" id="ions_NumberOfDiseaseIndications_lbl2">Number of disease indications</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="NumberOfDiseaseIndications" xlink:to="ions_NumberOfDiseaseIndications_lbl2" xlink:title="label: NumberOfDiseaseIndications to ions_NumberOfDiseaseIndications_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_GeographicAtrophyMember" xlink:label="GeographicAtrophyMember" xlink:title="GeographicAtrophyMember" />
    <link:label xlink:type="resource" xlink:label="ions_GeographicAtrophyMember_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_GeographicAtrophyMember_lbl" xml:lang="en-US" id="ions_GeographicAtrophyMember_lbl">Geographic Atrophy (GA) is the advanced stage of advanced aged-related macular degeneration (AMD).</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="GeographicAtrophyMember" xlink:to="ions_GeographicAtrophyMember_lbl" xlink:title="label: GeographicAtrophyMember to ions_GeographicAtrophyMember_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_GeographicAtrophyMember_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_GeographicAtrophyMember_lbl1" xml:lang="en-US" id="ions_GeographicAtrophyMember_lbl1">Geographic Atrophy [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="GeographicAtrophyMember" xlink:to="ions_GeographicAtrophyMember_lbl1" xlink:title="label: GeographicAtrophyMember to ions_GeographicAtrophyMember_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_GeographicAtrophyMember_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_GeographicAtrophyMember_lbl2" xml:lang="en-US" id="ions_GeographicAtrophyMember_lbl2">GA [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="GeographicAtrophyMember" xlink:to="ions_GeographicAtrophyMember_lbl2" xlink:title="label: GeographicAtrophyMember to ions_GeographicAtrophyMember_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_ImmunoglobulinANephropathyMember" xlink:label="ImmunoglobulinANephropathyMember" xlink:title="ImmunoglobulinANephropathyMember" />
    <link:label xlink:type="resource" xlink:label="ions_ImmunoglobulinANephropathyMember_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_ImmunoglobulinANephropathyMember_lbl" xml:lang="en-US" id="ions_ImmunoglobulinANephropathyMember_lbl">Immunoglobulin A (IgA) nephropathy is a chronic kidney disease.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="ImmunoglobulinANephropathyMember" xlink:to="ions_ImmunoglobulinANephropathyMember_lbl" xlink:title="label: ImmunoglobulinANephropathyMember to ions_ImmunoglobulinANephropathyMember_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_ImmunoglobulinANephropathyMember_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_ImmunoglobulinANephropathyMember_lbl1" xml:lang="en-US" id="ions_ImmunoglobulinANephropathyMember_lbl1">Immunoglobulin A Nephropathy [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="ImmunoglobulinANephropathyMember" xlink:to="ions_ImmunoglobulinANephropathyMember_lbl1" xlink:title="label: ImmunoglobulinANephropathyMember to ions_ImmunoglobulinANephropathyMember_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_ImmunoglobulinANephropathyMember_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_ImmunoglobulinANephropathyMember_lbl2" xml:lang="en-US" id="ions_ImmunoglobulinANephropathyMember_lbl2">IgA Nephropathy [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="ImmunoglobulinANephropathyMember" xlink:to="ions_ImmunoglobulinANephropathyMember_lbl2" xlink:title="label: ImmunoglobulinANephropathyMember to ions_ImmunoglobulinANephropathyMember_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_CollaborativeArrangementAndLicensingAgreementAbstract" xlink:label="CollaborativeArrangementAndLicensingAgreementAbstract" xlink:title="CollaborativeArrangementAndLicensingAgreementAbstract" />
    <link:label xlink:type="resource" xlink:label="ions_CollaborativeArrangementAndLicensingAgreementAbstract_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_CollaborativeArrangementAndLicensingAgreementAbstract_lbl1" xml:lang="en-US" id="ions_CollaborativeArrangementAndLicensingAgreementAbstract_lbl1">Collaborative Arrangement and Licensing Agreement [Abstract]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="CollaborativeArrangementAndLicensingAgreementAbstract" xlink:to="ions_CollaborativeArrangementAndLicensingAgreementAbstract_lbl1" xlink:title="label: CollaborativeArrangementAndLicensingAgreementAbstract to ions_CollaborativeArrangementAndLicensingAgreementAbstract_lbl1" />
    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_RevenueFromContractWithCustomerTransactionPrice" xlink:label="RevenueFromContractWithCustomerTransactionPrice" xlink:title="RevenueFromContractWithCustomerTransactionPrice" />
    <link:label xlink:type="resource" xlink:label="ions_RevenueFromContractWithCustomerTransactionPrice_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_RevenueFromContractWithCustomerTransactionPrice_lbl" xml:lang="en-US" id="ions_RevenueFromContractWithCustomerTransactionPrice_lbl">The amount of consideration the Company earned or is eligible to earn under the collaboration agreement, including any variable consideration.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="RevenueFromContractWithCustomerTransactionPrice" xlink:to="ions_RevenueFromContractWithCustomerTransactionPrice_lbl" xlink:title="label: RevenueFromContractWithCustomerTransactionPrice to ions_RevenueFromContractWithCustomerTransactionPrice_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_RevenueFromContractWithCustomerTransactionPrice_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_RevenueFromContractWithCustomerTransactionPrice_lbl1" xml:lang="en-US" id="ions_RevenueFromContractWithCustomerTransactionPrice_lbl1">Revenue from Contract with Customer, Transaction Price</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="RevenueFromContractWithCustomerTransactionPrice" xlink:to="ions_RevenueFromContractWithCustomerTransactionPrice_lbl1" xlink:title="label: RevenueFromContractWithCustomerTransactionPrice to ions_RevenueFromContractWithCustomerTransactionPrice_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_RevenueFromContractWithCustomerTransactionPrice_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_RevenueFromContractWithCustomerTransactionPrice_lbl2" xml:lang="en-US" id="ions_RevenueFromContractWithCustomerTransactionPrice_lbl2">Transaction price</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="RevenueFromContractWithCustomerTransactionPrice" xlink:to="ions_RevenueFromContractWithCustomerTransactionPrice_lbl2" xlink:title="label: RevenueFromContractWithCustomerTransactionPrice to ions_RevenueFromContractWithCustomerTransactionPrice_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_RevenueFromContractWithCustomerNumberOfSeparatePerformanceObligations" xlink:label="RevenueFromContractWithCustomerNumberOfSeparatePerformanceObligations" xlink:title="RevenueFromContractWithCustomerNumberOfSeparatePerformanceObligations" />
    <link:label xlink:type="resource" xlink:label="ions_RevenueFromContractWithCustomerNumberOfSeparatePerformanceObligations_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_RevenueFromContractWithCustomerNumberOfSeparatePerformanceObligations_lbl" xml:lang="en-US" id="ions_RevenueFromContractWithCustomerNumberOfSeparatePerformanceObligations_lbl">The number of separate performance obligations under the collaboration agreement.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="RevenueFromContractWithCustomerNumberOfSeparatePerformanceObligations" xlink:to="ions_RevenueFromContractWithCustomerNumberOfSeparatePerformanceObligations_lbl" xlink:title="label: RevenueFromContractWithCustomerNumberOfSeparatePerformanceObligations to ions_RevenueFromContractWithCustomerNumberOfSeparatePerformanceObligations_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_RevenueFromContractWithCustomerNumberOfSeparatePerformanceObligations_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_RevenueFromContractWithCustomerNumberOfSeparatePerformanceObligations_lbl1" xml:lang="en-US" id="ions_RevenueFromContractWithCustomerNumberOfSeparatePerformanceObligations_lbl1">Revenue from Contract with Customer, Number of separate performance obligations</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="RevenueFromContractWithCustomerNumberOfSeparatePerformanceObligations" xlink:to="ions_RevenueFromContractWithCustomerNumberOfSeparatePerformanceObligations_lbl1" xlink:title="label: RevenueFromContractWithCustomerNumberOfSeparatePerformanceObligations to ions_RevenueFromContractWithCustomerNumberOfSeparatePerformanceObligations_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_RevenueFromContractWithCustomerNumberOfSeparatePerformanceObligations_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_RevenueFromContractWithCustomerNumberOfSeparatePerformanceObligations_lbl2" xml:lang="en-US" id="ions_RevenueFromContractWithCustomerNumberOfSeparatePerformanceObligations_lbl2">Number of separate performance obligations</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="RevenueFromContractWithCustomerNumberOfSeparatePerformanceObligations" xlink:to="ions_RevenueFromContractWithCustomerNumberOfSeparatePerformanceObligations_lbl2" xlink:title="label: RevenueFromContractWithCustomerNumberOfSeparatePerformanceObligations to ions_RevenueFromContractWithCustomerNumberOfSeparatePerformanceObligations_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_MaximumAmountOfPaymentReceivableForEachAdditionalMedicineDeveloped" xlink:label="MaximumAmountOfPaymentReceivableForEachAdditionalMedicineDeveloped" xlink:title="MaximumAmountOfPaymentReceivableForEachAdditionalMedicineDeveloped" />
    <link:label xlink:type="resource" xlink:label="ions_MaximumAmountOfPaymentReceivableForEachAdditionalMedicineDeveloped_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_MaximumAmountOfPaymentReceivableForEachAdditionalMedicineDeveloped_lbl" xml:lang="en-US" id="ions_MaximumAmountOfPaymentReceivableForEachAdditionalMedicineDeveloped_lbl">The maximum amount of payments receivable for each additional medicine developed under the collaboration agreement.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="MaximumAmountOfPaymentReceivableForEachAdditionalMedicineDeveloped" xlink:to="ions_MaximumAmountOfPaymentReceivableForEachAdditionalMedicineDeveloped_lbl" xlink:title="label: MaximumAmountOfPaymentReceivableForEachAdditionalMedicineDeveloped to ions_MaximumAmountOfPaymentReceivableForEachAdditionalMedicineDeveloped_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_MaximumAmountOfPaymentReceivableForEachAdditionalMedicineDeveloped_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_MaximumAmountOfPaymentReceivableForEachAdditionalMedicineDeveloped_lbl1" xml:lang="en-US" id="ions_MaximumAmountOfPaymentReceivableForEachAdditionalMedicineDeveloped_lbl1">Maximum amount of payment receivable for each additional medicine developed</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="MaximumAmountOfPaymentReceivableForEachAdditionalMedicineDeveloped" xlink:to="ions_MaximumAmountOfPaymentReceivableForEachAdditionalMedicineDeveloped_lbl1" xlink:title="label: MaximumAmountOfPaymentReceivableForEachAdditionalMedicineDeveloped to ions_MaximumAmountOfPaymentReceivableForEachAdditionalMedicineDeveloped_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_MaximumAmountOfPaymentReceivableForEachAdditionalMedicineDeveloped_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_MaximumAmountOfPaymentReceivableForEachAdditionalMedicineDeveloped_lbl2" xml:lang="en-US" id="ions_MaximumAmountOfPaymentReceivableForEachAdditionalMedicineDeveloped_lbl2">Maximum amount of payment receivable for each additional medicine developed</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="MaximumAmountOfPaymentReceivableForEachAdditionalMedicineDeveloped" xlink:to="ions_MaximumAmountOfPaymentReceivableForEachAdditionalMedicineDeveloped_lbl2" xlink:title="label: MaximumAmountOfPaymentReceivableForEachAdditionalMedicineDeveloped to ions_MaximumAmountOfPaymentReceivableForEachAdditionalMedicineDeveloped_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_RoyaltyPercentageReceivedOnNetSalesOfMedicine" xlink:label="RoyaltyPercentageReceivedOnNetSalesOfMedicine" xlink:title="RoyaltyPercentageReceivedOnNetSalesOfMedicine" />
    <link:label xlink:type="resource" xlink:label="ions_RoyaltyPercentageReceivedOnNetSalesOfMedicine_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_RoyaltyPercentageReceivedOnNetSalesOfMedicine_lbl" xml:lang="en-US" id="ions_RoyaltyPercentageReceivedOnNetSalesOfMedicine_lbl">Royalty percentage received on the net sales of a medicine by a collaboration partner under the collaboration agreement.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="RoyaltyPercentageReceivedOnNetSalesOfMedicine" xlink:to="ions_RoyaltyPercentageReceivedOnNetSalesOfMedicine_lbl" xlink:title="label: RoyaltyPercentageReceivedOnNetSalesOfMedicine to ions_RoyaltyPercentageReceivedOnNetSalesOfMedicine_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_RoyaltyPercentageReceivedOnNetSalesOfMedicine_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_RoyaltyPercentageReceivedOnNetSalesOfMedicine_lbl1" xml:lang="en-US" id="ions_RoyaltyPercentageReceivedOnNetSalesOfMedicine_lbl1">Royalty percentage received on net sales of medicine</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="RoyaltyPercentageReceivedOnNetSalesOfMedicine" xlink:to="ions_RoyaltyPercentageReceivedOnNetSalesOfMedicine_lbl1" xlink:title="label: RoyaltyPercentageReceivedOnNetSalesOfMedicine to ions_RoyaltyPercentageReceivedOnNetSalesOfMedicine_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_RoyaltyPercentageReceivedOnNetSalesOfMedicine_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_RoyaltyPercentageReceivedOnNetSalesOfMedicine_lbl2" xml:lang="en-US" id="ions_RoyaltyPercentageReceivedOnNetSalesOfMedicine_lbl2">Royalty percentage received on net sales of medicine</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="RoyaltyPercentageReceivedOnNetSalesOfMedicine" xlink:to="ions_RoyaltyPercentageReceivedOnNetSalesOfMedicine_lbl2" xlink:title="label: RoyaltyPercentageReceivedOnNetSalesOfMedicine to ions_RoyaltyPercentageReceivedOnNetSalesOfMedicine_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_CumulativePaymentsReceived" xlink:label="CumulativePaymentsReceived" xlink:title="CumulativePaymentsReceived" />
    <link:label xlink:type="resource" xlink:label="ions_CumulativePaymentsReceived_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_CumulativePaymentsReceived_lbl" xml:lang="en-US" id="ions_CumulativePaymentsReceived_lbl">Cumulative amount of payments received under the collaboration agreement as of the end of the reporting period.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="CumulativePaymentsReceived" xlink:to="ions_CumulativePaymentsReceived_lbl" xlink:title="label: CumulativePaymentsReceived to ions_CumulativePaymentsReceived_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_CumulativePaymentsReceived_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_CumulativePaymentsReceived_lbl1" xml:lang="en-US" id="ions_CumulativePaymentsReceived_lbl1">Cumulative payments received</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="CumulativePaymentsReceived" xlink:to="ions_CumulativePaymentsReceived_lbl1" xlink:title="label: CumulativePaymentsReceived to ions_CumulativePaymentsReceived_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_CumulativePaymentsReceived_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_CumulativePaymentsReceived_lbl2" xml:lang="en-US" id="ions_CumulativePaymentsReceived_lbl2">Cumulative payments received</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="CumulativePaymentsReceived" xlink:to="ions_CumulativePaymentsReceived_lbl2" xlink:title="label: CumulativePaymentsReceived to ions_CumulativePaymentsReceived_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_MaximumAmountOfPaymentsReceivableForRegulatoryMilestones" xlink:label="MaximumAmountOfPaymentsReceivableForRegulatoryMilestones" xlink:title="MaximumAmountOfPaymentsReceivableForRegulatoryMilestones" />
    <link:label xlink:type="resource" xlink:label="ions_MaximumAmountOfPaymentsReceivableForRegulatoryMilestones_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_MaximumAmountOfPaymentsReceivableForRegulatoryMilestones_lbl" xml:lang="en-US" id="ions_MaximumAmountOfPaymentsReceivableForRegulatoryMilestones_lbl">The maximum amount of payments receivable for regulatory milestones under the collaboration agreement.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="MaximumAmountOfPaymentsReceivableForRegulatoryMilestones" xlink:to="ions_MaximumAmountOfPaymentsReceivableForRegulatoryMilestones_lbl" xlink:title="label: MaximumAmountOfPaymentsReceivableForRegulatoryMilestones to ions_MaximumAmountOfPaymentsReceivableForRegulatoryMilestones_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_MaximumAmountOfPaymentsReceivableForRegulatoryMilestones_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_MaximumAmountOfPaymentsReceivableForRegulatoryMilestones_lbl1" xml:lang="en-US" id="ions_MaximumAmountOfPaymentsReceivableForRegulatoryMilestones_lbl1">Maximum amount of payments receivable for regulatory milestones</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="MaximumAmountOfPaymentsReceivableForRegulatoryMilestones" xlink:to="ions_MaximumAmountOfPaymentsReceivableForRegulatoryMilestones_lbl1" xlink:title="label: MaximumAmountOfPaymentsReceivableForRegulatoryMilestones to ions_MaximumAmountOfPaymentsReceivableForRegulatoryMilestones_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_MaximumAmountOfPaymentsReceivableForRegulatoryMilestones_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_MaximumAmountOfPaymentsReceivableForRegulatoryMilestones_lbl2" xml:lang="en-US" id="ions_MaximumAmountOfPaymentsReceivableForRegulatoryMilestones_lbl2">Maximum amount of payments receivable for regulatory milestones</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="MaximumAmountOfPaymentsReceivableForRegulatoryMilestones" xlink:to="ions_MaximumAmountOfPaymentsReceivableForRegulatoryMilestones_lbl2" xlink:title="label: MaximumAmountOfPaymentsReceivableForRegulatoryMilestones to ions_MaximumAmountOfPaymentsReceivableForRegulatoryMilestones_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_UpfrontPaymentReceived" xlink:label="UpfrontPaymentReceived" xlink:title="UpfrontPaymentReceived" />
    <link:label xlink:type="resource" xlink:label="ions_UpfrontPaymentReceived_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_UpfrontPaymentReceived_lbl" xml:lang="en-US" id="ions_UpfrontPaymentReceived_lbl">The amount of upfront payments received during the period under the collaboration agreement.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="UpfrontPaymentReceived" xlink:to="ions_UpfrontPaymentReceived_lbl" xlink:title="label: UpfrontPaymentReceived to ions_UpfrontPaymentReceived_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_UpfrontPaymentReceived_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_UpfrontPaymentReceived_lbl1" xml:lang="en-US" id="ions_UpfrontPaymentReceived_lbl1">Upfront payment received</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="UpfrontPaymentReceived" xlink:to="ions_UpfrontPaymentReceived_lbl1" xlink:title="label: UpfrontPaymentReceived to ions_UpfrontPaymentReceived_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_UpfrontPaymentReceived_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_UpfrontPaymentReceived_lbl2" xml:lang="en-US" id="ions_UpfrontPaymentReceived_lbl2">Upfront payment received</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="UpfrontPaymentReceived" xlink:to="ions_UpfrontPaymentReceived_lbl2" xlink:title="label: UpfrontPaymentReceived to ions_UpfrontPaymentReceived_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_MaximumAmountOfPaymentsReceivableForLicenseFeesAndMilestones" xlink:label="MaximumAmountOfPaymentsReceivableForLicenseFeesAndMilestones" xlink:title="MaximumAmountOfPaymentsReceivableForLicenseFeesAndMilestones" />
    <link:label xlink:type="resource" xlink:label="ions_MaximumAmountOfPaymentsReceivableForLicenseFeesAndMilestones_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_MaximumAmountOfPaymentsReceivableForLicenseFeesAndMilestones_lbl" xml:lang="en-US" id="ions_MaximumAmountOfPaymentsReceivableForLicenseFeesAndMilestones_lbl">Maximum amount of payments receivable for license fees and milestone payments under the collaboration agreement.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="MaximumAmountOfPaymentsReceivableForLicenseFeesAndMilestones" xlink:to="ions_MaximumAmountOfPaymentsReceivableForLicenseFeesAndMilestones_lbl" xlink:title="label: MaximumAmountOfPaymentsReceivableForLicenseFeesAndMilestones to ions_MaximumAmountOfPaymentsReceivableForLicenseFeesAndMilestones_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_MaximumAmountOfPaymentsReceivableForLicenseFeesAndMilestones_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_MaximumAmountOfPaymentsReceivableForLicenseFeesAndMilestones_lbl1" xml:lang="en-US" id="ions_MaximumAmountOfPaymentsReceivableForLicenseFeesAndMilestones_lbl1">Maximum amount of payments receivable for license fees and milestones</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="MaximumAmountOfPaymentsReceivableForLicenseFeesAndMilestones" xlink:to="ions_MaximumAmountOfPaymentsReceivableForLicenseFeesAndMilestones_lbl1" xlink:title="label: MaximumAmountOfPaymentsReceivableForLicenseFeesAndMilestones to ions_MaximumAmountOfPaymentsReceivableForLicenseFeesAndMilestones_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_MaximumAmountOfPaymentsReceivableForLicenseFeesAndMilestones_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_MaximumAmountOfPaymentsReceivableForLicenseFeesAndMilestones_lbl2" xml:lang="en-US" id="ions_MaximumAmountOfPaymentsReceivableForLicenseFeesAndMilestones_lbl2">Maximum amount of payments receivable for license fees and milestones</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="MaximumAmountOfPaymentsReceivableForLicenseFeesAndMilestones" xlink:to="ions_MaximumAmountOfPaymentsReceivableForLicenseFeesAndMilestones_lbl2" xlink:title="label: MaximumAmountOfPaymentsReceivableForLicenseFeesAndMilestones to ions_MaximumAmountOfPaymentsReceivableForLicenseFeesAndMilestones_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_MilestonePaymentsReceived" xlink:label="MilestonePaymentsReceived" xlink:title="MilestonePaymentsReceived" />
    <link:label xlink:type="resource" xlink:label="ions_MilestonePaymentsReceived_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_MilestonePaymentsReceived_lbl" xml:lang="en-US" id="ions_MilestonePaymentsReceived_lbl">The amount of milestone payments received during the period under the collaboration agreement.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="MilestonePaymentsReceived" xlink:to="ions_MilestonePaymentsReceived_lbl" xlink:title="label: MilestonePaymentsReceived to ions_MilestonePaymentsReceived_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_MilestonePaymentsReceived_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_MilestonePaymentsReceived_lbl1" xml:lang="en-US" id="ions_MilestonePaymentsReceived_lbl1">Milestone payments received</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="MilestonePaymentsReceived" xlink:to="ions_MilestonePaymentsReceived_lbl1" xlink:title="label: MilestonePaymentsReceived to ions_MilestonePaymentsReceived_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_MilestonePaymentsReceived_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_MilestonePaymentsReceived_lbl2" xml:lang="en-US" id="ions_MilestonePaymentsReceived_lbl2">Milestone payment received</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="MilestonePaymentsReceived" xlink:to="ions_MilestonePaymentsReceived_lbl2" xlink:title="label: MilestonePaymentsReceived to ions_MilestonePaymentsReceived_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_MaximumAmountOfPaymentsReceivableForDevelopmentMilestones" xlink:label="MaximumAmountOfPaymentsReceivableForDevelopmentMilestones" xlink:title="MaximumAmountOfPaymentsReceivableForDevelopmentMilestones" />
    <link:label xlink:type="resource" xlink:label="ions_MaximumAmountOfPaymentsReceivableForDevelopmentMilestones_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_MaximumAmountOfPaymentsReceivableForDevelopmentMilestones_lbl" xml:lang="en-US" id="ions_MaximumAmountOfPaymentsReceivableForDevelopmentMilestones_lbl">The maximum amount of payments receivable for development milestones under the collaboration agreement.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="MaximumAmountOfPaymentsReceivableForDevelopmentMilestones" xlink:to="ions_MaximumAmountOfPaymentsReceivableForDevelopmentMilestones_lbl" xlink:title="label: MaximumAmountOfPaymentsReceivableForDevelopmentMilestones to ions_MaximumAmountOfPaymentsReceivableForDevelopmentMilestones_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_MaximumAmountOfPaymentsReceivableForDevelopmentMilestones_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_MaximumAmountOfPaymentsReceivableForDevelopmentMilestones_lbl1" xml:lang="en-US" id="ions_MaximumAmountOfPaymentsReceivableForDevelopmentMilestones_lbl1">Maximum amount of payments receivable for development milestones</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="MaximumAmountOfPaymentsReceivableForDevelopmentMilestones" xlink:to="ions_MaximumAmountOfPaymentsReceivableForDevelopmentMilestones_lbl1" xlink:title="label: MaximumAmountOfPaymentsReceivableForDevelopmentMilestones to ions_MaximumAmountOfPaymentsReceivableForDevelopmentMilestones_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_MaximumAmountOfPaymentsReceivableForDevelopmentMilestones_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_MaximumAmountOfPaymentsReceivableForDevelopmentMilestones_lbl2" xml:lang="en-US" id="ions_MaximumAmountOfPaymentsReceivableForDevelopmentMilestones_lbl2">Maximum amount of payments receivable for development milestones</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="MaximumAmountOfPaymentsReceivableForDevelopmentMilestones" xlink:to="ions_MaximumAmountOfPaymentsReceivableForDevelopmentMilestones_lbl2" xlink:title="label: MaximumAmountOfPaymentsReceivableForDevelopmentMilestones to ions_MaximumAmountOfPaymentsReceivableForDevelopmentMilestones_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_NextPotentialPayment" xlink:label="NextPotentialPayment" xlink:title="NextPotentialPayment" />
    <link:label xlink:type="resource" xlink:label="ions_NextPotentialPayment_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_NextPotentialPayment_lbl" xml:lang="en-US" id="ions_NextPotentialPayment_lbl">The next potential payment to be earned under the collaboration agreement.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="NextPotentialPayment" xlink:to="ions_NextPotentialPayment_lbl" xlink:title="label: NextPotentialPayment to ions_NextPotentialPayment_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_NextPotentialPayment_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_NextPotentialPayment_lbl1" xml:lang="en-US" id="ions_NextPotentialPayment_lbl1">Next potential payment</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="NextPotentialPayment" xlink:to="ions_NextPotentialPayment_lbl1" xlink:title="label: NextPotentialPayment to ions_NextPotentialPayment_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_NextPotentialPayment_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_NextPotentialPayment_lbl2" xml:lang="en-US" id="ions_NextPotentialPayment_lbl2">Next prospective payment</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="NextPotentialPayment" xlink:to="ions_NextPotentialPayment_lbl2" xlink:title="label: NextPotentialPayment to ions_NextPotentialPayment_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_MaximumAmountOfPaymentsReceivableForSalesMilestones" xlink:label="MaximumAmountOfPaymentsReceivableForSalesMilestones" xlink:title="MaximumAmountOfPaymentsReceivableForSalesMilestones" />
    <link:label xlink:type="resource" xlink:label="ions_MaximumAmountOfPaymentsReceivableForSalesMilestones_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_MaximumAmountOfPaymentsReceivableForSalesMilestones_lbl" xml:lang="en-US" id="ions_MaximumAmountOfPaymentsReceivableForSalesMilestones_lbl">The maximum amount of payments receivable for sales milestones under the collaboration agreement.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="MaximumAmountOfPaymentsReceivableForSalesMilestones" xlink:to="ions_MaximumAmountOfPaymentsReceivableForSalesMilestones_lbl" xlink:title="label: MaximumAmountOfPaymentsReceivableForSalesMilestones to ions_MaximumAmountOfPaymentsReceivableForSalesMilestones_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_MaximumAmountOfPaymentsReceivableForSalesMilestones_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_MaximumAmountOfPaymentsReceivableForSalesMilestones_lbl1" xml:lang="en-US" id="ions_MaximumAmountOfPaymentsReceivableForSalesMilestones_lbl1">Maximum amount of payments receivable for sales milestones</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="MaximumAmountOfPaymentsReceivableForSalesMilestones" xlink:to="ions_MaximumAmountOfPaymentsReceivableForSalesMilestones_lbl1" xlink:title="label: MaximumAmountOfPaymentsReceivableForSalesMilestones to ions_MaximumAmountOfPaymentsReceivableForSalesMilestones_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_MaximumAmountOfPaymentsReceivableForSalesMilestones_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_MaximumAmountOfPaymentsReceivableForSalesMilestones_lbl2" xml:lang="en-US" id="ions_MaximumAmountOfPaymentsReceivableForSalesMilestones_lbl2">Maximum amount of payments receivable for sales milestones</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="MaximumAmountOfPaymentsReceivableForSalesMilestones" xlink:to="ions_MaximumAmountOfPaymentsReceivableForSalesMilestones_lbl2" xlink:title="label: MaximumAmountOfPaymentsReceivableForSalesMilestones to ions_MaximumAmountOfPaymentsReceivableForSalesMilestones_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_RocheCollaborationIonisFbLForComplementMediatedDiseasesMember" xlink:label="RocheCollaborationIonisFbLForComplementMediatedDiseasesMember" xlink:title="RocheCollaborationIonisFbLForComplementMediatedDiseasesMember" />
    <link:label xlink:type="resource" xlink:label="ions_RocheCollaborationIonisFbLForComplementMediatedDiseasesMember_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_RocheCollaborationIonisFbLForComplementMediatedDiseasesMember_lbl" xml:lang="en-US" id="ions_RocheCollaborationIonisFbLForComplementMediatedDiseasesMember_lbl">Collaboration agreement entered into with Hoffman-La Roche Inc. and F. Hoffmann-La Roche Ltd., collectively Roche, in October 2018 to develop IONIS-FB-L for the treatment of complement-mediated diseases.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="RocheCollaborationIonisFbLForComplementMediatedDiseasesMember" xlink:to="ions_RocheCollaborationIonisFbLForComplementMediatedDiseasesMember_lbl" xlink:title="label: RocheCollaborationIonisFbLForComplementMediatedDiseasesMember to ions_RocheCollaborationIonisFbLForComplementMediatedDiseasesMember_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_RocheCollaborationIonisFbLForComplementMediatedDiseasesMember_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_RocheCollaborationIonisFbLForComplementMediatedDiseasesMember_lbl1" xml:lang="en-US" id="ions_RocheCollaborationIonisFbLForComplementMediatedDiseasesMember_lbl1">Roche Collaboration, Ionis-Fb-L for Complement-Mediated Diseases [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="RocheCollaborationIonisFbLForComplementMediatedDiseasesMember" xlink:to="ions_RocheCollaborationIonisFbLForComplementMediatedDiseasesMember_lbl1" xlink:title="label: RocheCollaborationIonisFbLForComplementMediatedDiseasesMember to ions_RocheCollaborationIonisFbLForComplementMediatedDiseasesMember_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_RocheCollaborationIonisFbLForComplementMediatedDiseasesMember_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_RocheCollaborationIonisFbLForComplementMediatedDiseasesMember_lbl2" xml:lang="en-US" id="ions_RocheCollaborationIonisFbLForComplementMediatedDiseasesMember_lbl2">IONIS-FB-L for Complement-Mediated Diseases [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="RocheCollaborationIonisFbLForComplementMediatedDiseasesMember" xlink:to="ions_RocheCollaborationIonisFbLForComplementMediatedDiseasesMember_lbl2" xlink:title="label: RocheCollaborationIonisFbLForComplementMediatedDiseasesMember to ions_RocheCollaborationIonisFbLForComplementMediatedDiseasesMember_lbl2" />
    <link:label xlink:type="resource" xlink:label="ions_RocheCollaborationIonisFbLForComplementMediatedDiseasesMember_lbl3" xlink:role="http://www.xbrl.org/2003/role/verboseLabel" xlink:title="ions_RocheCollaborationIonisFbLForComplementMediatedDiseasesMember_lbl3" xml:lang="en-US" id="ions_RocheCollaborationIonisFbLForComplementMediatedDiseasesMember_lbl3">Roche IONIS-FB-L for Complement-Mediated Diseases [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="RocheCollaborationIonisFbLForComplementMediatedDiseasesMember" xlink:to="ions_RocheCollaborationIonisFbLForComplementMediatedDiseasesMember_lbl3" xlink:title="label: RocheCollaborationIonisFbLForComplementMediatedDiseasesMember to ions_RocheCollaborationIonisFbLForComplementMediatedDiseasesMember_lbl3" />
    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_RocheCollaborationHuntingtonsDiseaseMember" xlink:label="RocheCollaborationHuntingtonsDiseaseMember" xlink:title="RocheCollaborationHuntingtonsDiseaseMember" />
    <link:label xlink:type="resource" xlink:label="ions_RocheCollaborationHuntingtonsDiseaseMember_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_RocheCollaborationHuntingtonsDiseaseMember_lbl" xml:lang="en-US" id="ions_RocheCollaborationHuntingtonsDiseaseMember_lbl">Collaboration agreement entered into with Hoffman-La Roche Inc. and F. Hoffmann-La Roche Ltd., collectively Roche, in April 2013 to develop treatments for Huntington's disease, or HD, based on the Company's antisense technology.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="RocheCollaborationHuntingtonsDiseaseMember" xlink:to="ions_RocheCollaborationHuntingtonsDiseaseMember_lbl" xlink:title="label: RocheCollaborationHuntingtonsDiseaseMember to ions_RocheCollaborationHuntingtonsDiseaseMember_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_RocheCollaborationHuntingtonsDiseaseMember_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_RocheCollaborationHuntingtonsDiseaseMember_lbl1" xml:lang="en-US" id="ions_RocheCollaborationHuntingtonsDiseaseMember_lbl1">Roche Collaboration, Huntington's Disease [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="RocheCollaborationHuntingtonsDiseaseMember" xlink:to="ions_RocheCollaborationHuntingtonsDiseaseMember_lbl1" xlink:title="label: RocheCollaborationHuntingtonsDiseaseMember to ions_RocheCollaborationHuntingtonsDiseaseMember_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_RocheCollaborationHuntingtonsDiseaseMember_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_RocheCollaborationHuntingtonsDiseaseMember_lbl2" xml:lang="en-US" id="ions_RocheCollaborationHuntingtonsDiseaseMember_lbl2">Huntington's Disease [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="RocheCollaborationHuntingtonsDiseaseMember" xlink:to="ions_RocheCollaborationHuntingtonsDiseaseMember_lbl2" xlink:title="label: RocheCollaborationHuntingtonsDiseaseMember to ions_RocheCollaborationHuntingtonsDiseaseMember_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_PaymentReceivedForAdvancingPrograms" xlink:label="PaymentReceivedForAdvancingPrograms" xlink:title="PaymentReceivedForAdvancingPrograms" />
    <link:label xlink:type="resource" xlink:label="ions_PaymentReceivedForAdvancingPrograms_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_PaymentReceivedForAdvancingPrograms_lbl" xml:lang="en-US" id="ions_PaymentReceivedForAdvancingPrograms_lbl">The amount of payments received during the period for advancing programs under the collaboration agreement.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="PaymentReceivedForAdvancingPrograms" xlink:to="ions_PaymentReceivedForAdvancingPrograms_lbl" xlink:title="label: PaymentReceivedForAdvancingPrograms to ions_PaymentReceivedForAdvancingPrograms_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_PaymentReceivedForAdvancingPrograms_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_PaymentReceivedForAdvancingPrograms_lbl1" xml:lang="en-US" id="ions_PaymentReceivedForAdvancingPrograms_lbl1">Payment received for advancing programs</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="PaymentReceivedForAdvancingPrograms" xlink:to="ions_PaymentReceivedForAdvancingPrograms_lbl1" xlink:title="label: PaymentReceivedForAdvancingPrograms to ions_PaymentReceivedForAdvancingPrograms_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_PaymentReceivedForAdvancingPrograms_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_PaymentReceivedForAdvancingPrograms_lbl2" xml:lang="en-US" id="ions_PaymentReceivedForAdvancingPrograms_lbl2">Payment received for advancing programs</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="PaymentReceivedForAdvancingPrograms" xlink:to="ions_PaymentReceivedForAdvancingPrograms_lbl2" xlink:title="label: PaymentReceivedForAdvancingPrograms to ions_PaymentReceivedForAdvancingPrograms_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_BayerCollaborationIonisFxiMember" xlink:label="BayerCollaborationIonisFxiMember" xlink:title="BayerCollaborationIonisFxiMember" />
    <link:label xlink:type="resource" xlink:label="ions_BayerCollaborationIonisFxiMember_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_BayerCollaborationIonisFxiMember_lbl" xml:lang="en-US" id="ions_BayerCollaborationIonisFxiMember_lbl">Collaboration agreement entered into with Bayer HealthCare in May 2015 to develop and commercialize IONIS-FXI for the prevention of thrombosis.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="BayerCollaborationIonisFxiMember" xlink:to="ions_BayerCollaborationIonisFxiMember_lbl" xlink:title="label: BayerCollaborationIonisFxiMember to ions_BayerCollaborationIonisFxiMember_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_BayerCollaborationIonisFxiMember_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_BayerCollaborationIonisFxiMember_lbl1" xml:lang="en-US" id="ions_BayerCollaborationIonisFxiMember_lbl1">Bayer Collaboration, Ionis-Fxi [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="BayerCollaborationIonisFxiMember" xlink:to="ions_BayerCollaborationIonisFxiMember_lbl1" xlink:title="label: BayerCollaborationIonisFxiMember to ions_BayerCollaborationIonisFxiMember_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_BayerCollaborationIonisFxiMember_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_BayerCollaborationIonisFxiMember_lbl2" xml:lang="en-US" id="ions_BayerCollaborationIonisFxiMember_lbl2">Bayer [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="BayerCollaborationIonisFxiMember" xlink:to="ions_BayerCollaborationIonisFxiMember_lbl2" xlink:title="label: BayerCollaborationIonisFxiMember to ions_BayerCollaborationIonisFxiMember_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_BayerCollaborationIonisFxiAmendmentMember" xlink:label="BayerCollaborationIonisFxiAmendmentMember" xlink:title="BayerCollaborationIonisFxiAmendmentMember" />
    <link:label xlink:type="resource" xlink:label="ions_BayerCollaborationIonisFxiAmendmentMember_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_BayerCollaborationIonisFxiAmendmentMember_lbl" xml:lang="en-US" id="ions_BayerCollaborationIonisFxiAmendmentMember_lbl">Collaboration agreement with Bayer HealthCare amended in February 2017 to advance IONIS-FXI for the prevention of thrombosis and to initiate development of IONIS-FXI-L.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="BayerCollaborationIonisFxiAmendmentMember" xlink:to="ions_BayerCollaborationIonisFxiAmendmentMember_lbl" xlink:title="label: BayerCollaborationIonisFxiAmendmentMember to ions_BayerCollaborationIonisFxiAmendmentMember_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_BayerCollaborationIonisFxiAmendmentMember_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_BayerCollaborationIonisFxiAmendmentMember_lbl1" xml:lang="en-US" id="ions_BayerCollaborationIonisFxiAmendmentMember_lbl1">Bayer Collaboration, Ionis-Fxi Amendment [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="BayerCollaborationIonisFxiAmendmentMember" xlink:to="ions_BayerCollaborationIonisFxiAmendmentMember_lbl1" xlink:title="label: BayerCollaborationIonisFxiAmendmentMember to ions_BayerCollaborationIonisFxiAmendmentMember_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_BayerCollaborationIonisFxiAmendmentMember_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_BayerCollaborationIonisFxiAmendmentMember_lbl2" xml:lang="en-US" id="ions_BayerCollaborationIonisFxiAmendmentMember_lbl2">Bayer [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="BayerCollaborationIonisFxiAmendmentMember" xlink:to="ions_BayerCollaborationIonisFxiAmendmentMember_lbl2" xlink:title="label: BayerCollaborationIonisFxiAmendmentMember to ions_BayerCollaborationIonisFxiAmendmentMember_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_FesomersenMember" xlink:label="FesomersenMember" xlink:title="FesomersenMember" />
    <link:label xlink:type="resource" xlink:label="ions_FesomersenMember_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_FesomersenMember_lbl" xml:lang="en-US" id="ions_FesomersenMember_lbl">Fesomersen, formerly known as IONIS-FXI-L, is a ligand-conjugated (LICA) investigational antisense medicine designed to reduce the production of Factor XI, a clotting factor produced in the liver that is an important component of the coagulation pathway.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="FesomersenMember" xlink:to="ions_FesomersenMember_lbl" xlink:title="label: FesomersenMember to ions_FesomersenMember_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_FesomersenMember_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_FesomersenMember_lbl1" xml:lang="en-US" id="ions_FesomersenMember_lbl1">Fesomersen [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="FesomersenMember" xlink:to="ions_FesomersenMember_lbl1" xlink:title="label: FesomersenMember to ions_FesomersenMember_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_FesomersenMember_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_FesomersenMember_lbl2" xml:lang="en-US" id="ions_FesomersenMember_lbl2">Fesomersen [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="FesomersenMember" xlink:to="ions_FesomersenMember_lbl2" xlink:title="label: FesomersenMember to ions_FesomersenMember_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_ResearchAndDevelopmentServicesForFesomersenMember" xlink:label="ResearchAndDevelopmentServicesForFesomersenMember" xlink:title="ResearchAndDevelopmentServicesForFesomersenMember" />
    <link:label xlink:type="resource" xlink:label="ions_ResearchAndDevelopmentServicesForFesomersenMember_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_ResearchAndDevelopmentServicesForFesomersenMember_lbl" xml:lang="en-US" id="ions_ResearchAndDevelopmentServicesForFesomersenMember_lbl">Research and development (R&amp;D) services for Fesomersen, formerly known as IONIS-FXI-L, a ligand-conjugated (LICA) investigational antisense medicine designed to reduce the production of Factor XI, a clotting factor produced in the liver that is an important component of the coagulation pathway.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="ResearchAndDevelopmentServicesForFesomersenMember" xlink:to="ions_ResearchAndDevelopmentServicesForFesomersenMember_lbl" xlink:title="label: ResearchAndDevelopmentServicesForFesomersenMember to ions_ResearchAndDevelopmentServicesForFesomersenMember_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_ResearchAndDevelopmentServicesForFesomersenMember_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_ResearchAndDevelopmentServicesForFesomersenMember_lbl1" xml:lang="en-US" id="ions_ResearchAndDevelopmentServicesForFesomersenMember_lbl1">Research and Development Services for Fesomersen [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="ResearchAndDevelopmentServicesForFesomersenMember" xlink:to="ions_ResearchAndDevelopmentServicesForFesomersenMember_lbl1" xlink:title="label: ResearchAndDevelopmentServicesForFesomersenMember to ions_ResearchAndDevelopmentServicesForFesomersenMember_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_ResearchAndDevelopmentServicesForFesomersenMember_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_ResearchAndDevelopmentServicesForFesomersenMember_lbl2" xml:lang="en-US" id="ions_ResearchAndDevelopmentServicesForFesomersenMember_lbl2">R&amp;D Services for Fesomersen [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="ResearchAndDevelopmentServicesForFesomersenMember" xlink:to="ions_ResearchAndDevelopmentServicesForFesomersenMember_lbl2" xlink:title="label: ResearchAndDevelopmentServicesForFesomersenMember to ions_ResearchAndDevelopmentServicesForFesomersenMember_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_RoyaltyPercentageReceivedOnGrossMarginsOfMedicinesUnderCollaborationAgreement" xlink:label="RoyaltyPercentageReceivedOnGrossMarginsOfMedicinesUnderCollaborationAgreement" xlink:title="RoyaltyPercentageReceivedOnGrossMarginsOfMedicinesUnderCollaborationAgreement" />
    <link:label xlink:type="resource" xlink:label="ions_RoyaltyPercentageReceivedOnGrossMarginsOfMedicinesUnderCollaborationAgreement_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_RoyaltyPercentageReceivedOnGrossMarginsOfMedicinesUnderCollaborationAgreement_lbl" xml:lang="en-US" id="ions_RoyaltyPercentageReceivedOnGrossMarginsOfMedicinesUnderCollaborationAgreement_lbl">The royalty percentage received on gross margins of medicines under the collaborative arrangement.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="RoyaltyPercentageReceivedOnGrossMarginsOfMedicinesUnderCollaborationAgreement" xlink:to="ions_RoyaltyPercentageReceivedOnGrossMarginsOfMedicinesUnderCollaborationAgreement_lbl" xlink:title="label: RoyaltyPercentageReceivedOnGrossMarginsOfMedicinesUnderCollaborationAgreement to ions_RoyaltyPercentageReceivedOnGrossMarginsOfMedicinesUnderCollaborationAgreement_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_RoyaltyPercentageReceivedOnGrossMarginsOfMedicinesUnderCollaborationAgreement_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_RoyaltyPercentageReceivedOnGrossMarginsOfMedicinesUnderCollaborationAgreement_lbl1" xml:lang="en-US" id="ions_RoyaltyPercentageReceivedOnGrossMarginsOfMedicinesUnderCollaborationAgreement_lbl1">Royalty percentage received on gross margins of medicines under collaboration agreement</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="RoyaltyPercentageReceivedOnGrossMarginsOfMedicinesUnderCollaborationAgreement" xlink:to="ions_RoyaltyPercentageReceivedOnGrossMarginsOfMedicinesUnderCollaborationAgreement_lbl1" xlink:title="label: RoyaltyPercentageReceivedOnGrossMarginsOfMedicinesUnderCollaborationAgreement to ions_RoyaltyPercentageReceivedOnGrossMarginsOfMedicinesUnderCollaborationAgreement_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_RoyaltyPercentageReceivedOnGrossMarginsOfMedicinesUnderCollaborationAgreement_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_RoyaltyPercentageReceivedOnGrossMarginsOfMedicinesUnderCollaborationAgreement_lbl2" xml:lang="en-US" id="ions_RoyaltyPercentageReceivedOnGrossMarginsOfMedicinesUnderCollaborationAgreement_lbl2">Royalty percentage received on gross margins of both medicines combined</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="RoyaltyPercentageReceivedOnGrossMarginsOfMedicinesUnderCollaborationAgreement" xlink:to="ions_RoyaltyPercentageReceivedOnGrossMarginsOfMedicinesUnderCollaborationAgreement_lbl2" xlink:title="label: RoyaltyPercentageReceivedOnGrossMarginsOfMedicinesUnderCollaborationAgreement to ions_RoyaltyPercentageReceivedOnGrossMarginsOfMedicinesUnderCollaborationAgreement_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_RevenueFromContractWithCustomerNumberOfNewPerformanceObligations" xlink:label="RevenueFromContractWithCustomerNumberOfNewPerformanceObligations" xlink:title="RevenueFromContractWithCustomerNumberOfNewPerformanceObligations" />
    <link:label xlink:type="resource" xlink:label="ions_RevenueFromContractWithCustomerNumberOfNewPerformanceObligations_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_RevenueFromContractWithCustomerNumberOfNewPerformanceObligations_lbl" xml:lang="en-US" id="ions_RevenueFromContractWithCustomerNumberOfNewPerformanceObligations_lbl">The number of new performance obligations identified under the collaboration agreement.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="RevenueFromContractWithCustomerNumberOfNewPerformanceObligations" xlink:to="ions_RevenueFromContractWithCustomerNumberOfNewPerformanceObligations_lbl" xlink:title="label: RevenueFromContractWithCustomerNumberOfNewPerformanceObligations to ions_RevenueFromContractWithCustomerNumberOfNewPerformanceObligations_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_RevenueFromContractWithCustomerNumberOfNewPerformanceObligations_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_RevenueFromContractWithCustomerNumberOfNewPerformanceObligations_lbl1" xml:lang="en-US" id="ions_RevenueFromContractWithCustomerNumberOfNewPerformanceObligations_lbl1">Revenue from Contract with Customer, Number of new performance obligations</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="RevenueFromContractWithCustomerNumberOfNewPerformanceObligations" xlink:to="ions_RevenueFromContractWithCustomerNumberOfNewPerformanceObligations_lbl1" xlink:title="label: RevenueFromContractWithCustomerNumberOfNewPerformanceObligations to ions_RevenueFromContractWithCustomerNumberOfNewPerformanceObligations_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_RevenueFromContractWithCustomerNumberOfNewPerformanceObligations_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_RevenueFromContractWithCustomerNumberOfNewPerformanceObligations_lbl2" xml:lang="en-US" id="ions_RevenueFromContractWithCustomerNumberOfNewPerformanceObligations_lbl2">Number of new performance obligations</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="RevenueFromContractWithCustomerNumberOfNewPerformanceObligations" xlink:to="ions_RevenueFromContractWithCustomerNumberOfNewPerformanceObligations_lbl2" xlink:title="label: RevenueFromContractWithCustomerNumberOfNewPerformanceObligations to ions_RevenueFromContractWithCustomerNumberOfNewPerformanceObligations_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_IonisMaptMember" xlink:label="IonisMaptMember" xlink:title="IonisMaptMember" />
    <link:label xlink:type="resource" xlink:label="ions_IonisMaptMember_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_IonisMaptMember_lbl" xml:lang="en-US" id="ions_IonisMaptMember_lbl">IONIS-MAPT is an antisense drug designed to selectively reduce the production of microtubule-associated protein tau (MAPT), or tau protein, in the brain, for the treatment of Alzheimer's disease.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="IonisMaptMember" xlink:to="ions_IonisMaptMember_lbl" xlink:title="label: IonisMaptMember to ions_IonisMaptMember_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_IonisMaptMember_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_IonisMaptMember_lbl1" xml:lang="en-US" id="ions_IonisMaptMember_lbl1">Ionis-Mapt [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="IonisMaptMember" xlink:to="ions_IonisMaptMember_lbl1" xlink:title="label: IonisMaptMember to ions_IonisMaptMember_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_IonisMaptMember_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_IonisMaptMember_lbl2" xml:lang="en-US" id="ions_IonisMaptMember_lbl2">IONIS-MAPT [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="IonisMaptMember" xlink:to="ions_IonisMaptMember_lbl2" xlink:title="label: IonisMaptMember to ions_IonisMaptMember_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_NumberOfProgramsBeingAdvanced" xlink:label="NumberOfProgramsBeingAdvanced" xlink:title="NumberOfProgramsBeingAdvanced" />
    <link:label xlink:type="resource" xlink:label="ions_NumberOfProgramsBeingAdvanced_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_NumberOfProgramsBeingAdvanced_lbl" xml:lang="en-US" id="ions_NumberOfProgramsBeingAdvanced_lbl">The number of programs being advanced under the collaboration agreement.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="NumberOfProgramsBeingAdvanced" xlink:to="ions_NumberOfProgramsBeingAdvanced_lbl" xlink:title="label: NumberOfProgramsBeingAdvanced to ions_NumberOfProgramsBeingAdvanced_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_NumberOfProgramsBeingAdvanced_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_NumberOfProgramsBeingAdvanced_lbl1" xml:lang="en-US" id="ions_NumberOfProgramsBeingAdvanced_lbl1">Number of programs being advanced</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="NumberOfProgramsBeingAdvanced" xlink:to="ions_NumberOfProgramsBeingAdvanced_lbl1" xlink:title="label: NumberOfProgramsBeingAdvanced to ions_NumberOfProgramsBeingAdvanced_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_NumberOfProgramsBeingAdvanced_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_NumberOfProgramsBeingAdvanced_lbl2" xml:lang="en-US" id="ions_NumberOfProgramsBeingAdvanced_lbl2">Number of programs being advanced</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="NumberOfProgramsBeingAdvanced" xlink:to="ions_NumberOfProgramsBeingAdvanced_lbl2" xlink:title="label: NumberOfProgramsBeingAdvanced to ions_NumberOfProgramsBeingAdvanced_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_MilestonePaymentsAchievedAndIncludedInTransactionPriceForPerformanceObligation" xlink:label="MilestonePaymentsAchievedAndIncludedInTransactionPriceForPerformanceObligation" xlink:title="MilestonePaymentsAchievedAndIncludedInTransactionPriceForPerformanceObligation" />
    <link:label xlink:type="resource" xlink:label="ions_MilestonePaymentsAchievedAndIncludedInTransactionPriceForPerformanceObligation_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_MilestonePaymentsAchievedAndIncludedInTransactionPriceForPerformanceObligation_lbl" xml:lang="en-US" id="ions_MilestonePaymentsAchievedAndIncludedInTransactionPriceForPerformanceObligation_lbl">Milestone payments achieved under the collaboration agreement during the period and included in the transaction price for the performance obligation.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="MilestonePaymentsAchievedAndIncludedInTransactionPriceForPerformanceObligation" xlink:to="ions_MilestonePaymentsAchievedAndIncludedInTransactionPriceForPerformanceObligation_lbl" xlink:title="label: MilestonePaymentsAchievedAndIncludedInTransactionPriceForPerformanceObligation to ions_MilestonePaymentsAchievedAndIncludedInTransactionPriceForPerformanceObligation_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_MilestonePaymentsAchievedAndIncludedInTransactionPriceForPerformanceObligation_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_MilestonePaymentsAchievedAndIncludedInTransactionPriceForPerformanceObligation_lbl1" xml:lang="en-US" id="ions_MilestonePaymentsAchievedAndIncludedInTransactionPriceForPerformanceObligation_lbl1">Milestone payments achieved and included in transaction price for performance obligation</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="MilestonePaymentsAchievedAndIncludedInTransactionPriceForPerformanceObligation" xlink:to="ions_MilestonePaymentsAchievedAndIncludedInTransactionPriceForPerformanceObligation_lbl1" xlink:title="label: MilestonePaymentsAchievedAndIncludedInTransactionPriceForPerformanceObligation to ions_MilestonePaymentsAchievedAndIncludedInTransactionPriceForPerformanceObligation_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_MilestonePaymentsAchievedAndIncludedInTransactionPriceForPerformanceObligation_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_MilestonePaymentsAchievedAndIncludedInTransactionPriceForPerformanceObligation_lbl2" xml:lang="en-US" id="ions_MilestonePaymentsAchievedAndIncludedInTransactionPriceForPerformanceObligation_lbl2">Milestone payments achieved and included in transaction price for performance obligation</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="MilestonePaymentsAchievedAndIncludedInTransactionPriceForPerformanceObligation" xlink:to="ions_MilestonePaymentsAchievedAndIncludedInTransactionPriceForPerformanceObligation_lbl2" xlink:title="label: MilestonePaymentsAchievedAndIncludedInTransactionPriceForPerformanceObligation to ions_MilestonePaymentsAchievedAndIncludedInTransactionPriceForPerformanceObligation_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_Ion306Member" xlink:label="Ion306Member" xlink:title="Ion306Member" />
    <link:label xlink:type="resource" xlink:label="ions_Ion306Member_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_Ion306Member_lbl" xml:lang="en-US" id="ions_Ion306Member_lbl">ION306 is an antisense oligonucleotide or ASO that is designed to boost production of the survival motor neuron protein, known as SMN.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="Ion306Member" xlink:to="ions_Ion306Member_lbl" xlink:title="label: Ion306Member to ions_Ion306Member_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_Ion306Member_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_Ion306Member_lbl1" xml:lang="en-US" id="ions_Ion306Member_lbl1">Ion306 [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="Ion306Member" xlink:to="ions_Ion306Member_lbl1" xlink:title="label: Ion306Member to ions_Ion306Member_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_Ion306Member_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_Ion306Member_lbl2" xml:lang="en-US" id="ions_Ion306Member_lbl2">ION306 [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="Ion306Member" xlink:to="ions_Ion306Member_lbl2" xlink:title="label: Ion306Member to ions_Ion306Member_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_MaximumAmountOfPaymentsReceivableForDevelopmentCommercializationAndSalesMilestones" xlink:label="MaximumAmountOfPaymentsReceivableForDevelopmentCommercializationAndSalesMilestones" xlink:title="MaximumAmountOfPaymentsReceivableForDevelopmentCommercializationAndSalesMilestones" />
    <link:label xlink:type="resource" xlink:label="ions_MaximumAmountOfPaymentsReceivableForDevelopmentCommercializationAndSalesMilestones_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_MaximumAmountOfPaymentsReceivableForDevelopmentCommercializationAndSalesMilestones_lbl" xml:lang="en-US" id="ions_MaximumAmountOfPaymentsReceivableForDevelopmentCommercializationAndSalesMilestones_lbl">The maximum amount of payments receivable for development, commercialization and sales milestones under the collaboration agreement.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="MaximumAmountOfPaymentsReceivableForDevelopmentCommercializationAndSalesMilestones" xlink:to="ions_MaximumAmountOfPaymentsReceivableForDevelopmentCommercializationAndSalesMilestones_lbl" xlink:title="label: MaximumAmountOfPaymentsReceivableForDevelopmentCommercializationAndSalesMilestones to ions_MaximumAmountOfPaymentsReceivableForDevelopmentCommercializationAndSalesMilestones_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_MaximumAmountOfPaymentsReceivableForDevelopmentCommercializationAndSalesMilestones_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_MaximumAmountOfPaymentsReceivableForDevelopmentCommercializationAndSalesMilestones_lbl1" xml:lang="en-US" id="ions_MaximumAmountOfPaymentsReceivableForDevelopmentCommercializationAndSalesMilestones_lbl1">Maximum amount of payments receivable for development, commercialization and sales milestones</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="MaximumAmountOfPaymentsReceivableForDevelopmentCommercializationAndSalesMilestones" xlink:to="ions_MaximumAmountOfPaymentsReceivableForDevelopmentCommercializationAndSalesMilestones_lbl1" xlink:title="label: MaximumAmountOfPaymentsReceivableForDevelopmentCommercializationAndSalesMilestones to ions_MaximumAmountOfPaymentsReceivableForDevelopmentCommercializationAndSalesMilestones_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_MaximumAmountOfPaymentsReceivableForDevelopmentCommercializationAndSalesMilestones_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_MaximumAmountOfPaymentsReceivableForDevelopmentCommercializationAndSalesMilestones_lbl2" xml:lang="en-US" id="ions_MaximumAmountOfPaymentsReceivableForDevelopmentCommercializationAndSalesMilestones_lbl2">Maximum amount of payments receivable for development, commercialization and sales milestones</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="MaximumAmountOfPaymentsReceivableForDevelopmentCommercializationAndSalesMilestones" xlink:to="ions_MaximumAmountOfPaymentsReceivableForDevelopmentCommercializationAndSalesMilestones_lbl2" xlink:title="label: MaximumAmountOfPaymentsReceivableForDevelopmentCommercializationAndSalesMilestones to ions_MaximumAmountOfPaymentsReceivableForDevelopmentCommercializationAndSalesMilestones_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_Ion541Member" xlink:label="Ion541Member" xlink:title="Ion541Member" />
    <link:label xlink:type="resource" xlink:label="ions_Ion541Member_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_Ion541Member_lbl" xml:lang="en-US" id="ions_Ion541Member_lbl">ION541, also known as BIIB105, is an investigational antisense medicine targeting ataxin 2 (ATXN2) RNA.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="Ion541Member" xlink:to="ions_Ion541Member_lbl" xlink:title="label: Ion541Member to ions_Ion541Member_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_Ion541Member_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_Ion541Member_lbl1" xml:lang="en-US" id="ions_Ion541Member_lbl1">Ion541 [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="Ion541Member" xlink:to="ions_Ion541Member_lbl1" xlink:title="label: Ion541Member to ions_Ion541Member_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_Ion541Member_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_Ion541Member_lbl2" xml:lang="en-US" id="ions_Ion541Member_lbl2">ION541 [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="Ion541Member" xlink:to="ions_Ion541Member_lbl2" xlink:title="label: Ion541Member to ions_Ion541Member_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_MedicinesForUndisclosedTargetsMember" xlink:label="MedicinesForUndisclosedTargetsMember" xlink:title="MedicinesForUndisclosedTargetsMember" />
    <link:label xlink:type="resource" xlink:label="ions_MedicinesForUndisclosedTargetsMember_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_MedicinesForUndisclosedTargetsMember_lbl" xml:lang="en-US" id="ions_MedicinesForUndisclosedTargetsMember_lbl">Medicines to treat undisclosed targets under the collaboration agreement.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="MedicinesForUndisclosedTargetsMember" xlink:to="ions_MedicinesForUndisclosedTargetsMember_lbl" xlink:title="label: MedicinesForUndisclosedTargetsMember to ions_MedicinesForUndisclosedTargetsMember_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_MedicinesForUndisclosedTargetsMember_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_MedicinesForUndisclosedTargetsMember_lbl1" xml:lang="en-US" id="ions_MedicinesForUndisclosedTargetsMember_lbl1">Medicines for Undisclosed Targets [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="MedicinesForUndisclosedTargetsMember" xlink:to="ions_MedicinesForUndisclosedTargetsMember_lbl1" xlink:title="label: MedicinesForUndisclosedTargetsMember to ions_MedicinesForUndisclosedTargetsMember_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_MedicinesForUndisclosedTargetsMember_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_MedicinesForUndisclosedTargetsMember_lbl2" xml:lang="en-US" id="ions_MedicinesForUndisclosedTargetsMember_lbl2">Medicines for Undisclosed Targets [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="MedicinesForUndisclosedTargetsMember" xlink:to="ions_MedicinesForUndisclosedTargetsMember_lbl2" xlink:title="label: MedicinesForUndisclosedTargetsMember to ions_MedicinesForUndisclosedTargetsMember_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_MaximumAmountOfPaymentsReceivablePerMedicineForMilestonePayments" xlink:label="MaximumAmountOfPaymentsReceivablePerMedicineForMilestonePayments" xlink:title="MaximumAmountOfPaymentsReceivablePerMedicineForMilestonePayments" />
    <link:label xlink:type="resource" xlink:label="ions_MaximumAmountOfPaymentsReceivablePerMedicineForMilestonePayments_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_MaximumAmountOfPaymentsReceivablePerMedicineForMilestonePayments_lbl" xml:lang="en-US" id="ions_MaximumAmountOfPaymentsReceivablePerMedicineForMilestonePayments_lbl">The maximum amount of payments receivable for milestone payments for each medicine that achieves marketing approval under the collaboration agreement.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="MaximumAmountOfPaymentsReceivablePerMedicineForMilestonePayments" xlink:to="ions_MaximumAmountOfPaymentsReceivablePerMedicineForMilestonePayments_lbl" xlink:title="label: MaximumAmountOfPaymentsReceivablePerMedicineForMilestonePayments to ions_MaximumAmountOfPaymentsReceivablePerMedicineForMilestonePayments_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_MaximumAmountOfPaymentsReceivablePerMedicineForMilestonePayments_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_MaximumAmountOfPaymentsReceivablePerMedicineForMilestonePayments_lbl1" xml:lang="en-US" id="ions_MaximumAmountOfPaymentsReceivablePerMedicineForMilestonePayments_lbl1">Maximum amount of payments receivable per medicine for milestone payments</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="MaximumAmountOfPaymentsReceivablePerMedicineForMilestonePayments" xlink:to="ions_MaximumAmountOfPaymentsReceivablePerMedicineForMilestonePayments_lbl1" xlink:title="label: MaximumAmountOfPaymentsReceivablePerMedicineForMilestonePayments to ions_MaximumAmountOfPaymentsReceivablePerMedicineForMilestonePayments_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_MaximumAmountOfPaymentsReceivablePerMedicineForMilestonePayments_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_MaximumAmountOfPaymentsReceivablePerMedicineForMilestonePayments_lbl2" xml:lang="en-US" id="ions_MaximumAmountOfPaymentsReceivablePerMedicineForMilestonePayments_lbl2">Maximum amount of payments receivable per medicine for milestone payments</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="MaximumAmountOfPaymentsReceivablePerMedicineForMilestonePayments" xlink:to="ions_MaximumAmountOfPaymentsReceivablePerMedicineForMilestonePayments_lbl2" xlink:title="label: MaximumAmountOfPaymentsReceivablePerMedicineForMilestonePayments to ions_MaximumAmountOfPaymentsReceivablePerMedicineForMilestonePayments_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_MedicinesForAmyotrophicLateralSclerosisMember" xlink:label="MedicinesForAmyotrophicLateralSclerosisMember" xlink:title="MedicinesForAmyotrophicLateralSclerosisMember" />
    <link:label xlink:type="resource" xlink:label="ions_MedicinesForAmyotrophicLateralSclerosisMember_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_MedicinesForAmyotrophicLateralSclerosisMember_lbl" xml:lang="en-US" id="ions_MedicinesForAmyotrophicLateralSclerosisMember_lbl">Medicines to treat amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease, a nervous system disease that weakens muscles and impacts physical function.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="MedicinesForAmyotrophicLateralSclerosisMember" xlink:to="ions_MedicinesForAmyotrophicLateralSclerosisMember_lbl" xlink:title="label: MedicinesForAmyotrophicLateralSclerosisMember to ions_MedicinesForAmyotrophicLateralSclerosisMember_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_MedicinesForAmyotrophicLateralSclerosisMember_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_MedicinesForAmyotrophicLateralSclerosisMember_lbl1" xml:lang="en-US" id="ions_MedicinesForAmyotrophicLateralSclerosisMember_lbl1">Medicines for Amyotrophic Lateral Sclerosis [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="MedicinesForAmyotrophicLateralSclerosisMember" xlink:to="ions_MedicinesForAmyotrophicLateralSclerosisMember_lbl1" xlink:title="label: MedicinesForAmyotrophicLateralSclerosisMember to ions_MedicinesForAmyotrophicLateralSclerosisMember_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_MedicinesForAmyotrophicLateralSclerosisMember_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_MedicinesForAmyotrophicLateralSclerosisMember_lbl2" xml:lang="en-US" id="ions_MedicinesForAmyotrophicLateralSclerosisMember_lbl2">Medicines for ALS [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="MedicinesForAmyotrophicLateralSclerosisMember" xlink:to="ions_MedicinesForAmyotrophicLateralSclerosisMember_lbl2" xlink:title="label: MedicinesForAmyotrophicLateralSclerosisMember to ions_MedicinesForAmyotrophicLateralSclerosisMember_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_TermOfExtensionStudy" xlink:label="TermOfExtensionStudy" xlink:title="TermOfExtensionStudy" />
    <link:label xlink:type="resource" xlink:label="ions_TermOfExtensionStudy_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_TermOfExtensionStudy_lbl" xml:lang="en-US" id="ions_TermOfExtensionStudy_lbl">Term of long-term open label extension study, in which patients participating in double blind placebo controlled trials of new medications are invited, on completion of the initial trial, to take the study drug for some further period, for example, 'P1Y5M13D' represents reported fact of one year, five months, and thirteen days.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="TermOfExtensionStudy" xlink:to="ions_TermOfExtensionStudy_lbl" xlink:title="label: TermOfExtensionStudy to ions_TermOfExtensionStudy_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_TermOfExtensionStudy_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_TermOfExtensionStudy_lbl1" xml:lang="en-US" id="ions_TermOfExtensionStudy_lbl1">Term of extension study</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="TermOfExtensionStudy" xlink:to="ions_TermOfExtensionStudy_lbl1" xlink:title="label: TermOfExtensionStudy to ions_TermOfExtensionStudy_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_TermOfExtensionStudy_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_TermOfExtensionStudy_lbl2" xml:lang="en-US" id="ions_TermOfExtensionStudy_lbl2">Term of extension study</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="TermOfExtensionStudy" xlink:to="ions_TermOfExtensionStudy_lbl2" xlink:title="label: TermOfExtensionStudy to ions_TermOfExtensionStudy_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_Ion582Member" xlink:label="Ion582Member" xlink:title="Ion582Member" />
    <link:label xlink:type="resource" xlink:label="ions_Ion582Member_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_Ion582Member_lbl" xml:lang="en-US" id="ions_Ion582Member_lbl">ION582 is an antisense investigational medicine that targets Ubiquitin Protein Ligase E3A-Antisense Transcript (UBE3A-ATS), which is a long non-coding ribonucleic acid (lncRNA).</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="Ion582Member" xlink:to="ions_Ion582Member_lbl" xlink:title="label: Ion582Member to ions_Ion582Member_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_Ion582Member_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_Ion582Member_lbl1" xml:lang="en-US" id="ions_Ion582Member_lbl1">Ion582 [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="Ion582Member" xlink:to="ions_Ion582Member_lbl1" xlink:title="label: Ion582Member to ions_Ion582Member_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_Ion582Member_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_Ion582Member_lbl2" xml:lang="en-US" id="ions_Ion582Member_lbl2">ION582 [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="Ion582Member" xlink:to="ions_Ion582Member_lbl2" xlink:title="label: Ion582Member to ions_Ion582Member_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_MedicinesForParkinsonsDiseaseMember" xlink:label="MedicinesForParkinsonsDiseaseMember" xlink:title="MedicinesForParkinsonsDiseaseMember" />
    <link:label xlink:type="resource" xlink:label="ions_MedicinesForParkinsonsDiseaseMember_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_MedicinesForParkinsonsDiseaseMember_lbl" xml:lang="en-US" id="ions_MedicinesForParkinsonsDiseaseMember_lbl">Medicines to treat Parkinson's disease, a disorder of the central nervous system that affects movement, often including tremors.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="MedicinesForParkinsonsDiseaseMember" xlink:to="ions_MedicinesForParkinsonsDiseaseMember_lbl" xlink:title="label: MedicinesForParkinsonsDiseaseMember to ions_MedicinesForParkinsonsDiseaseMember_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_MedicinesForParkinsonsDiseaseMember_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_MedicinesForParkinsonsDiseaseMember_lbl1" xml:lang="en-US" id="ions_MedicinesForParkinsonsDiseaseMember_lbl1">Medicines for Parkinson's Disease [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="MedicinesForParkinsonsDiseaseMember" xlink:to="ions_MedicinesForParkinsonsDiseaseMember_lbl1" xlink:title="label: MedicinesForParkinsonsDiseaseMember to ions_MedicinesForParkinsonsDiseaseMember_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_MedicinesForParkinsonsDiseaseMember_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_MedicinesForParkinsonsDiseaseMember_lbl2" xml:lang="en-US" id="ions_MedicinesForParkinsonsDiseaseMember_lbl2">Medicines for Parkinson's Disease [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="MedicinesForParkinsonsDiseaseMember" xlink:to="ions_MedicinesForParkinsonsDiseaseMember_lbl2" xlink:title="label: MedicinesForParkinsonsDiseaseMember to ions_MedicinesForParkinsonsDiseaseMember_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_MedicinesForMultipleSystemAtrophyMember" xlink:label="MedicinesForMultipleSystemAtrophyMember" xlink:title="MedicinesForMultipleSystemAtrophyMember" />
    <link:label xlink:type="resource" xlink:label="ions_MedicinesForMultipleSystemAtrophyMember_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_MedicinesForMultipleSystemAtrophyMember_lbl" xml:lang="en-US" id="ions_MedicinesForMultipleSystemAtrophyMember_lbl">Medicines to treat multiple system atrophy (MSA), a progressive neurodegenerative disorder characterized by a combination of symptoms that affect both the autonomic nervous system and movement.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="MedicinesForMultipleSystemAtrophyMember" xlink:to="ions_MedicinesForMultipleSystemAtrophyMember_lbl" xlink:title="label: MedicinesForMultipleSystemAtrophyMember to ions_MedicinesForMultipleSystemAtrophyMember_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_MedicinesForMultipleSystemAtrophyMember_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_MedicinesForMultipleSystemAtrophyMember_lbl1" xml:lang="en-US" id="ions_MedicinesForMultipleSystemAtrophyMember_lbl1">Medicines for Multiple System Atrophy [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="MedicinesForMultipleSystemAtrophyMember" xlink:to="ions_MedicinesForMultipleSystemAtrophyMember_lbl1" xlink:title="label: MedicinesForMultipleSystemAtrophyMember to ions_MedicinesForMultipleSystemAtrophyMember_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_MedicinesForMultipleSystemAtrophyMember_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_MedicinesForMultipleSystemAtrophyMember_lbl2" xml:lang="en-US" id="ions_MedicinesForMultipleSystemAtrophyMember_lbl2">Medicines for Multiple System Atrophy [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="MedicinesForMultipleSystemAtrophyMember" xlink:to="ions_MedicinesForMultipleSystemAtrophyMember_lbl2" xlink:title="label: MedicinesForMultipleSystemAtrophyMember to ions_MedicinesForMultipleSystemAtrophyMember_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_PercentageCashPremiumPaidOnSharesPurchased" xlink:label="PercentageCashPremiumPaidOnSharesPurchased" xlink:title="PercentageCashPremiumPaidOnSharesPurchased" />
    <link:label xlink:type="resource" xlink:label="ions_PercentageCashPremiumPaidOnSharesPurchased_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_PercentageCashPremiumPaidOnSharesPurchased_lbl" xml:lang="en-US" id="ions_PercentageCashPremiumPaidOnSharesPurchased_lbl">The percentage cash premium paid per share of the Company's common stock under the collaboration agreement.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="PercentageCashPremiumPaidOnSharesPurchased" xlink:to="ions_PercentageCashPremiumPaidOnSharesPurchased_lbl" xlink:title="label: PercentageCashPremiumPaidOnSharesPurchased to ions_PercentageCashPremiumPaidOnSharesPurchased_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_PercentageCashPremiumPaidOnSharesPurchased_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_PercentageCashPremiumPaidOnSharesPurchased_lbl1" xml:lang="en-US" id="ions_PercentageCashPremiumPaidOnSharesPurchased_lbl1">Percentage cash premium paid on shares purchased</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="PercentageCashPremiumPaidOnSharesPurchased" xlink:to="ions_PercentageCashPremiumPaidOnSharesPurchased_lbl1" xlink:title="label: PercentageCashPremiumPaidOnSharesPurchased to ions_PercentageCashPremiumPaidOnSharesPurchased_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_PercentageCashPremiumPaidOnSharesPurchased_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_PercentageCashPremiumPaidOnSharesPurchased_lbl2" xml:lang="en-US" id="ions_PercentageCashPremiumPaidOnSharesPurchased_lbl2">Percentage cash premium paid on shares purchased</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="PercentageCashPremiumPaidOnSharesPurchased" xlink:to="ions_PercentageCashPremiumPaidOnSharesPurchased_lbl2" xlink:title="label: PercentageCashPremiumPaidOnSharesPurchased to ions_PercentageCashPremiumPaidOnSharesPurchased_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_MaximumAmountOfPaymentsReceivableForLicenseFeesMilestonePaymentsAndOtherPayments" xlink:label="MaximumAmountOfPaymentsReceivableForLicenseFeesMilestonePaymentsAndOtherPayments" xlink:title="MaximumAmountOfPaymentsReceivableForLicenseFeesMilestonePaymentsAndOtherPayments" />
    <link:label xlink:type="resource" xlink:label="ions_MaximumAmountOfPaymentsReceivableForLicenseFeesMilestonePaymentsAndOtherPayments_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_MaximumAmountOfPaymentsReceivableForLicenseFeesMilestonePaymentsAndOtherPayments_lbl" xml:lang="en-US" id="ions_MaximumAmountOfPaymentsReceivableForLicenseFeesMilestonePaymentsAndOtherPayments_lbl">Maximum amount of payments receivable for license fees, milestone payments and other payments under the collaboration agreement.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="MaximumAmountOfPaymentsReceivableForLicenseFeesMilestonePaymentsAndOtherPayments" xlink:to="ions_MaximumAmountOfPaymentsReceivableForLicenseFeesMilestonePaymentsAndOtherPayments_lbl" xlink:title="label: MaximumAmountOfPaymentsReceivableForLicenseFeesMilestonePaymentsAndOtherPayments to ions_MaximumAmountOfPaymentsReceivableForLicenseFeesMilestonePaymentsAndOtherPayments_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_MaximumAmountOfPaymentsReceivableForLicenseFeesMilestonePaymentsAndOtherPayments_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_MaximumAmountOfPaymentsReceivableForLicenseFeesMilestonePaymentsAndOtherPayments_lbl1" xml:lang="en-US" id="ions_MaximumAmountOfPaymentsReceivableForLicenseFeesMilestonePaymentsAndOtherPayments_lbl1">Maximum amount of payments receivable for license fees, milestone payments and other payments</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="MaximumAmountOfPaymentsReceivableForLicenseFeesMilestonePaymentsAndOtherPayments" xlink:to="ions_MaximumAmountOfPaymentsReceivableForLicenseFeesMilestonePaymentsAndOtherPayments_lbl1" xlink:title="label: MaximumAmountOfPaymentsReceivableForLicenseFeesMilestonePaymentsAndOtherPayments to ions_MaximumAmountOfPaymentsReceivableForLicenseFeesMilestonePaymentsAndOtherPayments_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_MaximumAmountOfPaymentsReceivableForLicenseFeesMilestonePaymentsAndOtherPayments_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_MaximumAmountOfPaymentsReceivableForLicenseFeesMilestonePaymentsAndOtherPayments_lbl2" xml:lang="en-US" id="ions_MaximumAmountOfPaymentsReceivableForLicenseFeesMilestonePaymentsAndOtherPayments_lbl2">Maximum amount of payments receivable for license fees, milestone payments and other payments</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="MaximumAmountOfPaymentsReceivableForLicenseFeesMilestonePaymentsAndOtherPayments" xlink:to="ions_MaximumAmountOfPaymentsReceivableForLicenseFeesMilestonePaymentsAndOtherPayments_lbl2" xlink:title="label: MaximumAmountOfPaymentsReceivableForLicenseFeesMilestonePaymentsAndOtherPayments to ions_MaximumAmountOfPaymentsReceivableForLicenseFeesMilestonePaymentsAndOtherPayments_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_NumberOfMedicinesCurrentlyBeingAdvanced" xlink:label="NumberOfMedicinesCurrentlyBeingAdvanced" xlink:title="NumberOfMedicinesCurrentlyBeingAdvanced" />
    <link:label xlink:type="resource" xlink:label="ions_NumberOfMedicinesCurrentlyBeingAdvanced_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_NumberOfMedicinesCurrentlyBeingAdvanced_lbl" xml:lang="en-US" id="ions_NumberOfMedicinesCurrentlyBeingAdvanced_lbl">The number of medicines currently being advanced under the collaboration agreement.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="NumberOfMedicinesCurrentlyBeingAdvanced" xlink:to="ions_NumberOfMedicinesCurrentlyBeingAdvanced_lbl" xlink:title="label: NumberOfMedicinesCurrentlyBeingAdvanced to ions_NumberOfMedicinesCurrentlyBeingAdvanced_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_NumberOfMedicinesCurrentlyBeingAdvanced_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_NumberOfMedicinesCurrentlyBeingAdvanced_lbl1" xml:lang="en-US" id="ions_NumberOfMedicinesCurrentlyBeingAdvanced_lbl1">Number of medicines currently being advanced</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="NumberOfMedicinesCurrentlyBeingAdvanced" xlink:to="ions_NumberOfMedicinesCurrentlyBeingAdvanced_lbl1" xlink:title="label: NumberOfMedicinesCurrentlyBeingAdvanced to ions_NumberOfMedicinesCurrentlyBeingAdvanced_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_NumberOfMedicinesCurrentlyBeingAdvanced_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_NumberOfMedicinesCurrentlyBeingAdvanced_lbl2" xml:lang="en-US" id="ions_NumberOfMedicinesCurrentlyBeingAdvanced_lbl2">Number of medicines currently being advanced</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="NumberOfMedicinesCurrentlyBeingAdvanced" xlink:to="ions_NumberOfMedicinesCurrentlyBeingAdvanced_lbl2" xlink:title="label: NumberOfMedicinesCurrentlyBeingAdvanced to ions_NumberOfMedicinesCurrentlyBeingAdvanced_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_PremiumPaidOnSharesPurchased" xlink:label="PremiumPaidOnSharesPurchased" xlink:title="PremiumPaidOnSharesPurchased" />
    <link:label xlink:type="resource" xlink:label="ions_PremiumPaidOnSharesPurchased_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_PremiumPaidOnSharesPurchased_lbl" xml:lang="en-US" id="ions_PremiumPaidOnSharesPurchased_lbl">The cash premium paid on the purchase of the Company's common stock under the collaboration agreement.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="PremiumPaidOnSharesPurchased" xlink:to="ions_PremiumPaidOnSharesPurchased_lbl" xlink:title="label: PremiumPaidOnSharesPurchased to ions_PremiumPaidOnSharesPurchased_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_PremiumPaidOnSharesPurchased_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_PremiumPaidOnSharesPurchased_lbl1" xml:lang="en-US" id="ions_PremiumPaidOnSharesPurchased_lbl1">Premium paid on shares purchased</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="PremiumPaidOnSharesPurchased" xlink:to="ions_PremiumPaidOnSharesPurchased_lbl1" xlink:title="label: PremiumPaidOnSharesPurchased to ions_PremiumPaidOnSharesPurchased_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_PremiumPaidOnSharesPurchased_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_PremiumPaidOnSharesPurchased_lbl2" xml:lang="en-US" id="ions_PremiumPaidOnSharesPurchased_lbl2">Premium paid on shares purchased</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="PremiumPaidOnSharesPurchased" xlink:to="ions_PremiumPaidOnSharesPurchased_lbl2" xlink:title="label: PremiumPaidOnSharesPurchased to ions_PremiumPaidOnSharesPurchased_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_MaximumAmountOfPaymentsReceivablePerProgramForDevelopmentMilestones" xlink:label="MaximumAmountOfPaymentsReceivablePerProgramForDevelopmentMilestones" xlink:title="MaximumAmountOfPaymentsReceivablePerProgramForDevelopmentMilestones" />
    <link:label xlink:type="resource" xlink:label="ions_MaximumAmountOfPaymentsReceivablePerProgramForDevelopmentMilestones_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_MaximumAmountOfPaymentsReceivablePerProgramForDevelopmentMilestones_lbl" xml:lang="en-US" id="ions_MaximumAmountOfPaymentsReceivablePerProgramForDevelopmentMilestones_lbl">The maximum amount of payments receivable per program for development milestone payments under the collaboration agreement.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="MaximumAmountOfPaymentsReceivablePerProgramForDevelopmentMilestones" xlink:to="ions_MaximumAmountOfPaymentsReceivablePerProgramForDevelopmentMilestones_lbl" xlink:title="label: MaximumAmountOfPaymentsReceivablePerProgramForDevelopmentMilestones to ions_MaximumAmountOfPaymentsReceivablePerProgramForDevelopmentMilestones_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_MaximumAmountOfPaymentsReceivablePerProgramForDevelopmentMilestones_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_MaximumAmountOfPaymentsReceivablePerProgramForDevelopmentMilestones_lbl1" xml:lang="en-US" id="ions_MaximumAmountOfPaymentsReceivablePerProgramForDevelopmentMilestones_lbl1">Maximum amount of payments receivable per program for development milestones</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="MaximumAmountOfPaymentsReceivablePerProgramForDevelopmentMilestones" xlink:to="ions_MaximumAmountOfPaymentsReceivablePerProgramForDevelopmentMilestones_lbl1" xlink:title="label: MaximumAmountOfPaymentsReceivablePerProgramForDevelopmentMilestones to ions_MaximumAmountOfPaymentsReceivablePerProgramForDevelopmentMilestones_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_MaximumAmountOfPaymentsReceivablePerProgramForDevelopmentMilestones_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_MaximumAmountOfPaymentsReceivablePerProgramForDevelopmentMilestones_lbl2" xml:lang="en-US" id="ions_MaximumAmountOfPaymentsReceivablePerProgramForDevelopmentMilestones_lbl2">Maximum amount of payments receivable per program for development milestones</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="MaximumAmountOfPaymentsReceivablePerProgramForDevelopmentMilestones" xlink:to="ions_MaximumAmountOfPaymentsReceivablePerProgramForDevelopmentMilestones_lbl2" xlink:title="label: MaximumAmountOfPaymentsReceivablePerProgramForDevelopmentMilestones to ions_MaximumAmountOfPaymentsReceivablePerProgramForDevelopmentMilestones_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_NumberOfProgramsUnderWhichMedicinesAreToBeDevelopedAndCommercialized" xlink:label="NumberOfProgramsUnderWhichMedicinesAreToBeDevelopedAndCommercialized" xlink:title="NumberOfProgramsUnderWhichMedicinesAreToBeDevelopedAndCommercialized" />
    <link:label xlink:type="resource" xlink:label="ions_NumberOfProgramsUnderWhichMedicinesAreToBeDevelopedAndCommercialized_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_NumberOfProgramsUnderWhichMedicinesAreToBeDevelopedAndCommercialized_lbl" xml:lang="en-US" id="ions_NumberOfProgramsUnderWhichMedicinesAreToBeDevelopedAndCommercialized_lbl">The number of programs under which medicines are to be developed and commercialized under the collaboration agreement.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="NumberOfProgramsUnderWhichMedicinesAreToBeDevelopedAndCommercialized" xlink:to="ions_NumberOfProgramsUnderWhichMedicinesAreToBeDevelopedAndCommercialized_lbl" xlink:title="label: NumberOfProgramsUnderWhichMedicinesAreToBeDevelopedAndCommercialized to ions_NumberOfProgramsUnderWhichMedicinesAreToBeDevelopedAndCommercialized_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_NumberOfProgramsUnderWhichMedicinesAreToBeDevelopedAndCommercialized_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_NumberOfProgramsUnderWhichMedicinesAreToBeDevelopedAndCommercialized_lbl1" xml:lang="en-US" id="ions_NumberOfProgramsUnderWhichMedicinesAreToBeDevelopedAndCommercialized_lbl1">Number of programs under which medicines are to be developed and commercialized</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="NumberOfProgramsUnderWhichMedicinesAreToBeDevelopedAndCommercialized" xlink:to="ions_NumberOfProgramsUnderWhichMedicinesAreToBeDevelopedAndCommercialized_lbl1" xlink:title="label: NumberOfProgramsUnderWhichMedicinesAreToBeDevelopedAndCommercialized to ions_NumberOfProgramsUnderWhichMedicinesAreToBeDevelopedAndCommercialized_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_NumberOfProgramsUnderWhichMedicinesAreToBeDevelopedAndCommercialized_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_NumberOfProgramsUnderWhichMedicinesAreToBeDevelopedAndCommercialized_lbl2" xml:lang="en-US" id="ions_NumberOfProgramsUnderWhichMedicinesAreToBeDevelopedAndCommercialized_lbl2">Number of programs under which medicines are to be developed and commercialized</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="NumberOfProgramsUnderWhichMedicinesAreToBeDevelopedAndCommercialized" xlink:to="ions_NumberOfProgramsUnderWhichMedicinesAreToBeDevelopedAndCommercialized_lbl2" xlink:title="label: NumberOfProgramsUnderWhichMedicinesAreToBeDevelopedAndCommercialized to ions_NumberOfProgramsUnderWhichMedicinesAreToBeDevelopedAndCommercialized_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_AntisenseMoleculeMember" xlink:label="AntisenseMoleculeMember" xlink:title="AntisenseMoleculeMember" />
    <link:label xlink:type="resource" xlink:label="ions_AntisenseMoleculeMember_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_AntisenseMoleculeMember_lbl" xml:lang="en-US" id="ions_AntisenseMoleculeMember_lbl">Each antisense molecule that is chosen for drug discovery and development to advance the treatment of neurological diseases.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="AntisenseMoleculeMember" xlink:to="ions_AntisenseMoleculeMember_lbl" xlink:title="label: AntisenseMoleculeMember to ions_AntisenseMoleculeMember_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_AntisenseMoleculeMember_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_AntisenseMoleculeMember_lbl1" xml:lang="en-US" id="ions_AntisenseMoleculeMember_lbl1">Antisense Molecule [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="AntisenseMoleculeMember" xlink:to="ions_AntisenseMoleculeMember_lbl1" xlink:title="label: AntisenseMoleculeMember to ions_AntisenseMoleculeMember_lbl1" />
    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_UpfrontPaymentReceivedIncludingPurchaseOfStock" xlink:label="UpfrontPaymentReceivedIncludingPurchaseOfStock" xlink:title="UpfrontPaymentReceivedIncludingPurchaseOfStock" />
    <link:label xlink:type="resource" xlink:label="ions_UpfrontPaymentReceivedIncludingPurchaseOfStock_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_UpfrontPaymentReceivedIncludingPurchaseOfStock_lbl" xml:lang="en-US" id="ions_UpfrontPaymentReceivedIncludingPurchaseOfStock_lbl">The total amount of the upfront payment received, including the purchase of shares of the Company's stock, under the collaboration agreement.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="UpfrontPaymentReceivedIncludingPurchaseOfStock" xlink:to="ions_UpfrontPaymentReceivedIncludingPurchaseOfStock_lbl" xlink:title="label: UpfrontPaymentReceivedIncludingPurchaseOfStock to ions_UpfrontPaymentReceivedIncludingPurchaseOfStock_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_UpfrontPaymentReceivedIncludingPurchaseOfStock_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_UpfrontPaymentReceivedIncludingPurchaseOfStock_lbl1" xml:lang="en-US" id="ions_UpfrontPaymentReceivedIncludingPurchaseOfStock_lbl1">Upfront payment received, including purchase of stock</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="UpfrontPaymentReceivedIncludingPurchaseOfStock" xlink:to="ions_UpfrontPaymentReceivedIncludingPurchaseOfStock_lbl1" xlink:title="label: UpfrontPaymentReceivedIncludingPurchaseOfStock to ions_UpfrontPaymentReceivedIncludingPurchaseOfStock_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_UpfrontPaymentReceivedIncludingPurchaseOfStock_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_UpfrontPaymentReceivedIncludingPurchaseOfStock_lbl2" xml:lang="en-US" id="ions_UpfrontPaymentReceivedIncludingPurchaseOfStock_lbl2">Upfront payment received, including purchase of stock</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="UpfrontPaymentReceivedIncludingPurchaseOfStock" xlink:to="ions_UpfrontPaymentReceivedIncludingPurchaseOfStock_lbl2" xlink:title="label: UpfrontPaymentReceivedIncludingPurchaseOfStock to ions_UpfrontPaymentReceivedIncludingPurchaseOfStock_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_MaximumAmountOfPaymentsReceivablePerProgramForLicenseFeesAndSubstantiveMilestonePayments" xlink:label="MaximumAmountOfPaymentsReceivablePerProgramForLicenseFeesAndSubstantiveMilestonePayments" xlink:title="MaximumAmountOfPaymentsReceivablePerProgramForLicenseFeesAndSubstantiveMilestonePayments" />
    <link:label xlink:type="resource" xlink:label="ions_MaximumAmountOfPaymentsReceivablePerProgramForLicenseFeesAndSubstantiveMilestonePayments_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_MaximumAmountOfPaymentsReceivablePerProgramForLicenseFeesAndSubstantiveMilestonePayments_lbl" xml:lang="en-US" id="ions_MaximumAmountOfPaymentsReceivablePerProgramForLicenseFeesAndSubstantiveMilestonePayments_lbl">The maximum amount of payments receivable per program for license fees and/or substantive milestone payments under the collaboration agreement.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="MaximumAmountOfPaymentsReceivablePerProgramForLicenseFeesAndSubstantiveMilestonePayments" xlink:to="ions_MaximumAmountOfPaymentsReceivablePerProgramForLicenseFeesAndSubstantiveMilestonePayments_lbl" xlink:title="label: MaximumAmountOfPaymentsReceivablePerProgramForLicenseFeesAndSubstantiveMilestonePayments to ions_MaximumAmountOfPaymentsReceivablePerProgramForLicenseFeesAndSubstantiveMilestonePayments_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_MaximumAmountOfPaymentsReceivablePerProgramForLicenseFeesAndSubstantiveMilestonePayments_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_MaximumAmountOfPaymentsReceivablePerProgramForLicenseFeesAndSubstantiveMilestonePayments_lbl1" xml:lang="en-US" id="ions_MaximumAmountOfPaymentsReceivablePerProgramForLicenseFeesAndSubstantiveMilestonePayments_lbl1">Maximum amount of payments receivable per program for license fees and substantive milestone payments</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="MaximumAmountOfPaymentsReceivablePerProgramForLicenseFeesAndSubstantiveMilestonePayments" xlink:to="ions_MaximumAmountOfPaymentsReceivablePerProgramForLicenseFeesAndSubstantiveMilestonePayments_lbl1" xlink:title="label: MaximumAmountOfPaymentsReceivablePerProgramForLicenseFeesAndSubstantiveMilestonePayments to ions_MaximumAmountOfPaymentsReceivablePerProgramForLicenseFeesAndSubstantiveMilestonePayments_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_MaximumAmountOfPaymentsReceivablePerProgramForLicenseFeesAndSubstantiveMilestonePayments_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_MaximumAmountOfPaymentsReceivablePerProgramForLicenseFeesAndSubstantiveMilestonePayments_lbl2" xml:lang="en-US" id="ions_MaximumAmountOfPaymentsReceivablePerProgramForLicenseFeesAndSubstantiveMilestonePayments_lbl2">Maximum amount of payments receivable per program for license fee and milestone payments</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="MaximumAmountOfPaymentsReceivablePerProgramForLicenseFeesAndSubstantiveMilestonePayments" xlink:to="ions_MaximumAmountOfPaymentsReceivablePerProgramForLicenseFeesAndSubstantiveMilestonePayments_lbl2" xlink:title="label: MaximumAmountOfPaymentsReceivablePerProgramForLicenseFeesAndSubstantiveMilestonePayments to ions_MaximumAmountOfPaymentsReceivablePerProgramForLicenseFeesAndSubstantiveMilestonePayments_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_BiogenCollaboration2012NeurologyMember" xlink:label="BiogenCollaboration2012NeurologyMember" xlink:title="BiogenCollaboration2012NeurologyMember" />
    <link:label xlink:type="resource" xlink:label="ions_BiogenCollaboration2012NeurologyMember_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_BiogenCollaboration2012NeurologyMember_lbl" xml:lang="en-US" id="ions_BiogenCollaboration2012NeurologyMember_lbl">Collaborative agreement entered into with Biogen Inc. in December 2012 focused on developing and commercializing novel antisense drugs for up to three targets to treat neurological or neuromuscular diseases.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="BiogenCollaboration2012NeurologyMember" xlink:to="ions_BiogenCollaboration2012NeurologyMember_lbl" xlink:title="label: BiogenCollaboration2012NeurologyMember to ions_BiogenCollaboration2012NeurologyMember_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_BiogenCollaboration2012NeurologyMember_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_BiogenCollaboration2012NeurologyMember_lbl1" xml:lang="en-US" id="ions_BiogenCollaboration2012NeurologyMember_lbl1">Biogen Collaboration, 2012 Neurology [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="BiogenCollaboration2012NeurologyMember" xlink:to="ions_BiogenCollaboration2012NeurologyMember_lbl1" xlink:title="label: BiogenCollaboration2012NeurologyMember to ions_BiogenCollaboration2012NeurologyMember_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_BiogenCollaboration2012NeurologyMember_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_BiogenCollaboration2012NeurologyMember_lbl2" xml:lang="en-US" id="ions_BiogenCollaboration2012NeurologyMember_lbl2">2012 Neurology [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="BiogenCollaboration2012NeurologyMember" xlink:to="ions_BiogenCollaboration2012NeurologyMember_lbl2" xlink:title="label: BiogenCollaboration2012NeurologyMember to ions_BiogenCollaboration2012NeurologyMember_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_BiogenCollaboration2018StrategicNeurologyMember" xlink:label="BiogenCollaboration2018StrategicNeurologyMember" xlink:title="BiogenCollaboration2018StrategicNeurologyMember" />
    <link:label xlink:type="resource" xlink:label="ions_BiogenCollaboration2018StrategicNeurologyMember_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_BiogenCollaboration2018StrategicNeurologyMember_lbl" xml:lang="en-US" id="ions_BiogenCollaboration2018StrategicNeurologyMember_lbl">Collaboration agreement entered into with Biogen Inc. in April 2018 to develop novel antisense drug candidates for a broad range of neurological diseases.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="BiogenCollaboration2018StrategicNeurologyMember" xlink:to="ions_BiogenCollaboration2018StrategicNeurologyMember_lbl" xlink:title="label: BiogenCollaboration2018StrategicNeurologyMember to ions_BiogenCollaboration2018StrategicNeurologyMember_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_BiogenCollaboration2018StrategicNeurologyMember_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_BiogenCollaboration2018StrategicNeurologyMember_lbl1" xml:lang="en-US" id="ions_BiogenCollaboration2018StrategicNeurologyMember_lbl1">Biogen Collaboration, 2018 Strategic Neurology [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="BiogenCollaboration2018StrategicNeurologyMember" xlink:to="ions_BiogenCollaboration2018StrategicNeurologyMember_lbl1" xlink:title="label: BiogenCollaboration2018StrategicNeurologyMember to ions_BiogenCollaboration2018StrategicNeurologyMember_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_BiogenCollaboration2018StrategicNeurologyMember_lbl2" xlink:role="http://www.xbrl.org/2003/role/verboseLabel" xlink:title="ions_BiogenCollaboration2018StrategicNeurologyMember_lbl2" xml:lang="en-US" id="ions_BiogenCollaboration2018StrategicNeurologyMember_lbl2">Biogen 2018 Strategic Neurology [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="BiogenCollaboration2018StrategicNeurologyMember" xlink:to="ions_BiogenCollaboration2018StrategicNeurologyMember_lbl2" xlink:title="label: BiogenCollaboration2018StrategicNeurologyMember to ions_BiogenCollaboration2018StrategicNeurologyMember_lbl2" />
    <link:label xlink:type="resource" xlink:label="ions_BiogenCollaboration2018StrategicNeurologyMember_lbl3" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_BiogenCollaboration2018StrategicNeurologyMember_lbl3" xml:lang="en-US" id="ions_BiogenCollaboration2018StrategicNeurologyMember_lbl3">2018 Strategic Neurology [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="BiogenCollaboration2018StrategicNeurologyMember" xlink:to="ions_BiogenCollaboration2018StrategicNeurologyMember_lbl3" xlink:title="label: BiogenCollaboration2018StrategicNeurologyMember to ions_BiogenCollaboration2018StrategicNeurologyMember_lbl3" />
    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_BiogenCollaboration2013StrategicNeurologyMember" xlink:label="BiogenCollaboration2013StrategicNeurologyMember" xlink:title="BiogenCollaboration2013StrategicNeurologyMember" />
    <link:label xlink:type="resource" xlink:label="ions_BiogenCollaboration2013StrategicNeurologyMember_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_BiogenCollaboration2013StrategicNeurologyMember_lbl" xml:lang="en-US" id="ions_BiogenCollaboration2013StrategicNeurologyMember_lbl">Collaborative agreement entered into with Biogen Inc. in September 2013 focused on applying antisense technology to advance the treatment of neurodegenerative diseases.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="BiogenCollaboration2013StrategicNeurologyMember" xlink:to="ions_BiogenCollaboration2013StrategicNeurologyMember_lbl" xlink:title="label: BiogenCollaboration2013StrategicNeurologyMember to ions_BiogenCollaboration2013StrategicNeurologyMember_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_BiogenCollaboration2013StrategicNeurologyMember_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_BiogenCollaboration2013StrategicNeurologyMember_lbl1" xml:lang="en-US" id="ions_BiogenCollaboration2013StrategicNeurologyMember_lbl1">Biogen Collaboration, 2013 Strategic Neurology [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="BiogenCollaboration2013StrategicNeurologyMember" xlink:to="ions_BiogenCollaboration2013StrategicNeurologyMember_lbl1" xlink:title="label: BiogenCollaboration2013StrategicNeurologyMember to ions_BiogenCollaboration2013StrategicNeurologyMember_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_BiogenCollaboration2013StrategicNeurologyMember_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_BiogenCollaboration2013StrategicNeurologyMember_lbl2" xml:lang="en-US" id="ions_BiogenCollaboration2013StrategicNeurologyMember_lbl2">2013 Strategic Neurology [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="BiogenCollaboration2013StrategicNeurologyMember" xlink:to="ions_BiogenCollaboration2013StrategicNeurologyMember_lbl2" xlink:title="label: BiogenCollaboration2013StrategicNeurologyMember to ions_BiogenCollaboration2013StrategicNeurologyMember_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_BiogenCollaborationSpinrazaMember" xlink:label="BiogenCollaborationSpinrazaMember" xlink:title="BiogenCollaborationSpinrazaMember" />
    <link:label xlink:type="resource" xlink:label="ions_BiogenCollaborationSpinrazaMember_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_BiogenCollaborationSpinrazaMember_lbl" xml:lang="en-US" id="ions_BiogenCollaborationSpinrazaMember_lbl">Collaboration agreement entered into with Biogen Inc. in January 2012 to develop and commercialize nusinersen for the treatment of spinal muscular atrophy, or SMA, a severe motor-neuron disease that is the leading genetic cause of infant mortality.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="BiogenCollaborationSpinrazaMember" xlink:to="ions_BiogenCollaborationSpinrazaMember_lbl" xlink:title="label: BiogenCollaborationSpinrazaMember to ions_BiogenCollaborationSpinrazaMember_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_BiogenCollaborationSpinrazaMember_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_BiogenCollaborationSpinrazaMember_lbl1" xml:lang="en-US" id="ions_BiogenCollaborationSpinrazaMember_lbl1">Biogen Collaboration, Spinraza [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="BiogenCollaborationSpinrazaMember" xlink:to="ions_BiogenCollaborationSpinrazaMember_lbl1" xlink:title="label: BiogenCollaborationSpinrazaMember to ions_BiogenCollaborationSpinrazaMember_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_BiogenCollaborationSpinrazaMember_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_BiogenCollaborationSpinrazaMember_lbl2" xml:lang="en-US" id="ions_BiogenCollaborationSpinrazaMember_lbl2">SPINRAZA [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="BiogenCollaborationSpinrazaMember" xlink:to="ions_BiogenCollaborationSpinrazaMember_lbl2" xlink:title="label: BiogenCollaborationSpinrazaMember to ions_BiogenCollaborationSpinrazaMember_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_BiogenCollaborationNewAntisenseMedicinesForTreatmentOfSmaMember" xlink:label="BiogenCollaborationNewAntisenseMedicinesForTreatmentOfSmaMember" xlink:title="BiogenCollaborationNewAntisenseMedicinesForTreatmentOfSmaMember" />
    <link:label xlink:type="resource" xlink:label="ions_BiogenCollaborationNewAntisenseMedicinesForTreatmentOfSmaMember_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_BiogenCollaborationNewAntisenseMedicinesForTreatmentOfSmaMember_lbl" xml:lang="en-US" id="ions_BiogenCollaborationNewAntisenseMedicinesForTreatmentOfSmaMember_lbl">Collaboration agreement entered into with Biogen Inc. in December 2017 to identify new antisense oligonucleotide drug candidates for the treatment of spinal muscular atrophy, or SMA.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="BiogenCollaborationNewAntisenseMedicinesForTreatmentOfSmaMember" xlink:to="ions_BiogenCollaborationNewAntisenseMedicinesForTreatmentOfSmaMember_lbl" xlink:title="label: BiogenCollaborationNewAntisenseMedicinesForTreatmentOfSmaMember to ions_BiogenCollaborationNewAntisenseMedicinesForTreatmentOfSmaMember_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_BiogenCollaborationNewAntisenseMedicinesForTreatmentOfSmaMember_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_BiogenCollaborationNewAntisenseMedicinesForTreatmentOfSmaMember_lbl1" xml:lang="en-US" id="ions_BiogenCollaborationNewAntisenseMedicinesForTreatmentOfSmaMember_lbl1">Biogen Collaboration, New Antisense Medicines for Treatment of SMA [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="BiogenCollaborationNewAntisenseMedicinesForTreatmentOfSmaMember" xlink:to="ions_BiogenCollaborationNewAntisenseMedicinesForTreatmentOfSmaMember_lbl1" xlink:title="label: BiogenCollaborationNewAntisenseMedicinesForTreatmentOfSmaMember to ions_BiogenCollaborationNewAntisenseMedicinesForTreatmentOfSmaMember_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_BiogenCollaborationNewAntisenseMedicinesForTreatmentOfSmaMember_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_BiogenCollaborationNewAntisenseMedicinesForTreatmentOfSmaMember_lbl2" xml:lang="en-US" id="ions_BiogenCollaborationNewAntisenseMedicinesForTreatmentOfSmaMember_lbl2">New Antisense Medicines for the Treatment of SMA [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="BiogenCollaborationNewAntisenseMedicinesForTreatmentOfSmaMember" xlink:to="ions_BiogenCollaborationNewAntisenseMedicinesForTreatmentOfSmaMember_lbl2" xlink:title="label: BiogenCollaborationNewAntisenseMedicinesForTreatmentOfSmaMember to ions_BiogenCollaborationNewAntisenseMedicinesForTreatmentOfSmaMember_lbl2" />
    <link:label xlink:type="resource" xlink:label="ions_BiogenCollaborationNewAntisenseMedicinesForTreatmentOfSmaMember_lbl3" xlink:role="http://www.xbrl.org/2003/role/verboseLabel" xlink:title="ions_BiogenCollaborationNewAntisenseMedicinesForTreatmentOfSmaMember_lbl3" xml:lang="en-US" id="ions_BiogenCollaborationNewAntisenseMedicinesForTreatmentOfSmaMember_lbl3">Biogen Treatment of SMA [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="BiogenCollaborationNewAntisenseMedicinesForTreatmentOfSmaMember" xlink:to="ions_BiogenCollaborationNewAntisenseMedicinesForTreatmentOfSmaMember_lbl3" xlink:title="label: BiogenCollaborationNewAntisenseMedicinesForTreatmentOfSmaMember to ions_BiogenCollaborationNewAntisenseMedicinesForTreatmentOfSmaMember_lbl3" />
    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_TermOfCollaborationAgreement" xlink:label="TermOfCollaborationAgreement" xlink:title="TermOfCollaborationAgreement" />
    <link:label xlink:type="resource" xlink:label="ions_TermOfCollaborationAgreement_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_TermOfCollaborationAgreement_lbl" xml:lang="en-US" id="ions_TermOfCollaborationAgreement_lbl">Term of the collaboration agreement, in 'PnYnMnDTnHnMnS' format, for example, 'P1Y5M13D' represents the reported fact of one year, five months, and thirteen days.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="TermOfCollaborationAgreement" xlink:to="ions_TermOfCollaborationAgreement_lbl" xlink:title="label: TermOfCollaborationAgreement to ions_TermOfCollaborationAgreement_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_TermOfCollaborationAgreement_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_TermOfCollaborationAgreement_lbl1" xml:lang="en-US" id="ions_TermOfCollaborationAgreement_lbl1">Term of collaboration agreement</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="TermOfCollaborationAgreement" xlink:to="ions_TermOfCollaborationAgreement_lbl1" xlink:title="label: TermOfCollaborationAgreement to ions_TermOfCollaborationAgreement_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_TermOfCollaborationAgreement_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_TermOfCollaborationAgreement_lbl2" xml:lang="en-US" id="ions_TermOfCollaborationAgreement_lbl2">Term of collaboration agreement</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="TermOfCollaborationAgreement" xlink:to="ions_TermOfCollaborationAgreement_lbl2" xlink:title="label: TermOfCollaborationAgreement to ions_TermOfCollaborationAgreement_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_CumulativePaymentsIncludedInTransactionPriceForPerformanceObligation" xlink:label="CumulativePaymentsIncludedInTransactionPriceForPerformanceObligation" xlink:title="CumulativePaymentsIncludedInTransactionPriceForPerformanceObligation" />
    <link:label xlink:type="resource" xlink:label="ions_CumulativePaymentsIncludedInTransactionPriceForPerformanceObligation_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_CumulativePaymentsIncludedInTransactionPriceForPerformanceObligation_lbl" xml:lang="en-US" id="ions_CumulativePaymentsIncludedInTransactionPriceForPerformanceObligation_lbl">Cumulative payments received since inception of the collaboration agreement included in the transaction price for the performance obligation.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="CumulativePaymentsIncludedInTransactionPriceForPerformanceObligation" xlink:to="ions_CumulativePaymentsIncludedInTransactionPriceForPerformanceObligation_lbl" xlink:title="label: CumulativePaymentsIncludedInTransactionPriceForPerformanceObligation to ions_CumulativePaymentsIncludedInTransactionPriceForPerformanceObligation_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_CumulativePaymentsIncludedInTransactionPriceForPerformanceObligation_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_CumulativePaymentsIncludedInTransactionPriceForPerformanceObligation_lbl1" xml:lang="en-US" id="ions_CumulativePaymentsIncludedInTransactionPriceForPerformanceObligation_lbl1">Cumulative payments included in transaction price for performance obligation</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="CumulativePaymentsIncludedInTransactionPriceForPerformanceObligation" xlink:to="ions_CumulativePaymentsIncludedInTransactionPriceForPerformanceObligation_lbl1" xlink:title="label: CumulativePaymentsIncludedInTransactionPriceForPerformanceObligation to ions_CumulativePaymentsIncludedInTransactionPriceForPerformanceObligation_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_CumulativePaymentsIncludedInTransactionPriceForPerformanceObligation_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_CumulativePaymentsIncludedInTransactionPriceForPerformanceObligation_lbl2" xml:lang="en-US" id="ions_CumulativePaymentsIncludedInTransactionPriceForPerformanceObligation_lbl2">Cumulative payments included in transaction price for performance obligation</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="CumulativePaymentsIncludedInTransactionPriceForPerformanceObligation" xlink:to="ions_CumulativePaymentsIncludedInTransactionPriceForPerformanceObligation_lbl2" xlink:title="label: CumulativePaymentsIncludedInTransactionPriceForPerformanceObligation to ions_CumulativePaymentsIncludedInTransactionPriceForPerformanceObligation_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_NumberOfMedicinesBeingDeveloped" xlink:label="NumberOfMedicinesBeingDeveloped" xlink:title="NumberOfMedicinesBeingDeveloped" />
    <link:label xlink:type="resource" xlink:label="ions_NumberOfMedicinesBeingDeveloped_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_NumberOfMedicinesBeingDeveloped_lbl" xml:lang="en-US" id="ions_NumberOfMedicinesBeingDeveloped_lbl">The number of medicines currently being developed under the collaboration agreement(s).</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="NumberOfMedicinesBeingDeveloped" xlink:to="ions_NumberOfMedicinesBeingDeveloped_lbl" xlink:title="label: NumberOfMedicinesBeingDeveloped to ions_NumberOfMedicinesBeingDeveloped_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_NumberOfMedicinesBeingDeveloped_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_NumberOfMedicinesBeingDeveloped_lbl1" xml:lang="en-US" id="ions_NumberOfMedicinesBeingDeveloped_lbl1">Number of medicines being developed</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="NumberOfMedicinesBeingDeveloped" xlink:to="ions_NumberOfMedicinesBeingDeveloped_lbl1" xlink:title="label: NumberOfMedicinesBeingDeveloped to ions_NumberOfMedicinesBeingDeveloped_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_NumberOfMedicinesBeingDeveloped_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_NumberOfMedicinesBeingDeveloped_lbl2" xml:lang="en-US" id="ions_NumberOfMedicinesBeingDeveloped_lbl2">Number of medicines currently being developed</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="NumberOfMedicinesBeingDeveloped" xlink:to="ions_NumberOfMedicinesBeingDeveloped_lbl2" xlink:title="label: NumberOfMedicinesBeingDeveloped to ions_NumberOfMedicinesBeingDeveloped_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_MaximumAmountOfPaymentsReceivablePerProgramForRegulatoryMilestones" xlink:label="MaximumAmountOfPaymentsReceivablePerProgramForRegulatoryMilestones" xlink:title="MaximumAmountOfPaymentsReceivablePerProgramForRegulatoryMilestones" />
    <link:label xlink:type="resource" xlink:label="ions_MaximumAmountOfPaymentsReceivablePerProgramForRegulatoryMilestones_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_MaximumAmountOfPaymentsReceivablePerProgramForRegulatoryMilestones_lbl" xml:lang="en-US" id="ions_MaximumAmountOfPaymentsReceivablePerProgramForRegulatoryMilestones_lbl">The maximum amount of payments receivable per program for regulatory milestone payments under the collaboration agreement.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="MaximumAmountOfPaymentsReceivablePerProgramForRegulatoryMilestones" xlink:to="ions_MaximumAmountOfPaymentsReceivablePerProgramForRegulatoryMilestones_lbl" xlink:title="label: MaximumAmountOfPaymentsReceivablePerProgramForRegulatoryMilestones to ions_MaximumAmountOfPaymentsReceivablePerProgramForRegulatoryMilestones_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_MaximumAmountOfPaymentsReceivablePerProgramForRegulatoryMilestones_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_MaximumAmountOfPaymentsReceivablePerProgramForRegulatoryMilestones_lbl1" xml:lang="en-US" id="ions_MaximumAmountOfPaymentsReceivablePerProgramForRegulatoryMilestones_lbl1">Maximum amount of payments receivable per program for regulatory milestones</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="MaximumAmountOfPaymentsReceivablePerProgramForRegulatoryMilestones" xlink:to="ions_MaximumAmountOfPaymentsReceivablePerProgramForRegulatoryMilestones_lbl1" xlink:title="label: MaximumAmountOfPaymentsReceivablePerProgramForRegulatoryMilestones to ions_MaximumAmountOfPaymentsReceivablePerProgramForRegulatoryMilestones_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_MaximumAmountOfPaymentsReceivablePerProgramForRegulatoryMilestones_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_MaximumAmountOfPaymentsReceivablePerProgramForRegulatoryMilestones_lbl2" xml:lang="en-US" id="ions_MaximumAmountOfPaymentsReceivablePerProgramForRegulatoryMilestones_lbl2">Maximum amount of payments receivable per program for regulatory milestones</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="MaximumAmountOfPaymentsReceivablePerProgramForRegulatoryMilestones" xlink:to="ions_MaximumAmountOfPaymentsReceivablePerProgramForRegulatoryMilestones_lbl2" xlink:title="label: MaximumAmountOfPaymentsReceivablePerProgramForRegulatoryMilestones to ions_MaximumAmountOfPaymentsReceivablePerProgramForRegulatoryMilestones_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_CumulativeRevenueFromContractWithCustomerExcludingAssessedTax" xlink:label="CumulativeRevenueFromContractWithCustomerExcludingAssessedTax" xlink:title="CumulativeRevenueFromContractWithCustomerExcludingAssessedTax" />
    <link:label xlink:type="resource" xlink:label="ions_CumulativeRevenueFromContractWithCustomerExcludingAssessedTax_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_CumulativeRevenueFromContractWithCustomerExcludingAssessedTax_lbl" xml:lang="en-US" id="ions_CumulativeRevenueFromContractWithCustomerExcludingAssessedTax_lbl">Cumulative amount, excluding tax collected from customer, of revenue from satisfaction of performance obligation by transferring promised good or service to customer. Tax collected from customer is tax assessed by governmental authority that is both imposed on and concurrent with specific revenue-producing transaction, including, but not limited to, sales, use, value added and excise.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="CumulativeRevenueFromContractWithCustomerExcludingAssessedTax" xlink:to="ions_CumulativeRevenueFromContractWithCustomerExcludingAssessedTax_lbl" xlink:title="label: CumulativeRevenueFromContractWithCustomerExcludingAssessedTax to ions_CumulativeRevenueFromContractWithCustomerExcludingAssessedTax_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_CumulativeRevenueFromContractWithCustomerExcludingAssessedTax_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_CumulativeRevenueFromContractWithCustomerExcludingAssessedTax_lbl1" xml:lang="en-US" id="ions_CumulativeRevenueFromContractWithCustomerExcludingAssessedTax_lbl1">Cumulative Revenue from Contract with Customer, Excluding Assessed Tax</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="CumulativeRevenueFromContractWithCustomerExcludingAssessedTax" xlink:to="ions_CumulativeRevenueFromContractWithCustomerExcludingAssessedTax_lbl1" xlink:title="label: CumulativeRevenueFromContractWithCustomerExcludingAssessedTax to ions_CumulativeRevenueFromContractWithCustomerExcludingAssessedTax_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_CumulativeRevenueFromContractWithCustomerExcludingAssessedTax_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_CumulativeRevenueFromContractWithCustomerExcludingAssessedTax_lbl2" xml:lang="en-US" id="ions_CumulativeRevenueFromContractWithCustomerExcludingAssessedTax_lbl2">Cumulative revenue earned</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="CumulativeRevenueFromContractWithCustomerExcludingAssessedTax" xlink:to="ions_CumulativeRevenueFromContractWithCustomerExcludingAssessedTax_lbl2" xlink:title="label: CumulativeRevenueFromContractWithCustomerExcludingAssessedTax to ions_CumulativeRevenueFromContractWithCustomerExcludingAssessedTax_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_Ion736Member" xlink:label="Ion736Member" xlink:title="Ion736Member" />
    <link:label xlink:type="resource" xlink:label="ions_Ion736Member_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_Ion736Member_lbl" xml:lang="en-US" id="ions_Ion736Member_lbl">ION736, formerly known as IONIS-AZ7-2.5, is a Generation 2.5 antisense drug.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="Ion736Member" xlink:to="ions_Ion736Member_lbl" xlink:title="label: Ion736Member to ions_Ion736Member_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_Ion736Member_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_Ion736Member_lbl1" xml:lang="en-US" id="ions_Ion736Member_lbl1">Ion736 [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="Ion736Member" xlink:to="ions_Ion736Member_lbl1" xlink:title="label: Ion736Member to ions_Ion736Member_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_Ion736Member_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_Ion736Member_lbl2" xml:lang="en-US" id="ions_Ion736Member_lbl2">ION736 [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="Ion736Member" xlink:to="ions_Ion736Member_lbl2" xlink:title="label: Ion736Member to ions_Ion736Member_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_AstrazenecaCollaborationEplontersenMember" xlink:label="AstrazenecaCollaborationEplontersenMember" xlink:title="AstrazenecaCollaborationEplontersenMember" />
    <link:label xlink:type="resource" xlink:label="ions_AstrazenecaCollaborationEplontersenMember_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_AstrazenecaCollaborationEplontersenMember_lbl" xml:lang="en-US" id="ions_AstrazenecaCollaborationEplontersenMember_lbl">Collaboration agreement entered into with AstraZeneca PLC in December 2021 to develop and commercialize eplontersen. Eplontersen, formerly known as IONIS-TTR-L and AKCEA-TTR-L, is a ligand-conjugated (LICA) investigational antisense medicine designed to reduce the production of transthyretin, or TTR protein, to treat all types of TTR amyloidosis (ATTR), a systemic, progressive and fatal disease.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="AstrazenecaCollaborationEplontersenMember" xlink:to="ions_AstrazenecaCollaborationEplontersenMember_lbl" xlink:title="label: AstrazenecaCollaborationEplontersenMember to ions_AstrazenecaCollaborationEplontersenMember_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_AstrazenecaCollaborationEplontersenMember_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_AstrazenecaCollaborationEplontersenMember_lbl1" xml:lang="en-US" id="ions_AstrazenecaCollaborationEplontersenMember_lbl1">AstraZeneca Collaboration, Eplontersen [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="AstrazenecaCollaborationEplontersenMember" xlink:to="ions_AstrazenecaCollaborationEplontersenMember_lbl1" xlink:title="label: AstrazenecaCollaborationEplontersenMember to ions_AstrazenecaCollaborationEplontersenMember_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_AstrazenecaCollaborationEplontersenMember_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_AstrazenecaCollaborationEplontersenMember_lbl2" xml:lang="en-US" id="ions_AstrazenecaCollaborationEplontersenMember_lbl2">AstraZeneca [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="AstrazenecaCollaborationEplontersenMember" xlink:to="ions_AstrazenecaCollaborationEplontersenMember_lbl2" xlink:title="label: AstrazenecaCollaborationEplontersenMember to ions_AstrazenecaCollaborationEplontersenMember_lbl2" />
    <link:label xlink:type="resource" xlink:label="ions_AstrazenecaCollaborationEplontersenMember_lbl3" xlink:role="http://www.xbrl.org/2003/role/verboseLabel" xlink:title="ions_AstrazenecaCollaborationEplontersenMember_lbl3" xml:lang="en-US" id="ions_AstrazenecaCollaborationEplontersenMember_lbl3">Eplontersen Collaboration [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="AstrazenecaCollaborationEplontersenMember" xlink:to="ions_AstrazenecaCollaborationEplontersenMember_lbl3" xlink:title="label: AstrazenecaCollaborationEplontersenMember to ions_AstrazenecaCollaborationEplontersenMember_lbl3" />
    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_AstraZenecaCollaborationsResearchAndDevelopmentMember" xlink:label="AstraZenecaCollaborationsResearchAndDevelopmentMember" xlink:title="AstraZenecaCollaborationsResearchAndDevelopmentMember" />
    <link:label xlink:type="resource" xlink:label="ions_AstraZenecaCollaborationsResearchAndDevelopmentMember_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_AstraZenecaCollaborationsResearchAndDevelopmentMember_lbl" xml:lang="en-US" id="ions_AstraZenecaCollaborationsResearchAndDevelopmentMember_lbl">Collaboration agreements entered into with AstraZeneca PLC for research and development, excluding the Eplontersen Collaboration.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="AstraZenecaCollaborationsResearchAndDevelopmentMember" xlink:to="ions_AstraZenecaCollaborationsResearchAndDevelopmentMember_lbl" xlink:title="label: AstraZenecaCollaborationsResearchAndDevelopmentMember to ions_AstraZenecaCollaborationsResearchAndDevelopmentMember_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_AstraZenecaCollaborationsResearchAndDevelopmentMember_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_AstraZenecaCollaborationsResearchAndDevelopmentMember_lbl1" xml:lang="en-US" id="ions_AstraZenecaCollaborationsResearchAndDevelopmentMember_lbl1">AstraZeneca Collaborations, Research and Development [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="AstraZenecaCollaborationsResearchAndDevelopmentMember" xlink:to="ions_AstraZenecaCollaborationsResearchAndDevelopmentMember_lbl1" xlink:title="label: AstraZenecaCollaborationsResearchAndDevelopmentMember to ions_AstraZenecaCollaborationsResearchAndDevelopmentMember_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_AstraZenecaCollaborationsResearchAndDevelopmentMember_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_AstraZenecaCollaborationsResearchAndDevelopmentMember_lbl2" xml:lang="en-US" id="ions_AstraZenecaCollaborationsResearchAndDevelopmentMember_lbl2">Research and Development Collaborations [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="AstraZenecaCollaborationsResearchAndDevelopmentMember" xlink:to="ions_AstraZenecaCollaborationsResearchAndDevelopmentMember_lbl2" xlink:title="label: AstraZenecaCollaborationsResearchAndDevelopmentMember to ions_AstraZenecaCollaborationsResearchAndDevelopmentMember_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_MaximumAmountOfPaymentsReceivableForDevelopmentAndRegulatoryMilestones" xlink:label="MaximumAmountOfPaymentsReceivableForDevelopmentAndRegulatoryMilestones" xlink:title="MaximumAmountOfPaymentsReceivableForDevelopmentAndRegulatoryMilestones" />
    <link:label xlink:type="resource" xlink:label="ions_MaximumAmountOfPaymentsReceivableForDevelopmentAndRegulatoryMilestones_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_MaximumAmountOfPaymentsReceivableForDevelopmentAndRegulatoryMilestones_lbl" xml:lang="en-US" id="ions_MaximumAmountOfPaymentsReceivableForDevelopmentAndRegulatoryMilestones_lbl">The maximum amount of payments receivable for development and regulatory milestones under the collaboration agreement.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="MaximumAmountOfPaymentsReceivableForDevelopmentAndRegulatoryMilestones" xlink:to="ions_MaximumAmountOfPaymentsReceivableForDevelopmentAndRegulatoryMilestones_lbl" xlink:title="label: MaximumAmountOfPaymentsReceivableForDevelopmentAndRegulatoryMilestones to ions_MaximumAmountOfPaymentsReceivableForDevelopmentAndRegulatoryMilestones_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_MaximumAmountOfPaymentsReceivableForDevelopmentAndRegulatoryMilestones_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_MaximumAmountOfPaymentsReceivableForDevelopmentAndRegulatoryMilestones_lbl1" xml:lang="en-US" id="ions_MaximumAmountOfPaymentsReceivableForDevelopmentAndRegulatoryMilestones_lbl1">Maximum amount of payments receivable for development and regulatory milestones</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="MaximumAmountOfPaymentsReceivableForDevelopmentAndRegulatoryMilestones" xlink:to="ions_MaximumAmountOfPaymentsReceivableForDevelopmentAndRegulatoryMilestones_lbl1" xlink:title="label: MaximumAmountOfPaymentsReceivableForDevelopmentAndRegulatoryMilestones to ions_MaximumAmountOfPaymentsReceivableForDevelopmentAndRegulatoryMilestones_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_MaximumAmountOfPaymentsReceivableForDevelopmentAndRegulatoryMilestones_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_MaximumAmountOfPaymentsReceivableForDevelopmentAndRegulatoryMilestones_lbl2" xml:lang="en-US" id="ions_MaximumAmountOfPaymentsReceivableForDevelopmentAndRegulatoryMilestones_lbl2">Maximum amount of payments receivable for development and regulatory milestones</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="MaximumAmountOfPaymentsReceivableForDevelopmentAndRegulatoryMilestones" xlink:to="ions_MaximumAmountOfPaymentsReceivableForDevelopmentAndRegulatoryMilestones_lbl2" xlink:title="label: MaximumAmountOfPaymentsReceivableForDevelopmentAndRegulatoryMilestones to ions_MaximumAmountOfPaymentsReceivableForDevelopmentAndRegulatoryMilestones_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_MaximumAmountOfPaymentsReceivableForSalesRelatedMilestones" xlink:label="MaximumAmountOfPaymentsReceivableForSalesRelatedMilestones" xlink:title="MaximumAmountOfPaymentsReceivableForSalesRelatedMilestones" />
    <link:label xlink:type="resource" xlink:label="ions_MaximumAmountOfPaymentsReceivableForSalesRelatedMilestones_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_MaximumAmountOfPaymentsReceivableForSalesRelatedMilestones_lbl" xml:lang="en-US" id="ions_MaximumAmountOfPaymentsReceivableForSalesRelatedMilestones_lbl">The maximum amount of payments receivable for sales-related milestones under the collaboration agreement.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="MaximumAmountOfPaymentsReceivableForSalesRelatedMilestones" xlink:to="ions_MaximumAmountOfPaymentsReceivableForSalesRelatedMilestones_lbl" xlink:title="label: MaximumAmountOfPaymentsReceivableForSalesRelatedMilestones to ions_MaximumAmountOfPaymentsReceivableForSalesRelatedMilestones_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_MaximumAmountOfPaymentsReceivableForSalesRelatedMilestones_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_MaximumAmountOfPaymentsReceivableForSalesRelatedMilestones_lbl1" xml:lang="en-US" id="ions_MaximumAmountOfPaymentsReceivableForSalesRelatedMilestones_lbl1">Maximum amount of payments receivable for sales-related milestones</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="MaximumAmountOfPaymentsReceivableForSalesRelatedMilestones" xlink:to="ions_MaximumAmountOfPaymentsReceivableForSalesRelatedMilestones_lbl1" xlink:title="label: MaximumAmountOfPaymentsReceivableForSalesRelatedMilestones to ions_MaximumAmountOfPaymentsReceivableForSalesRelatedMilestones_lbl1" />
    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_RoyaltyPercentageReceivedOnSalesOfMedicineInUnitedStates" xlink:label="RoyaltyPercentageReceivedOnSalesOfMedicineInUnitedStates" xlink:title="RoyaltyPercentageReceivedOnSalesOfMedicineInUnitedStates" />
    <link:label xlink:type="resource" xlink:label="ions_RoyaltyPercentageReceivedOnSalesOfMedicineInUnitedStates_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_RoyaltyPercentageReceivedOnSalesOfMedicineInUnitedStates_lbl" xml:lang="en-US" id="ions_RoyaltyPercentageReceivedOnSalesOfMedicineInUnitedStates_lbl">Royalty percentage received on sales of a medicine in the United States by a collaboration partner under the collaboration agreement.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="RoyaltyPercentageReceivedOnSalesOfMedicineInUnitedStates" xlink:to="ions_RoyaltyPercentageReceivedOnSalesOfMedicineInUnitedStates_lbl" xlink:title="label: RoyaltyPercentageReceivedOnSalesOfMedicineInUnitedStates to ions_RoyaltyPercentageReceivedOnSalesOfMedicineInUnitedStates_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_RoyaltyPercentageReceivedOnSalesOfMedicineInUnitedStates_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_RoyaltyPercentageReceivedOnSalesOfMedicineInUnitedStates_lbl1" xml:lang="en-US" id="ions_RoyaltyPercentageReceivedOnSalesOfMedicineInUnitedStates_lbl1">Royalty percentage received on sales of medicine in United States</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="RoyaltyPercentageReceivedOnSalesOfMedicineInUnitedStates" xlink:to="ions_RoyaltyPercentageReceivedOnSalesOfMedicineInUnitedStates_lbl1" xlink:title="label: RoyaltyPercentageReceivedOnSalesOfMedicineInUnitedStates to ions_RoyaltyPercentageReceivedOnSalesOfMedicineInUnitedStates_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_RoyaltyPercentageReceivedOnSalesOfMedicineInUnitedStates_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_RoyaltyPercentageReceivedOnSalesOfMedicineInUnitedStates_lbl2" xml:lang="en-US" id="ions_RoyaltyPercentageReceivedOnSalesOfMedicineInUnitedStates_lbl2">Royalty percentage received on sales of medicine in U.S.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="RoyaltyPercentageReceivedOnSalesOfMedicineInUnitedStates" xlink:to="ions_RoyaltyPercentageReceivedOnSalesOfMedicineInUnitedStates_lbl2" xlink:title="label: RoyaltyPercentageReceivedOnSalesOfMedicineInUnitedStates to ions_RoyaltyPercentageReceivedOnSalesOfMedicineInUnitedStates_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_NumberOfMaterialComponents" xlink:label="NumberOfMaterialComponents" xlink:title="NumberOfMaterialComponents" />
    <link:label xlink:type="resource" xlink:label="ions_NumberOfMaterialComponents_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_NumberOfMaterialComponents_lbl" xml:lang="en-US" id="ions_NumberOfMaterialComponents_lbl">The number of material components identified in the collaboration agreement under Accounting Standards Codification (ASC) 808, Collaborative Arrangements.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="NumberOfMaterialComponents" xlink:to="ions_NumberOfMaterialComponents_lbl" xlink:title="label: NumberOfMaterialComponents to ions_NumberOfMaterialComponents_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_NumberOfMaterialComponents_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_NumberOfMaterialComponents_lbl1" xml:lang="en-US" id="ions_NumberOfMaterialComponents_lbl1">Number of material components</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="NumberOfMaterialComponents" xlink:to="ions_NumberOfMaterialComponents_lbl1" xlink:title="label: NumberOfMaterialComponents to ions_NumberOfMaterialComponents_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_NumberOfMaterialComponents_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_NumberOfMaterialComponents_lbl2" xml:lang="en-US" id="ions_NumberOfMaterialComponents_lbl2">Number of material components</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="NumberOfMaterialComponents" xlink:to="ions_NumberOfMaterialComponents_lbl2" xlink:title="label: NumberOfMaterialComponents to ions_NumberOfMaterialComponents_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_PercentageOfCostsAssociatedWithOngoingGlobalPhase3DevelopmentProgramPaidByCollaborationPartner" xlink:label="PercentageOfCostsAssociatedWithOngoingGlobalPhase3DevelopmentProgramPaidByCollaborationPartner" xlink:title="PercentageOfCostsAssociatedWithOngoingGlobalPhase3DevelopmentProgramPaidByCollaborationPartner" />
    <link:label xlink:type="resource" xlink:label="ions_PercentageOfCostsAssociatedWithOngoingGlobalPhase3DevelopmentProgramPaidByCollaborationPartner_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_PercentageOfCostsAssociatedWithOngoingGlobalPhase3DevelopmentProgramPaidByCollaborationPartner_lbl" xml:lang="en-US" id="ions_PercentageOfCostsAssociatedWithOngoingGlobalPhase3DevelopmentProgramPaidByCollaborationPartner_lbl">Percentage of costs associated with the ongoing global Phase 3 development program paid by a collaboration partner under the collaboration agreement.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="PercentageOfCostsAssociatedWithOngoingGlobalPhase3DevelopmentProgramPaidByCollaborationPartner" xlink:to="ions_PercentageOfCostsAssociatedWithOngoingGlobalPhase3DevelopmentProgramPaidByCollaborationPartner_lbl" xlink:title="label: PercentageOfCostsAssociatedWithOngoingGlobalPhase3DevelopmentProgramPaidByCollaborationPartner to ions_PercentageOfCostsAssociatedWithOngoingGlobalPhase3DevelopmentProgramPaidByCollaborationPartner_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_PercentageOfCostsAssociatedWithOngoingGlobalPhase3DevelopmentProgramPaidByCollaborationPartner_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_PercentageOfCostsAssociatedWithOngoingGlobalPhase3DevelopmentProgramPaidByCollaborationPartner_lbl1" xml:lang="en-US" id="ions_PercentageOfCostsAssociatedWithOngoingGlobalPhase3DevelopmentProgramPaidByCollaborationPartner_lbl1">Percentage of costs associated with ongoing global Phase 3 development program paid by Collaboration Partner</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="PercentageOfCostsAssociatedWithOngoingGlobalPhase3DevelopmentProgramPaidByCollaborationPartner" xlink:to="ions_PercentageOfCostsAssociatedWithOngoingGlobalPhase3DevelopmentProgramPaidByCollaborationPartner_lbl1" xlink:title="label: PercentageOfCostsAssociatedWithOngoingGlobalPhase3DevelopmentProgramPaidByCollaborationPartner to ions_PercentageOfCostsAssociatedWithOngoingGlobalPhase3DevelopmentProgramPaidByCollaborationPartner_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_PercentageOfCostsAssociatedWithOngoingGlobalPhase3DevelopmentProgramPaidByCollaborationPartner_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_PercentageOfCostsAssociatedWithOngoingGlobalPhase3DevelopmentProgramPaidByCollaborationPartner_lbl2" xml:lang="en-US" id="ions_PercentageOfCostsAssociatedWithOngoingGlobalPhase3DevelopmentProgramPaidByCollaborationPartner_lbl2">Percentage of costs associated with ongoing global Phase 3 development program paid by AstraZeneca</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="PercentageOfCostsAssociatedWithOngoingGlobalPhase3DevelopmentProgramPaidByCollaborationPartner" xlink:to="ions_PercentageOfCostsAssociatedWithOngoingGlobalPhase3DevelopmentProgramPaidByCollaborationPartner_lbl2" xlink:title="label: PercentageOfCostsAssociatedWithOngoingGlobalPhase3DevelopmentProgramPaidByCollaborationPartner to ions_PercentageOfCostsAssociatedWithOngoingGlobalPhase3DevelopmentProgramPaidByCollaborationPartner_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_TargetForMetabolicDiseaseMember" xlink:label="TargetForMetabolicDiseaseMember" xlink:title="TargetForMetabolicDiseaseMember" />
    <link:label xlink:type="resource" xlink:label="ions_TargetForMetabolicDiseaseMember_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_TargetForMetabolicDiseaseMember_lbl" xml:lang="en-US" id="ions_TargetForMetabolicDiseaseMember_lbl">A target medicine for a metabolic disease.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="TargetForMetabolicDiseaseMember" xlink:to="ions_TargetForMetabolicDiseaseMember_lbl" xlink:title="label: TargetForMetabolicDiseaseMember to ions_TargetForMetabolicDiseaseMember_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_TargetForMetabolicDiseaseMember_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_TargetForMetabolicDiseaseMember_lbl1" xml:lang="en-US" id="ions_TargetForMetabolicDiseaseMember_lbl1">Target for Metabolic Disease [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="TargetForMetabolicDiseaseMember" xlink:to="ions_TargetForMetabolicDiseaseMember_lbl1" xlink:title="label: TargetForMetabolicDiseaseMember to ions_TargetForMetabolicDiseaseMember_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_TargetForMetabolicDiseaseMember_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_TargetForMetabolicDiseaseMember_lbl2" xml:lang="en-US" id="ions_TargetForMetabolicDiseaseMember_lbl2">Target for Metabolic Disease [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="TargetForMetabolicDiseaseMember" xlink:to="ions_TargetForMetabolicDiseaseMember_lbl2" xlink:title="label: TargetForMetabolicDiseaseMember to ions_TargetForMetabolicDiseaseMember_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_NumberOfCollaborationAgreements" xlink:label="NumberOfCollaborationAgreements" xlink:title="NumberOfCollaborationAgreements" />
    <link:label xlink:type="resource" xlink:label="ions_NumberOfCollaborationAgreements_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_NumberOfCollaborationAgreements_lbl" xml:lang="en-US" id="ions_NumberOfCollaborationAgreements_lbl">The number of collaboration agreements with the collaboration partner.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="NumberOfCollaborationAgreements" xlink:to="ions_NumberOfCollaborationAgreements_lbl" xlink:title="label: NumberOfCollaborationAgreements to ions_NumberOfCollaborationAgreements_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_NumberOfCollaborationAgreements_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_NumberOfCollaborationAgreements_lbl1" xml:lang="en-US" id="ions_NumberOfCollaborationAgreements_lbl1">Number of collaboration agreements</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="NumberOfCollaborationAgreements" xlink:to="ions_NumberOfCollaborationAgreements_lbl1" xlink:title="label: NumberOfCollaborationAgreements to ions_NumberOfCollaborationAgreements_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_NumberOfCollaborationAgreements_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_NumberOfCollaborationAgreements_lbl2" xml:lang="en-US" id="ions_NumberOfCollaborationAgreements_lbl2">Number of collaboration agreements</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="NumberOfCollaborationAgreements" xlink:to="ions_NumberOfCollaborationAgreements_lbl2" xlink:title="label: NumberOfCollaborationAgreements to ions_NumberOfCollaborationAgreements_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_MaximumAmountOfPaymentsReceivableForCommercializationMilestones" xlink:label="MaximumAmountOfPaymentsReceivableForCommercializationMilestones" xlink:title="MaximumAmountOfPaymentsReceivableForCommercializationMilestones" />
    <link:label xlink:type="resource" xlink:label="ions_MaximumAmountOfPaymentsReceivableForCommercializationMilestones_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_MaximumAmountOfPaymentsReceivableForCommercializationMilestones_lbl" xml:lang="en-US" id="ions_MaximumAmountOfPaymentsReceivableForCommercializationMilestones_lbl">The maximum amount of payments receivable for commercialization milestones under the collaboration agreement.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="MaximumAmountOfPaymentsReceivableForCommercializationMilestones" xlink:to="ions_MaximumAmountOfPaymentsReceivableForCommercializationMilestones_lbl" xlink:title="label: MaximumAmountOfPaymentsReceivableForCommercializationMilestones to ions_MaximumAmountOfPaymentsReceivableForCommercializationMilestones_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_MaximumAmountOfPaymentsReceivableForCommercializationMilestones_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_MaximumAmountOfPaymentsReceivableForCommercializationMilestones_lbl1" xml:lang="en-US" id="ions_MaximumAmountOfPaymentsReceivableForCommercializationMilestones_lbl1">Maximum amount of payments receivable for commercialization milestones</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="MaximumAmountOfPaymentsReceivableForCommercializationMilestones" xlink:to="ions_MaximumAmountOfPaymentsReceivableForCommercializationMilestones_lbl1" xlink:title="label: MaximumAmountOfPaymentsReceivableForCommercializationMilestones to ions_MaximumAmountOfPaymentsReceivableForCommercializationMilestones_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_MaximumAmountOfPaymentsReceivableForCommercializationMilestones_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_MaximumAmountOfPaymentsReceivableForCommercializationMilestones_lbl2" xml:lang="en-US" id="ions_MaximumAmountOfPaymentsReceivableForCommercializationMilestones_lbl2">Maximum amount of payments receivable for commercialization milestones</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="MaximumAmountOfPaymentsReceivableForCommercializationMilestones" xlink:to="ions_MaximumAmountOfPaymentsReceivableForCommercializationMilestones_lbl2" xlink:title="label: MaximumAmountOfPaymentsReceivableForCommercializationMilestones to ions_MaximumAmountOfPaymentsReceivableForCommercializationMilestones_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_Ion839Member" xlink:label="Ion839Member" xlink:title="Ion839Member" />
    <link:label xlink:type="resource" xlink:label="ions_Ion839Member_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_Ion839Member_lbl" xml:lang="en-US" id="ions_Ion839Member_lbl">A drug designed to inhibit an undisclosed target to treat patients with nonalcoholic steatohepatitis, or NASH.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="Ion839Member" xlink:to="ions_Ion839Member_lbl" xlink:title="label: Ion839Member to ions_Ion839Member_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_Ion839Member_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_Ion839Member_lbl1" xml:lang="en-US" id="ions_Ion839Member_lbl1">Ion839 [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="Ion839Member" xlink:to="ions_Ion839Member_lbl1" xlink:title="label: Ion839Member to ions_Ion839Member_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_Ion839Member_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_Ion839Member_lbl2" xml:lang="en-US" id="ions_Ion839Member_lbl2">ION839 [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="Ion839Member" xlink:to="ions_Ion839Member_lbl2" xlink:title="label: Ion839Member to ions_Ion839Member_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_NumberOfLicensedMedicines" xlink:label="NumberOfLicensedMedicines" xlink:title="NumberOfLicensedMedicines" />
    <link:label xlink:type="resource" xlink:label="ions_NumberOfLicensedMedicines_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_NumberOfLicensedMedicines_lbl" xml:lang="en-US" id="ions_NumberOfLicensedMedicines_lbl">The number of medicines that have been licensed under the collaboration agreement.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="NumberOfLicensedMedicines" xlink:to="ions_NumberOfLicensedMedicines_lbl" xlink:title="label: NumberOfLicensedMedicines to ions_NumberOfLicensedMedicines_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_NumberOfLicensedMedicines_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_NumberOfLicensedMedicines_lbl1" xml:lang="en-US" id="ions_NumberOfLicensedMedicines_lbl1">Number of licensed medicines</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="NumberOfLicensedMedicines" xlink:to="ions_NumberOfLicensedMedicines_lbl1" xlink:title="label: NumberOfLicensedMedicines to ions_NumberOfLicensedMedicines_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_NumberOfLicensedMedicines_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_NumberOfLicensedMedicines_lbl2" xml:lang="en-US" id="ions_NumberOfLicensedMedicines_lbl2">Number of licensed medicines</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="NumberOfLicensedMedicines" xlink:to="ions_NumberOfLicensedMedicines_lbl2" xlink:title="label: NumberOfLicensedMedicines to ions_NumberOfLicensedMedicines_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_AstrazenecaCollaborationOncologyMember" xlink:label="AstrazenecaCollaborationOncologyMember" xlink:title="AstrazenecaCollaborationOncologyMember" />
    <link:label xlink:type="resource" xlink:label="ions_AstrazenecaCollaborationOncologyMember_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_AstrazenecaCollaborationOncologyMember_lbl" xml:lang="en-US" id="ions_AstrazenecaCollaborationOncologyMember_lbl">Collaboration agreement entered into with AstraZeneca PLC in December 2012 and amended in January 2016 to discover and develop antisense drugs for cancer.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="AstrazenecaCollaborationOncologyMember" xlink:to="ions_AstrazenecaCollaborationOncologyMember_lbl" xlink:title="label: AstrazenecaCollaborationOncologyMember to ions_AstrazenecaCollaborationOncologyMember_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_AstrazenecaCollaborationOncologyMember_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_AstrazenecaCollaborationOncologyMember_lbl1" xml:lang="en-US" id="ions_AstrazenecaCollaborationOncologyMember_lbl1">AstraZeneca Collaboration, Oncology [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="AstrazenecaCollaborationOncologyMember" xlink:to="ions_AstrazenecaCollaborationOncologyMember_lbl1" xlink:title="label: AstrazenecaCollaborationOncologyMember to ions_AstrazenecaCollaborationOncologyMember_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_AstrazenecaCollaborationOncologyMember_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_AstrazenecaCollaborationOncologyMember_lbl2" xml:lang="en-US" id="ions_AstrazenecaCollaborationOncologyMember_lbl2">Oncology Collaboration [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="AstrazenecaCollaborationOncologyMember" xlink:to="ions_AstrazenecaCollaborationOncologyMember_lbl2" xlink:title="label: AstrazenecaCollaborationOncologyMember to ions_AstrazenecaCollaborationOncologyMember_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_AstrazenecaCollaborationCardiovascularRenalAndMetabolicDiseasesMember" xlink:label="AstrazenecaCollaborationCardiovascularRenalAndMetabolicDiseasesMember" xlink:title="AstrazenecaCollaborationCardiovascularRenalAndMetabolicDiseasesMember" />
    <link:label xlink:type="resource" xlink:label="ions_AstrazenecaCollaborationCardiovascularRenalAndMetabolicDiseasesMember_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_AstrazenecaCollaborationCardiovascularRenalAndMetabolicDiseasesMember_lbl" xml:lang="en-US" id="ions_AstrazenecaCollaborationCardiovascularRenalAndMetabolicDiseasesMember_lbl">Collaboration agreement entered into with AstraZeneca PLC in July 2015 to discover and develop antisense therapies for treating cardiovascular and metabolic diseases primarily focused on targets in the kidney and renal diseases.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="AstrazenecaCollaborationCardiovascularRenalAndMetabolicDiseasesMember" xlink:to="ions_AstrazenecaCollaborationCardiovascularRenalAndMetabolicDiseasesMember_lbl" xlink:title="label: AstrazenecaCollaborationCardiovascularRenalAndMetabolicDiseasesMember to ions_AstrazenecaCollaborationCardiovascularRenalAndMetabolicDiseasesMember_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_AstrazenecaCollaborationCardiovascularRenalAndMetabolicDiseasesMember_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_AstrazenecaCollaborationCardiovascularRenalAndMetabolicDiseasesMember_lbl1" xml:lang="en-US" id="ions_AstrazenecaCollaborationCardiovascularRenalAndMetabolicDiseasesMember_lbl1">AstraZeneca Collaboration, Cardiovascular, Renal and Metabolic Diseases [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="AstrazenecaCollaborationCardiovascularRenalAndMetabolicDiseasesMember" xlink:to="ions_AstrazenecaCollaborationCardiovascularRenalAndMetabolicDiseasesMember_lbl1" xlink:title="label: AstrazenecaCollaborationCardiovascularRenalAndMetabolicDiseasesMember to ions_AstrazenecaCollaborationCardiovascularRenalAndMetabolicDiseasesMember_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_AstrazenecaCollaborationCardiovascularRenalAndMetabolicDiseasesMember_lbl2" xlink:role="http://www.xbrl.org/2003/role/verboseLabel" xlink:title="ions_AstrazenecaCollaborationCardiovascularRenalAndMetabolicDiseasesMember_lbl2" xml:lang="en-US" id="ions_AstrazenecaCollaborationCardiovascularRenalAndMetabolicDiseasesMember_lbl2">AstraZeneca [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="AstrazenecaCollaborationCardiovascularRenalAndMetabolicDiseasesMember" xlink:to="ions_AstrazenecaCollaborationCardiovascularRenalAndMetabolicDiseasesMember_lbl2" xlink:title="label: AstrazenecaCollaborationCardiovascularRenalAndMetabolicDiseasesMember to ions_AstrazenecaCollaborationCardiovascularRenalAndMetabolicDiseasesMember_lbl2" />
    <link:label xlink:type="resource" xlink:label="ions_AstrazenecaCollaborationCardiovascularRenalAndMetabolicDiseasesMember_lbl3" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_AstrazenecaCollaborationCardiovascularRenalAndMetabolicDiseasesMember_lbl3" xml:lang="en-US" id="ions_AstrazenecaCollaborationCardiovascularRenalAndMetabolicDiseasesMember_lbl3">Cardiovascular, Renal and Metabolic Diseases Collaboration [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="AstrazenecaCollaborationCardiovascularRenalAndMetabolicDiseasesMember" xlink:to="ions_AstrazenecaCollaborationCardiovascularRenalAndMetabolicDiseasesMember_lbl3" xlink:title="label: AstrazenecaCollaborationCardiovascularRenalAndMetabolicDiseasesMember to ions_AstrazenecaCollaborationCardiovascularRenalAndMetabolicDiseasesMember_lbl3" />
    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_Ion532AndIon449Member" xlink:label="Ion532AndIon449Member" xlink:title="Ion532AndIon449Member" />
    <link:label xlink:type="resource" xlink:label="ions_Ion532AndIon449Member_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_Ion532AndIon449Member_lbl" xml:lang="en-US" id="ions_Ion532AndIon449Member_lbl">ION532 (formerly IONIS-AZ5-2.5Rx ), also known as AZD2373, is an investigational antisense medicine designed to reduce the production of apolipoprotein L1 (APOL1) for the treatment of APOL1-associated chronic kidney disease (CKD). ION449 (formerly IONIS-AZ4-2.5-LRx), also known as AZD8233, is a ligand-conjugated (LICA) investigational antisense medicine designed to reduce plasma levels of proprotein convertase subtilisin/kexin type 9 (PCSK9).</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="Ion532AndIon449Member" xlink:to="ions_Ion532AndIon449Member_lbl" xlink:title="label: Ion532AndIon449Member to ions_Ion532AndIon449Member_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_Ion532AndIon449Member_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_Ion532AndIon449Member_lbl1" xml:lang="en-US" id="ions_Ion532AndIon449Member_lbl1">Ion532 and Ion449 [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="Ion532AndIon449Member" xlink:to="ions_Ion532AndIon449Member_lbl1" xlink:title="label: Ion532AndIon449Member to ions_Ion532AndIon449Member_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_Ion532AndIon449Member_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_Ion532AndIon449Member_lbl2" xml:lang="en-US" id="ions_Ion532AndIon449Member_lbl2">ION532 and ION449 [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="Ion532AndIon449Member" xlink:to="ions_Ion532AndIon449Member_lbl2" xlink:title="label: Ion532AndIon449Member to ions_Ion532AndIon449Member_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_PercentageEnrollmentInPhase3Study" xlink:label="PercentageEnrollmentInPhase3Study" xlink:title="PercentageEnrollmentInPhase3Study" />
    <link:label xlink:type="resource" xlink:label="ions_PercentageEnrollmentInPhase3Study_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_PercentageEnrollmentInPhase3Study_lbl" xml:lang="en-US" id="ions_PercentageEnrollmentInPhase3Study_lbl">Percentage enrollment in the Lp(a) HORIZON Phase 3 cardiovascular outcome study of pelacarsen.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="PercentageEnrollmentInPhase3Study" xlink:to="ions_PercentageEnrollmentInPhase3Study_lbl" xlink:title="label: PercentageEnrollmentInPhase3Study to ions_PercentageEnrollmentInPhase3Study_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_PercentageEnrollmentInPhase3Study_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_PercentageEnrollmentInPhase3Study_lbl1" xml:lang="en-US" id="ions_PercentageEnrollmentInPhase3Study_lbl1">Percentage enrollment in Phase 3 study</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="PercentageEnrollmentInPhase3Study" xlink:to="ions_PercentageEnrollmentInPhase3Study_lbl1" xlink:title="label: PercentageEnrollmentInPhase3Study to ions_PercentageEnrollmentInPhase3Study_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_PercentageEnrollmentInPhase3Study_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_PercentageEnrollmentInPhase3Study_lbl2" xml:lang="en-US" id="ions_PercentageEnrollmentInPhase3Study_lbl2">Percentage enrollment in Lp(a) HORIZON Phase 3 cardiovascular outcome study</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="PercentageEnrollmentInPhase3Study" xlink:to="ions_PercentageEnrollmentInPhase3Study_lbl2" xlink:title="label: PercentageEnrollmentInPhase3Study to ions_PercentageEnrollmentInPhase3Study_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_ResearchAndDevelopmentServicesForPelacarsenMember" xlink:label="ResearchAndDevelopmentServicesForPelacarsenMember" xlink:title="ResearchAndDevelopmentServicesForPelacarsenMember" />
    <link:label xlink:type="resource" xlink:label="ions_ResearchAndDevelopmentServicesForPelacarsenMember_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_ResearchAndDevelopmentServicesForPelacarsenMember_lbl" xml:lang="en-US" id="ions_ResearchAndDevelopmentServicesForPelacarsenMember_lbl">Research and development (R&amp;D) services for Pelacarsen, an antisense therapy with the potential to significantly reduce cardiovascular risk in patients suffering from high levels of the lipoprotein Lp(a).</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="ResearchAndDevelopmentServicesForPelacarsenMember" xlink:to="ions_ResearchAndDevelopmentServicesForPelacarsenMember_lbl" xlink:title="label: ResearchAndDevelopmentServicesForPelacarsenMember to ions_ResearchAndDevelopmentServicesForPelacarsenMember_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_ResearchAndDevelopmentServicesForPelacarsenMember_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_ResearchAndDevelopmentServicesForPelacarsenMember_lbl1" xml:lang="en-US" id="ions_ResearchAndDevelopmentServicesForPelacarsenMember_lbl1">Research and Development Services for Pelacarsen [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="ResearchAndDevelopmentServicesForPelacarsenMember" xlink:to="ions_ResearchAndDevelopmentServicesForPelacarsenMember_lbl1" xlink:title="label: ResearchAndDevelopmentServicesForPelacarsenMember to ions_ResearchAndDevelopmentServicesForPelacarsenMember_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_ResearchAndDevelopmentServicesForPelacarsenMember_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_ResearchAndDevelopmentServicesForPelacarsenMember_lbl2" xml:lang="en-US" id="ions_ResearchAndDevelopmentServicesForPelacarsenMember_lbl2">R&amp;D Services for Pelacarsen [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="ResearchAndDevelopmentServicesForPelacarsenMember" xlink:to="ions_ResearchAndDevelopmentServicesForPelacarsenMember_lbl2" xlink:title="label: ResearchAndDevelopmentServicesForPelacarsenMember to ions_ResearchAndDevelopmentServicesForPelacarsenMember_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_ProceedsFromSaleOfCommonStockIncludingPremiumPaid" xlink:label="ProceedsFromSaleOfCommonStockIncludingPremiumPaid" xlink:title="ProceedsFromSaleOfCommonStockIncludingPremiumPaid" />
    <link:label xlink:type="resource" xlink:label="ions_ProceedsFromSaleOfCommonStockIncludingPremiumPaid_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_ProceedsFromSaleOfCommonStockIncludingPremiumPaid_lbl" xml:lang="en-US" id="ions_ProceedsFromSaleOfCommonStockIncludingPremiumPaid_lbl">The cash inflow from the sale of common stock, including the premium paid for the purchase of common stock.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="ProceedsFromSaleOfCommonStockIncludingPremiumPaid" xlink:to="ions_ProceedsFromSaleOfCommonStockIncludingPremiumPaid_lbl" xlink:title="label: ProceedsFromSaleOfCommonStockIncludingPremiumPaid to ions_ProceedsFromSaleOfCommonStockIncludingPremiumPaid_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_ProceedsFromSaleOfCommonStockIncludingPremiumPaid_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_ProceedsFromSaleOfCommonStockIncludingPremiumPaid_lbl1" xml:lang="en-US" id="ions_ProceedsFromSaleOfCommonStockIncludingPremiumPaid_lbl1">Proceeds from sale of common stock, including premium paid</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="ProceedsFromSaleOfCommonStockIncludingPremiumPaid" xlink:to="ions_ProceedsFromSaleOfCommonStockIncludingPremiumPaid_lbl1" xlink:title="label: ProceedsFromSaleOfCommonStockIncludingPremiumPaid to ions_ProceedsFromSaleOfCommonStockIncludingPremiumPaid_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_ProceedsFromSaleOfCommonStockIncludingPremiumPaid_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_ProceedsFromSaleOfCommonStockIncludingPremiumPaid_lbl2" xml:lang="en-US" id="ions_ProceedsFromSaleOfCommonStockIncludingPremiumPaid_lbl2">Proceeds from sale of common stock</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="ProceedsFromSaleOfCommonStockIncludingPremiumPaid" xlink:to="ions_ProceedsFromSaleOfCommonStockIncludingPremiumPaid_lbl2" xlink:title="label: ProceedsFromSaleOfCommonStockIncludingPremiumPaid to ions_ProceedsFromSaleOfCommonStockIncludingPremiumPaid_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_RoyaltyPercentageReceivedOnSalesOfMedicine" xlink:label="RoyaltyPercentageReceivedOnSalesOfMedicine" xlink:title="RoyaltyPercentageReceivedOnSalesOfMedicine" />
    <link:label xlink:type="resource" xlink:label="ions_RoyaltyPercentageReceivedOnSalesOfMedicine_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_RoyaltyPercentageReceivedOnSalesOfMedicine_lbl" xml:lang="en-US" id="ions_RoyaltyPercentageReceivedOnSalesOfMedicine_lbl">Royalty percentage received on the sales of a medicine by a collaboration partner under the collaboration agreement.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="RoyaltyPercentageReceivedOnSalesOfMedicine" xlink:to="ions_RoyaltyPercentageReceivedOnSalesOfMedicine_lbl" xlink:title="label: RoyaltyPercentageReceivedOnSalesOfMedicine to ions_RoyaltyPercentageReceivedOnSalesOfMedicine_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_RoyaltyPercentageReceivedOnSalesOfMedicine_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_RoyaltyPercentageReceivedOnSalesOfMedicine_lbl1" xml:lang="en-US" id="ions_RoyaltyPercentageReceivedOnSalesOfMedicine_lbl1">Royalty percentage received on sales of medicine</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="RoyaltyPercentageReceivedOnSalesOfMedicine" xlink:to="ions_RoyaltyPercentageReceivedOnSalesOfMedicine_lbl1" xlink:title="label: RoyaltyPercentageReceivedOnSalesOfMedicine to ions_RoyaltyPercentageReceivedOnSalesOfMedicine_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_RoyaltyPercentageReceivedOnSalesOfMedicine_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_RoyaltyPercentageReceivedOnSalesOfMedicine_lbl2" xml:lang="en-US" id="ions_RoyaltyPercentageReceivedOnSalesOfMedicine_lbl2">Royalty percentage received on sales of medicine</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="RoyaltyPercentageReceivedOnSalesOfMedicine" xlink:to="ions_RoyaltyPercentageReceivedOnSalesOfMedicine_lbl2" xlink:title="label: RoyaltyPercentageReceivedOnSalesOfMedicine to ions_RoyaltyPercentageReceivedOnSalesOfMedicine_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_OlezarsenActivePharmaceuticalIngredientMember" xlink:label="OlezarsenActivePharmaceuticalIngredientMember" xlink:title="OlezarsenActivePharmaceuticalIngredientMember" />
    <link:label xlink:type="resource" xlink:label="ions_OlezarsenActivePharmaceuticalIngredientMember_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_OlezarsenActivePharmaceuticalIngredientMember_lbl" xml:lang="en-US" id="ions_OlezarsenActivePharmaceuticalIngredientMember_lbl">The active pharmaceutical ingredient, or API, for Olezarsen, an antisense therapy with the potential to significantly reduce cardiovascular risk in patients suffering from high levels of the lipoprotein ApoCIII.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="OlezarsenActivePharmaceuticalIngredientMember" xlink:to="ions_OlezarsenActivePharmaceuticalIngredientMember_lbl" xlink:title="label: OlezarsenActivePharmaceuticalIngredientMember to ions_OlezarsenActivePharmaceuticalIngredientMember_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_OlezarsenActivePharmaceuticalIngredientMember_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_OlezarsenActivePharmaceuticalIngredientMember_lbl1" xml:lang="en-US" id="ions_OlezarsenActivePharmaceuticalIngredientMember_lbl1">Olezarsen Active Pharmaceutical Ingredient [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="OlezarsenActivePharmaceuticalIngredientMember" xlink:to="ions_OlezarsenActivePharmaceuticalIngredientMember_lbl1" xlink:title="label: OlezarsenActivePharmaceuticalIngredientMember to ions_OlezarsenActivePharmaceuticalIngredientMember_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_OlezarsenActivePharmaceuticalIngredientMember_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_OlezarsenActivePharmaceuticalIngredientMember_lbl2" xml:lang="en-US" id="ions_OlezarsenActivePharmaceuticalIngredientMember_lbl2">Olezarsen API [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="OlezarsenActivePharmaceuticalIngredientMember" xlink:to="ions_OlezarsenActivePharmaceuticalIngredientMember_lbl2" xlink:title="label: OlezarsenActivePharmaceuticalIngredientMember to ions_OlezarsenActivePharmaceuticalIngredientMember_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_ResearchAndDevelopmentServicesForOlezarsenMember" xlink:label="ResearchAndDevelopmentServicesForOlezarsenMember" xlink:title="ResearchAndDevelopmentServicesForOlezarsenMember" />
    <link:label xlink:type="resource" xlink:label="ions_ResearchAndDevelopmentServicesForOlezarsenMember_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_ResearchAndDevelopmentServicesForOlezarsenMember_lbl" xml:lang="en-US" id="ions_ResearchAndDevelopmentServicesForOlezarsenMember_lbl">Research and development (R&amp;D) services for olezarsen, an antisense therapy with the potential to significantly reduce cardiovascular risk in patients suffering from high levels of the lipoprotein ApoCIII.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="ResearchAndDevelopmentServicesForOlezarsenMember" xlink:to="ions_ResearchAndDevelopmentServicesForOlezarsenMember_lbl" xlink:title="label: ResearchAndDevelopmentServicesForOlezarsenMember to ions_ResearchAndDevelopmentServicesForOlezarsenMember_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_ResearchAndDevelopmentServicesForOlezarsenMember_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_ResearchAndDevelopmentServicesForOlezarsenMember_lbl1" xml:lang="en-US" id="ions_ResearchAndDevelopmentServicesForOlezarsenMember_lbl1">Research and Development Services for Olezarsen [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="ResearchAndDevelopmentServicesForOlezarsenMember" xlink:to="ions_ResearchAndDevelopmentServicesForOlezarsenMember_lbl1" xlink:title="label: ResearchAndDevelopmentServicesForOlezarsenMember to ions_ResearchAndDevelopmentServicesForOlezarsenMember_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_ResearchAndDevelopmentServicesForOlezarsenMember_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_ResearchAndDevelopmentServicesForOlezarsenMember_lbl2" xml:lang="en-US" id="ions_ResearchAndDevelopmentServicesForOlezarsenMember_lbl2">R&amp;D Services for Olezarsen [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="ResearchAndDevelopmentServicesForOlezarsenMember" xlink:to="ions_ResearchAndDevelopmentServicesForOlezarsenMember_lbl2" xlink:title="label: ResearchAndDevelopmentServicesForOlezarsenMember to ions_ResearchAndDevelopmentServicesForOlezarsenMember_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_PelacarsenActivePharmaceuticalIngredientMember" xlink:label="PelacarsenActivePharmaceuticalIngredientMember" xlink:title="PelacarsenActivePharmaceuticalIngredientMember" />
    <link:label xlink:type="resource" xlink:label="ions_PelacarsenActivePharmaceuticalIngredientMember_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_PelacarsenActivePharmaceuticalIngredientMember_lbl" xml:lang="en-US" id="ions_PelacarsenActivePharmaceuticalIngredientMember_lbl">The active pharmaceutical ingredient, or API, for Pelacarsen, an antisense therapy with the potential to significantly reduce cardiovascular risk in patients suffering from high levels of the lipoprotein Lp(a).</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="PelacarsenActivePharmaceuticalIngredientMember" xlink:to="ions_PelacarsenActivePharmaceuticalIngredientMember_lbl" xlink:title="label: PelacarsenActivePharmaceuticalIngredientMember to ions_PelacarsenActivePharmaceuticalIngredientMember_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_PelacarsenActivePharmaceuticalIngredientMember_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_PelacarsenActivePharmaceuticalIngredientMember_lbl1" xml:lang="en-US" id="ions_PelacarsenActivePharmaceuticalIngredientMember_lbl1">Pelacarsen Active Pharmaceutical Ingredient [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="PelacarsenActivePharmaceuticalIngredientMember" xlink:to="ions_PelacarsenActivePharmaceuticalIngredientMember_lbl1" xlink:title="label: PelacarsenActivePharmaceuticalIngredientMember to ions_PelacarsenActivePharmaceuticalIngredientMember_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_PelacarsenActivePharmaceuticalIngredientMember_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_PelacarsenActivePharmaceuticalIngredientMember_lbl2" xml:lang="en-US" id="ions_PelacarsenActivePharmaceuticalIngredientMember_lbl2">Pelacarsen API [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="PelacarsenActivePharmaceuticalIngredientMember" xlink:to="ions_PelacarsenActivePharmaceuticalIngredientMember_lbl2" xlink:title="label: PelacarsenActivePharmaceuticalIngredientMember to ions_PelacarsenActivePharmaceuticalIngredientMember_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_MaximumAmountOfPaymentsReceivableForMilestones" xlink:label="MaximumAmountOfPaymentsReceivableForMilestones" xlink:title="MaximumAmountOfPaymentsReceivableForMilestones" />
    <link:label xlink:type="resource" xlink:label="ions_MaximumAmountOfPaymentsReceivableForMilestones_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_MaximumAmountOfPaymentsReceivableForMilestones_lbl" xml:lang="en-US" id="ions_MaximumAmountOfPaymentsReceivableForMilestones_lbl">The maximum amount of payments receivable for milestones under the collaboration agreement.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="MaximumAmountOfPaymentsReceivableForMilestones" xlink:to="ions_MaximumAmountOfPaymentsReceivableForMilestones_lbl" xlink:title="label: MaximumAmountOfPaymentsReceivableForMilestones to ions_MaximumAmountOfPaymentsReceivableForMilestones_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_MaximumAmountOfPaymentsReceivableForMilestones_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_MaximumAmountOfPaymentsReceivableForMilestones_lbl1" xml:lang="en-US" id="ions_MaximumAmountOfPaymentsReceivableForMilestones_lbl1">Maximum amount of payments receivable for milestones</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="MaximumAmountOfPaymentsReceivableForMilestones" xlink:to="ions_MaximumAmountOfPaymentsReceivableForMilestones_lbl1" xlink:title="label: MaximumAmountOfPaymentsReceivableForMilestones to ions_MaximumAmountOfPaymentsReceivableForMilestones_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_MaximumAmountOfPaymentsReceivableForMilestones_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_MaximumAmountOfPaymentsReceivableForMilestones_lbl2" xml:lang="en-US" id="ions_MaximumAmountOfPaymentsReceivableForMilestones_lbl2">Maximum amount of payments receivable for milestones</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="MaximumAmountOfPaymentsReceivableForMilestones" xlink:to="ions_MaximumAmountOfPaymentsReceivableForMilestones_lbl2" xlink:title="label: MaximumAmountOfPaymentsReceivableForMilestones to ions_MaximumAmountOfPaymentsReceivableForMilestones_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_PremiumReceivedOnSharesIssued" xlink:label="PremiumReceivedOnSharesIssued" xlink:title="PremiumReceivedOnSharesIssued" />
    <link:label xlink:type="resource" xlink:label="ions_PremiumReceivedOnSharesIssued_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_PremiumReceivedOnSharesIssued_lbl" xml:lang="en-US" id="ions_PremiumReceivedOnSharesIssued_lbl">The total amount of the premium received over the trading price of common stock at the time of purchase.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="PremiumReceivedOnSharesIssued" xlink:to="ions_PremiumReceivedOnSharesIssued_lbl" xlink:title="label: PremiumReceivedOnSharesIssued to ions_PremiumReceivedOnSharesIssued_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_PremiumReceivedOnSharesIssued_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_PremiumReceivedOnSharesIssued_lbl1" xml:lang="en-US" id="ions_PremiumReceivedOnSharesIssued_lbl1">Premium received on shares issued</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="PremiumReceivedOnSharesIssued" xlink:to="ions_PremiumReceivedOnSharesIssued_lbl1" xlink:title="label: PremiumReceivedOnSharesIssued to ions_PremiumReceivedOnSharesIssued_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_PremiumReceivedOnSharesIssued_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_PremiumReceivedOnSharesIssued_lbl2" xml:lang="en-US" id="ions_PremiumReceivedOnSharesIssued_lbl2">Premium received on shares issued</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="PremiumReceivedOnSharesIssued" xlink:to="ions_PremiumReceivedOnSharesIssued_lbl2" xlink:title="label: PremiumReceivedOnSharesIssued to ions_PremiumReceivedOnSharesIssued_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_PotentialPremiumReceivedIfCommonStockIsPurchasedInFuture" xlink:label="PotentialPremiumReceivedIfCommonStockIsPurchasedInFuture" xlink:title="PotentialPremiumReceivedIfCommonStockIsPurchasedInFuture" />
    <link:label xlink:type="resource" xlink:label="ions_PotentialPremiumReceivedIfCommonStockIsPurchasedInFuture_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_PotentialPremiumReceivedIfCommonStockIsPurchasedInFuture_lbl" xml:lang="en-US" id="ions_PotentialPremiumReceivedIfCommonStockIsPurchasedInFuture_lbl">The potential premium received if common stock is purchased in the future under a Stock Purchase Agreement (SPA) in conjunction with the collaboration agreement.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="PotentialPremiumReceivedIfCommonStockIsPurchasedInFuture" xlink:to="ions_PotentialPremiumReceivedIfCommonStockIsPurchasedInFuture_lbl" xlink:title="label: PotentialPremiumReceivedIfCommonStockIsPurchasedInFuture to ions_PotentialPremiumReceivedIfCommonStockIsPurchasedInFuture_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_PotentialPremiumReceivedIfCommonStockIsPurchasedInFuture_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_PotentialPremiumReceivedIfCommonStockIsPurchasedInFuture_lbl1" xml:lang="en-US" id="ions_PotentialPremiumReceivedIfCommonStockIsPurchasedInFuture_lbl1">Potential premium received if common stock is purchased in future</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="PotentialPremiumReceivedIfCommonStockIsPurchasedInFuture" xlink:to="ions_PotentialPremiumReceivedIfCommonStockIsPurchasedInFuture_lbl1" xlink:title="label: PotentialPremiumReceivedIfCommonStockIsPurchasedInFuture to ions_PotentialPremiumReceivedIfCommonStockIsPurchasedInFuture_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_PotentialPremiumReceivedIfCommonStockIsPurchasedInFuture_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_PotentialPremiumReceivedIfCommonStockIsPurchasedInFuture_lbl2" xml:lang="en-US" id="ions_PotentialPremiumReceivedIfCommonStockIsPurchasedInFuture_lbl2">Potential premium received if common stock is purchased in the future</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="PotentialPremiumReceivedIfCommonStockIsPurchasedInFuture" xlink:to="ions_PotentialPremiumReceivedIfCommonStockIsPurchasedInFuture_lbl2" xlink:title="label: PotentialPremiumReceivedIfCommonStockIsPurchasedInFuture to ions_PotentialPremiumReceivedIfCommonStockIsPurchasedInFuture_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_PtcTherapeuticsCollaborationMember" xlink:label="PtcTherapeuticsCollaborationMember" xlink:title="PtcTherapeuticsCollaborationMember" />
    <link:label xlink:type="resource" xlink:label="ions_PtcTherapeuticsCollaborationMember_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_PtcTherapeuticsCollaborationMember_lbl" xml:lang="en-US" id="ions_PtcTherapeuticsCollaborationMember_lbl">Exclusive license agreement entered into with PTC Therapeutics in August 2018 to commercialize TEGSEDI and WAYLIVRA in Latin America and certain Caribbean countries.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="PtcTherapeuticsCollaborationMember" xlink:to="ions_PtcTherapeuticsCollaborationMember_lbl" xlink:title="label: PtcTherapeuticsCollaborationMember to ions_PtcTherapeuticsCollaborationMember_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_PtcTherapeuticsCollaborationMember_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_PtcTherapeuticsCollaborationMember_lbl1" xml:lang="en-US" id="ions_PtcTherapeuticsCollaborationMember_lbl1">PTC Therapeutics Collaboration [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="PtcTherapeuticsCollaborationMember" xlink:to="ions_PtcTherapeuticsCollaborationMember_lbl1" xlink:title="label: PtcTherapeuticsCollaborationMember to ions_PtcTherapeuticsCollaborationMember_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_PtcTherapeuticsCollaborationMember_lbl2" xlink:role="http://www.xbrl.org/2003/role/verboseLabel" xlink:title="ions_PtcTherapeuticsCollaborationMember_lbl2" xml:lang="en-US" id="ions_PtcTherapeuticsCollaborationMember_lbl2">PTC Therapeutics [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="PtcTherapeuticsCollaborationMember" xlink:to="ions_PtcTherapeuticsCollaborationMember_lbl2" xlink:title="label: PtcTherapeuticsCollaborationMember to ions_PtcTherapeuticsCollaborationMember_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_RoyaltyPercentageReceivedOnNetSalesOfEachMedicineFromCollaborationPartner" xlink:label="RoyaltyPercentageReceivedOnNetSalesOfEachMedicineFromCollaborationPartner" xlink:title="RoyaltyPercentageReceivedOnNetSalesOfEachMedicineFromCollaborationPartner" />
    <link:label xlink:type="resource" xlink:label="ions_RoyaltyPercentageReceivedOnNetSalesOfEachMedicineFromCollaborationPartner_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_RoyaltyPercentageReceivedOnNetSalesOfEachMedicineFromCollaborationPartner_lbl" xml:lang="en-US" id="ions_RoyaltyPercentageReceivedOnNetSalesOfEachMedicineFromCollaborationPartner_lbl">Royalty percentage received on the net sales of each medicine from the collaboration partner under the collaboration agreement.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="RoyaltyPercentageReceivedOnNetSalesOfEachMedicineFromCollaborationPartner" xlink:to="ions_RoyaltyPercentageReceivedOnNetSalesOfEachMedicineFromCollaborationPartner_lbl" xlink:title="label: RoyaltyPercentageReceivedOnNetSalesOfEachMedicineFromCollaborationPartner to ions_RoyaltyPercentageReceivedOnNetSalesOfEachMedicineFromCollaborationPartner_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_RoyaltyPercentageReceivedOnNetSalesOfEachMedicineFromCollaborationPartner_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_RoyaltyPercentageReceivedOnNetSalesOfEachMedicineFromCollaborationPartner_lbl1" xml:lang="en-US" id="ions_RoyaltyPercentageReceivedOnNetSalesOfEachMedicineFromCollaborationPartner_lbl1">Royalty percentage received on net sales of each medicine from collaboration partner</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="RoyaltyPercentageReceivedOnNetSalesOfEachMedicineFromCollaborationPartner" xlink:to="ions_RoyaltyPercentageReceivedOnNetSalesOfEachMedicineFromCollaborationPartner_lbl1" xlink:title="label: RoyaltyPercentageReceivedOnNetSalesOfEachMedicineFromCollaborationPartner to ions_RoyaltyPercentageReceivedOnNetSalesOfEachMedicineFromCollaborationPartner_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_RoyaltyPercentageReceivedOnNetSalesOfEachMedicineFromCollaborationPartner_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_RoyaltyPercentageReceivedOnNetSalesOfEachMedicineFromCollaborationPartner_lbl2" xml:lang="en-US" id="ions_RoyaltyPercentageReceivedOnNetSalesOfEachMedicineFromCollaborationPartner_lbl2">Royalty percentage received on net sales of each medicine from PTC</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="RoyaltyPercentageReceivedOnNetSalesOfEachMedicineFromCollaborationPartner" xlink:to="ions_RoyaltyPercentageReceivedOnNetSalesOfEachMedicineFromCollaborationPartner_lbl2" xlink:title="label: RoyaltyPercentageReceivedOnNetSalesOfEachMedicineFromCollaborationPartner to ions_RoyaltyPercentageReceivedOnNetSalesOfEachMedicineFromCollaborationPartner_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_EplontersenMember" xlink:label="EplontersenMember" xlink:title="EplontersenMember" />
    <link:label xlink:type="resource" xlink:label="ions_EplontersenMember_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_EplontersenMember_lbl" xml:lang="en-US" id="ions_EplontersenMember_lbl">Eplontersen, formerly known as IONIS-TTR-L and AKCEA-TTR-L, is a ligand-conjugated (LICA) investigational antisense medicine designed to reduce the production of transthyretin, or TTR protein, to treat all types of TTR amyloidosis (ATTR), a systemic, progressive and fatal disease.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="EplontersenMember" xlink:to="ions_EplontersenMember_lbl" xlink:title="label: EplontersenMember to ions_EplontersenMember_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_EplontersenMember_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_EplontersenMember_lbl1" xml:lang="en-US" id="ions_EplontersenMember_lbl1">Eplontersen [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="EplontersenMember" xlink:to="ions_EplontersenMember_lbl1" xlink:title="label: EplontersenMember to ions_EplontersenMember_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_EplontersenMember_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_EplontersenMember_lbl2" xml:lang="en-US" id="ions_EplontersenMember_lbl2">Eplontersen [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="EplontersenMember" xlink:to="ions_EplontersenMember_lbl2" xlink:title="label: EplontersenMember to ions_EplontersenMember_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_AlnylamCollaborationMember" xlink:label="AlnylamCollaborationMember" xlink:title="AlnylamCollaborationMember" />
    <link:label xlink:type="resource" xlink:label="ions_AlnylamCollaborationMember_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_AlnylamCollaborationMember_lbl" xml:lang="en-US" id="ions_AlnylamCollaborationMember_lbl">Collaboration agreement entered into with Alnylam Pharmaceuticals, Inc. in March 2004 to develop and commercialize RNAi therapeutics.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="AlnylamCollaborationMember" xlink:to="ions_AlnylamCollaborationMember_lbl" xlink:title="label: AlnylamCollaborationMember to ions_AlnylamCollaborationMember_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_AlnylamCollaborationMember_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_AlnylamCollaborationMember_lbl1" xml:lang="en-US" id="ions_AlnylamCollaborationMember_lbl1">Alnylam Collaboration [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="AlnylamCollaborationMember" xlink:to="ions_AlnylamCollaborationMember_lbl1" xlink:title="label: AlnylamCollaborationMember to ions_AlnylamCollaborationMember_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_AlnylamCollaborationMember_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_AlnylamCollaborationMember_lbl2" xml:lang="en-US" id="ions_AlnylamCollaborationMember_lbl2">Alnylam [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="AlnylamCollaborationMember" xlink:to="ions_AlnylamCollaborationMember_lbl2" xlink:title="label: AlnylamCollaborationMember to ions_AlnylamCollaborationMember_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_RevenueFromContractWithCustomerTransactionPriceAdditions" xlink:label="RevenueFromContractWithCustomerTransactionPriceAdditions" xlink:title="RevenueFromContractWithCustomerTransactionPriceAdditions" />
    <link:label xlink:type="resource" xlink:label="ions_RevenueFromContractWithCustomerTransactionPriceAdditions_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_RevenueFromContractWithCustomerTransactionPriceAdditions_lbl" xml:lang="en-US" id="ions_RevenueFromContractWithCustomerTransactionPriceAdditions_lbl">The additional amount of consideration the Company earned under the collaboration agreement that is added to the transaction price.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="RevenueFromContractWithCustomerTransactionPriceAdditions" xlink:to="ions_RevenueFromContractWithCustomerTransactionPriceAdditions_lbl" xlink:title="label: RevenueFromContractWithCustomerTransactionPriceAdditions to ions_RevenueFromContractWithCustomerTransactionPriceAdditions_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_RevenueFromContractWithCustomerTransactionPriceAdditions_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_RevenueFromContractWithCustomerTransactionPriceAdditions_lbl1" xml:lang="en-US" id="ions_RevenueFromContractWithCustomerTransactionPriceAdditions_lbl1">Revenue from Contract with Customer, Transaction Price, Additions</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="RevenueFromContractWithCustomerTransactionPriceAdditions" xlink:to="ions_RevenueFromContractWithCustomerTransactionPriceAdditions_lbl1" xlink:title="label: RevenueFromContractWithCustomerTransactionPriceAdditions to ions_RevenueFromContractWithCustomerTransactionPriceAdditions_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_RevenueFromContractWithCustomerTransactionPriceAdditions_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_RevenueFromContractWithCustomerTransactionPriceAdditions_lbl2" xml:lang="en-US" id="ions_RevenueFromContractWithCustomerTransactionPriceAdditions_lbl2">Milestone payment received and added to transaction price</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="RevenueFromContractWithCustomerTransactionPriceAdditions" xlink:to="ions_RevenueFromContractWithCustomerTransactionPriceAdditions_lbl2" xlink:title="label: RevenueFromContractWithCustomerTransactionPriceAdditions to ions_RevenueFromContractWithCustomerTransactionPriceAdditions_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_NumberOfAgreementsWithCollaborationPartner" xlink:label="NumberOfAgreementsWithCollaborationPartner" xlink:title="NumberOfAgreementsWithCollaborationPartner" />
    <link:label xlink:type="resource" xlink:label="ions_NumberOfAgreementsWithCollaborationPartner_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_NumberOfAgreementsWithCollaborationPartner_lbl" xml:lang="en-US" id="ions_NumberOfAgreementsWithCollaborationPartner_lbl">The number of agreements entered into with the collaboration partner.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="NumberOfAgreementsWithCollaborationPartner" xlink:to="ions_NumberOfAgreementsWithCollaborationPartner_lbl" xlink:title="label: NumberOfAgreementsWithCollaborationPartner to ions_NumberOfAgreementsWithCollaborationPartner_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_NumberOfAgreementsWithCollaborationPartner_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_NumberOfAgreementsWithCollaborationPartner_lbl1" xml:lang="en-US" id="ions_NumberOfAgreementsWithCollaborationPartner_lbl1">Number of agreements with collaboration partner</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="NumberOfAgreementsWithCollaborationPartner" xlink:to="ions_NumberOfAgreementsWithCollaborationPartner_lbl1" xlink:title="label: NumberOfAgreementsWithCollaborationPartner to ions_NumberOfAgreementsWithCollaborationPartner_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_NumberOfAgreementsWithCollaborationPartner_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_NumberOfAgreementsWithCollaborationPartner_lbl2" xml:lang="en-US" id="ions_NumberOfAgreementsWithCollaborationPartner_lbl2">Number of agreements</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="NumberOfAgreementsWithCollaborationPartner" xlink:to="ions_NumberOfAgreementsWithCollaborationPartner_lbl2" xlink:title="label: NumberOfAgreementsWithCollaborationPartner to ions_NumberOfAgreementsWithCollaborationPartner_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_BiogenIncMember" xlink:label="BiogenIncMember" xlink:title="BiogenIncMember" />
    <link:label xlink:type="resource" xlink:label="ions_BiogenIncMember_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_BiogenIncMember_lbl" xml:lang="en-US" id="ions_BiogenIncMember_lbl">Biogen Inc. is an American multinational biotechnology company.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="BiogenIncMember" xlink:to="ions_BiogenIncMember_lbl" xlink:title="label: BiogenIncMember to ions_BiogenIncMember_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_BiogenIncMember_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_BiogenIncMember_lbl1" xml:lang="en-US" id="ions_BiogenIncMember_lbl1">Biogen Inc. [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="BiogenIncMember" xlink:to="ions_BiogenIncMember_lbl1" xlink:title="label: BiogenIncMember to ions_BiogenIncMember_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_BiogenIncMember_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_BiogenIncMember_lbl2" xml:lang="en-US" id="ions_BiogenIncMember_lbl2">Biogen [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="BiogenIncMember" xlink:to="ions_BiogenIncMember_lbl2" xlink:title="label: BiogenIncMember to ions_BiogenIncMember_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_NumberOfNewTargetsAdvanced" xlink:label="NumberOfNewTargetsAdvanced" xlink:title="NumberOfNewTargetsAdvanced" />
    <link:label xlink:type="resource" xlink:label="ions_NumberOfNewTargetsAdvanced_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_NumberOfNewTargetsAdvanced_lbl" xml:lang="en-US" id="ions_NumberOfNewTargetsAdvanced_lbl">The number of new targets advanced during the period under the collaboration agreement.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="NumberOfNewTargetsAdvanced" xlink:to="ions_NumberOfNewTargetsAdvanced_lbl" xlink:title="label: NumberOfNewTargetsAdvanced to ions_NumberOfNewTargetsAdvanced_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_NumberOfNewTargetsAdvanced_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_NumberOfNewTargetsAdvanced_lbl1" xml:lang="en-US" id="ions_NumberOfNewTargetsAdvanced_lbl1">Number of new targets advanced</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="NumberOfNewTargetsAdvanced" xlink:to="ions_NumberOfNewTargetsAdvanced_lbl1" xlink:title="label: NumberOfNewTargetsAdvanced to ions_NumberOfNewTargetsAdvanced_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_NumberOfNewTargetsAdvanced_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_NumberOfNewTargetsAdvanced_lbl2" xml:lang="en-US" id="ions_NumberOfNewTargetsAdvanced_lbl2">Number of new targets advanced</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="NumberOfNewTargetsAdvanced" xlink:to="ions_NumberOfNewTargetsAdvanced_lbl2" xlink:title="label: NumberOfNewTargetsAdvanced to ions_NumberOfNewTargetsAdvanced_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_RestructuringReserveRestructuringChargesNetOfReserveAdjustments" xlink:label="RestructuringReserveRestructuringChargesNetOfReserveAdjustments" xlink:title="RestructuringReserveRestructuringChargesNetOfReserveAdjustments" />
    <link:label xlink:type="resource" xlink:label="ions_RestructuringReserveRestructuringChargesNetOfReserveAdjustments_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_RestructuringReserveRestructuringChargesNetOfReserveAdjustments_lbl" xml:lang="en-US" id="ions_RestructuringReserveRestructuringChargesNetOfReserveAdjustments_lbl">Amount of expenses associated with exit or disposal activities pursuant to an authorized plan, net of adjustments to a previously accrued restructuring liability. Excludes expenses related to a discontinued operation or an asset retirement obligation.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="RestructuringReserveRestructuringChargesNetOfReserveAdjustments" xlink:to="ions_RestructuringReserveRestructuringChargesNetOfReserveAdjustments_lbl" xlink:title="label: RestructuringReserveRestructuringChargesNetOfReserveAdjustments to ions_RestructuringReserveRestructuringChargesNetOfReserveAdjustments_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_RestructuringReserveRestructuringChargesNetOfReserveAdjustments_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_RestructuringReserveRestructuringChargesNetOfReserveAdjustments_lbl1" xml:lang="en-US" id="ions_RestructuringReserveRestructuringChargesNetOfReserveAdjustments_lbl1">Restructuring Reserve, Restructuring Charges, Net of Reserve Adjustments</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="RestructuringReserveRestructuringChargesNetOfReserveAdjustments" xlink:to="ions_RestructuringReserveRestructuringChargesNetOfReserveAdjustments_lbl1" xlink:title="label: RestructuringReserveRestructuringChargesNetOfReserveAdjustments to ions_RestructuringReserveRestructuringChargesNetOfReserveAdjustments_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_RestructuringReserveRestructuringChargesNetOfReserveAdjustments_lbl2" xlink:role="http://www.xbrl.org/2003/role/totalLabel" xlink:title="ions_RestructuringReserveRestructuringChargesNetOfReserveAdjustments_lbl2" xml:lang="en-US" id="ions_RestructuringReserveRestructuringChargesNetOfReserveAdjustments_lbl2">Net amount expensed during the year</link:label>
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    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_PaymentsForCancelledEquityAwards" xlink:label="PaymentsForCancelledEquityAwards" xlink:title="PaymentsForCancelledEquityAwards" />
    <link:label xlink:type="resource" xlink:label="ions_PaymentsForCancelledEquityAwards_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_PaymentsForCancelledEquityAwards_lbl" xml:lang="en-US" id="ions_PaymentsForCancelledEquityAwards_lbl">The aggregate amount paid by the entity to cancel subsidiary's outstanding equity awards.</link:label>
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    <link:label xlink:type="resource" xlink:label="ions_PaymentsForCancelledEquityAwards_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_PaymentsForCancelledEquityAwards_lbl1" xml:lang="en-US" id="ions_PaymentsForCancelledEquityAwards_lbl1">Payments for cancelled equity awards</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="PaymentsForCancelledEquityAwards" xlink:to="ions_PaymentsForCancelledEquityAwards_lbl1" xlink:title="label: PaymentsForCancelledEquityAwards to ions_PaymentsForCancelledEquityAwards_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_PaymentsForCancelledEquityAwards_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_PaymentsForCancelledEquityAwards_lbl2" xml:lang="en-US" id="ions_PaymentsForCancelledEquityAwards_lbl2">Payments for cancelled equity awards</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="PaymentsForCancelledEquityAwards" xlink:to="ions_PaymentsForCancelledEquityAwards_lbl2" xlink:title="label: PaymentsForCancelledEquityAwards to ions_PaymentsForCancelledEquityAwards_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_ConsolidationLessThanWhollyOwnedSubsidiaryParentOwnershipInterestChangesPurchaseOfInterestByParentShares" xlink:label="ConsolidationLessThanWhollyOwnedSubsidiaryParentOwnershipInterestChangesPurchaseOfInterestByParentShares" xlink:title="ConsolidationLessThanWhollyOwnedSubsidiaryParentOwnershipInterestChangesPurchaseOfInterestByParentShares" />
    <link:label xlink:type="resource" xlink:label="ions_ConsolidationLessThanWhollyOwnedSubsidiaryParentOwnershipInterestChangesPurchaseOfInterestByParentShares_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_ConsolidationLessThanWhollyOwnedSubsidiaryParentOwnershipInterestChangesPurchaseOfInterestByParentShares_lbl" xml:lang="en-US" id="ions_ConsolidationLessThanWhollyOwnedSubsidiaryParentOwnershipInterestChangesPurchaseOfInterestByParentShares_lbl">Number of shares of the subsidiary purchased by the parent during the period, thereby effecting a change in total (consolidated) equity attributable to the parent.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="ConsolidationLessThanWhollyOwnedSubsidiaryParentOwnershipInterestChangesPurchaseOfInterestByParentShares" xlink:to="ions_ConsolidationLessThanWhollyOwnedSubsidiaryParentOwnershipInterestChangesPurchaseOfInterestByParentShares_lbl" xlink:title="label: ConsolidationLessThanWhollyOwnedSubsidiaryParentOwnershipInterestChangesPurchaseOfInterestByParentShares to ions_ConsolidationLessThanWhollyOwnedSubsidiaryParentOwnershipInterestChangesPurchaseOfInterestByParentShares_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_ConsolidationLessThanWhollyOwnedSubsidiaryParentOwnershipInterestChangesPurchaseOfInterestByParentShares_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_ConsolidationLessThanWhollyOwnedSubsidiaryParentOwnershipInterestChangesPurchaseOfInterestByParentShares_lbl1" xml:lang="en-US" id="ions_ConsolidationLessThanWhollyOwnedSubsidiaryParentOwnershipInterestChangesPurchaseOfInterestByParentShares_lbl1">Consolidation, Less than Wholly Owned Subsidiary, Parent Ownership Interest, Changes, Purchase of Interest by Parent, Shares</link:label>
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    <link:label xlink:type="resource" xlink:label="ions_ConsolidationLessThanWhollyOwnedSubsidiaryParentOwnershipInterestChangesPurchaseOfInterestByParentShares_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_ConsolidationLessThanWhollyOwnedSubsidiaryParentOwnershipInterestChangesPurchaseOfInterestByParentShares_lbl2" xml:lang="en-US" id="ions_ConsolidationLessThanWhollyOwnedSubsidiaryParentOwnershipInterestChangesPurchaseOfInterestByParentShares_lbl2">Shares purchased (in shares)</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="ConsolidationLessThanWhollyOwnedSubsidiaryParentOwnershipInterestChangesPurchaseOfInterestByParentShares" xlink:to="ions_ConsolidationLessThanWhollyOwnedSubsidiaryParentOwnershipInterestChangesPurchaseOfInterestByParentShares_lbl2" xlink:title="label: ConsolidationLessThanWhollyOwnedSubsidiaryParentOwnershipInterestChangesPurchaseOfInterestByParentShares to ions_ConsolidationLessThanWhollyOwnedSubsidiaryParentOwnershipInterestChangesPurchaseOfInterestByParentShares_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_ResearchDevelopmentAndPatentExpensesMember" xlink:label="ResearchDevelopmentAndPatentExpensesMember" xlink:title="ResearchDevelopmentAndPatentExpensesMember" />
    <link:label xlink:type="resource" xlink:label="ions_ResearchDevelopmentAndPatentExpensesMember_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_ResearchDevelopmentAndPatentExpensesMember_lbl" xml:lang="en-US" id="ions_ResearchDevelopmentAndPatentExpensesMember_lbl">Primary financial statement caption encompassing research, development and patent expenses.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="ResearchDevelopmentAndPatentExpensesMember" xlink:to="ions_ResearchDevelopmentAndPatentExpensesMember_lbl" xlink:title="label: ResearchDevelopmentAndPatentExpensesMember to ions_ResearchDevelopmentAndPatentExpensesMember_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_ResearchDevelopmentAndPatentExpensesMember_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_ResearchDevelopmentAndPatentExpensesMember_lbl1" xml:lang="en-US" id="ions_ResearchDevelopmentAndPatentExpensesMember_lbl1">Research, Development and Patent Expenses [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="ResearchDevelopmentAndPatentExpensesMember" xlink:to="ions_ResearchDevelopmentAndPatentExpensesMember_lbl1" xlink:title="label: ResearchDevelopmentAndPatentExpensesMember to ions_ResearchDevelopmentAndPatentExpensesMember_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_ResearchDevelopmentAndPatentExpensesMember_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_ResearchDevelopmentAndPatentExpensesMember_lbl2" xml:lang="en-US" id="ions_ResearchDevelopmentAndPatentExpensesMember_lbl2">R&amp;D Expenses [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="ResearchDevelopmentAndPatentExpensesMember" xlink:to="ions_ResearchDevelopmentAndPatentExpensesMember_lbl2" xlink:title="label: ResearchDevelopmentAndPatentExpensesMember to ions_ResearchDevelopmentAndPatentExpensesMember_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_EmployeeRelatedLiabilitiesCurrentMember" xlink:label="EmployeeRelatedLiabilitiesCurrentMember" xlink:title="EmployeeRelatedLiabilitiesCurrentMember" />
    <link:label xlink:type="resource" xlink:label="ions_EmployeeRelatedLiabilitiesCurrentMember_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_EmployeeRelatedLiabilitiesCurrentMember_lbl" xml:lang="en-US" id="ions_EmployeeRelatedLiabilitiesCurrentMember_lbl">Primary financial statement caption encompassing current employee-related liabilities.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="EmployeeRelatedLiabilitiesCurrentMember" xlink:to="ions_EmployeeRelatedLiabilitiesCurrentMember_lbl" xlink:title="label: EmployeeRelatedLiabilitiesCurrentMember to ions_EmployeeRelatedLiabilitiesCurrentMember_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_EmployeeRelatedLiabilitiesCurrentMember_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_EmployeeRelatedLiabilitiesCurrentMember_lbl1" xml:lang="en-US" id="ions_EmployeeRelatedLiabilitiesCurrentMember_lbl1">Employee-related Liabilities, Current [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="EmployeeRelatedLiabilitiesCurrentMember" xlink:to="ions_EmployeeRelatedLiabilitiesCurrentMember_lbl1" xlink:title="label: EmployeeRelatedLiabilitiesCurrentMember to ions_EmployeeRelatedLiabilitiesCurrentMember_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_EmployeeRelatedLiabilitiesCurrentMember_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_EmployeeRelatedLiabilitiesCurrentMember_lbl2" xml:lang="en-US" id="ions_EmployeeRelatedLiabilitiesCurrentMember_lbl2">Accrued Compensation [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="EmployeeRelatedLiabilitiesCurrentMember" xlink:to="ions_EmployeeRelatedLiabilitiesCurrentMember_lbl2" xlink:title="label: EmployeeRelatedLiabilitiesCurrentMember to ions_EmployeeRelatedLiabilitiesCurrentMember_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_AkceaMergerMember" xlink:label="AkceaMergerMember" xlink:title="AkceaMergerMember" />
    <link:label xlink:type="resource" xlink:label="ions_AkceaMergerMember_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_AkceaMergerMember_lbl" xml:lang="en-US" id="ions_AkceaMergerMember_lbl">In October 2020, the reacquired the shares of Akcea's common stock they did not own, increasing the Company's ownership to 100 percent.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="AkceaMergerMember" xlink:to="ions_AkceaMergerMember_lbl" xlink:title="label: AkceaMergerMember to ions_AkceaMergerMember_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_AkceaMergerMember_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_AkceaMergerMember_lbl1" xml:lang="en-US" id="ions_AkceaMergerMember_lbl1">Akcea Merger [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="AkceaMergerMember" xlink:to="ions_AkceaMergerMember_lbl1" xlink:title="label: AkceaMergerMember to ions_AkceaMergerMember_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_AkceaMergerMember_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_AkceaMergerMember_lbl2" xml:lang="en-US" id="ions_AkceaMergerMember_lbl2">Akcea Merger [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="AkceaMergerMember" xlink:to="ions_AkceaMergerMember_lbl2" xlink:title="label: AkceaMergerMember to ions_AkceaMergerMember_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_CashPurchasePriceOfEquityAwards" xlink:label="CashPurchasePriceOfEquityAwards" xlink:title="CashPurchasePriceOfEquityAwards" />
    <link:label xlink:type="resource" xlink:label="ions_CashPurchasePriceOfEquityAwards_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_CashPurchasePriceOfEquityAwards_lbl" xml:lang="en-US" id="ions_CashPurchasePriceOfEquityAwards_lbl">Cash purchase price for each equity award held, including stock options and restricted stock units (RSUs).</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="CashPurchasePriceOfEquityAwards" xlink:to="ions_CashPurchasePriceOfEquityAwards_lbl" xlink:title="label: CashPurchasePriceOfEquityAwards to ions_CashPurchasePriceOfEquityAwards_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_CashPurchasePriceOfEquityAwards_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_CashPurchasePriceOfEquityAwards_lbl1" xml:lang="en-US" id="ions_CashPurchasePriceOfEquityAwards_lbl1">Cash purchase price of equity awards</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="CashPurchasePriceOfEquityAwards" xlink:to="ions_CashPurchasePriceOfEquityAwards_lbl1" xlink:title="label: CashPurchasePriceOfEquityAwards to ions_CashPurchasePriceOfEquityAwards_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_CashPurchasePriceOfEquityAwards_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_CashPurchasePriceOfEquityAwards_lbl2" xml:lang="en-US" id="ions_CashPurchasePriceOfEquityAwards_lbl2">Cash purchase price of equity awards (in dollars per share)</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="CashPurchasePriceOfEquityAwards" xlink:to="ions_CashPurchasePriceOfEquityAwards_lbl2" xlink:title="label: CashPurchasePriceOfEquityAwards to ions_CashPurchasePriceOfEquityAwards_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_ConsolidationLessThanWhollyOwnedSubsidiaryParentOwnershipInterestChangesPurchaseOfInterestByParentPricePerShare" xlink:label="ConsolidationLessThanWhollyOwnedSubsidiaryParentOwnershipInterestChangesPurchaseOfInterestByParentPricePerShare" xlink:title="ConsolidationLessThanWhollyOwnedSubsidiaryParentOwnershipInterestChangesPurchaseOfInterestByParentPricePerShare" />
    <link:label xlink:type="resource" xlink:label="ions_ConsolidationLessThanWhollyOwnedSubsidiaryParentOwnershipInterestChangesPurchaseOfInterestByParentPricePerShare_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_ConsolidationLessThanWhollyOwnedSubsidiaryParentOwnershipInterestChangesPurchaseOfInterestByParentPricePerShare_lbl" xml:lang="en-US" id="ions_ConsolidationLessThanWhollyOwnedSubsidiaryParentOwnershipInterestChangesPurchaseOfInterestByParentPricePerShare_lbl">Per share amount paid for the shares of the subsidiary purchased by the parent during the period, thereby effecting a change in total (consolidated) equity attributable to the parent.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="ConsolidationLessThanWhollyOwnedSubsidiaryParentOwnershipInterestChangesPurchaseOfInterestByParentPricePerShare" xlink:to="ions_ConsolidationLessThanWhollyOwnedSubsidiaryParentOwnershipInterestChangesPurchaseOfInterestByParentPricePerShare_lbl" xlink:title="label: ConsolidationLessThanWhollyOwnedSubsidiaryParentOwnershipInterestChangesPurchaseOfInterestByParentPricePerShare to ions_ConsolidationLessThanWhollyOwnedSubsidiaryParentOwnershipInterestChangesPurchaseOfInterestByParentPricePerShare_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_ConsolidationLessThanWhollyOwnedSubsidiaryParentOwnershipInterestChangesPurchaseOfInterestByParentPricePerShare_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_ConsolidationLessThanWhollyOwnedSubsidiaryParentOwnershipInterestChangesPurchaseOfInterestByParentPricePerShare_lbl1" xml:lang="en-US" id="ions_ConsolidationLessThanWhollyOwnedSubsidiaryParentOwnershipInterestChangesPurchaseOfInterestByParentPricePerShare_lbl1">Consolidation, Less than Wholly Owned Subsidiary, Parent Ownership Interest, Changes, Purchase of Interest by Parent, Price per Share</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="ConsolidationLessThanWhollyOwnedSubsidiaryParentOwnershipInterestChangesPurchaseOfInterestByParentPricePerShare" xlink:to="ions_ConsolidationLessThanWhollyOwnedSubsidiaryParentOwnershipInterestChangesPurchaseOfInterestByParentPricePerShare_lbl1" xlink:title="label: ConsolidationLessThanWhollyOwnedSubsidiaryParentOwnershipInterestChangesPurchaseOfInterestByParentPricePerShare to ions_ConsolidationLessThanWhollyOwnedSubsidiaryParentOwnershipInterestChangesPurchaseOfInterestByParentPricePerShare_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_ConsolidationLessThanWhollyOwnedSubsidiaryParentOwnershipInterestChangesPurchaseOfInterestByParentPricePerShare_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_ConsolidationLessThanWhollyOwnedSubsidiaryParentOwnershipInterestChangesPurchaseOfInterestByParentPricePerShare_lbl2" xml:lang="en-US" id="ions_ConsolidationLessThanWhollyOwnedSubsidiaryParentOwnershipInterestChangesPurchaseOfInterestByParentPricePerShare_lbl2">Purchase price per share (in dollars per share)</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="ConsolidationLessThanWhollyOwnedSubsidiaryParentOwnershipInterestChangesPurchaseOfInterestByParentPricePerShare" xlink:to="ions_ConsolidationLessThanWhollyOwnedSubsidiaryParentOwnershipInterestChangesPurchaseOfInterestByParentPricePerShare_lbl2" xlink:title="label: ConsolidationLessThanWhollyOwnedSubsidiaryParentOwnershipInterestChangesPurchaseOfInterestByParentPricePerShare to ions_ConsolidationLessThanWhollyOwnedSubsidiaryParentOwnershipInterestChangesPurchaseOfInterestByParentPricePerShare_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_UpdatedEuropeanDistributionModelEmployeeSeveranceAndRetentionMember" xlink:label="UpdatedEuropeanDistributionModelEmployeeSeveranceAndRetentionMember" xlink:title="UpdatedEuropeanDistributionModelEmployeeSeveranceAndRetentionMember" />
    <link:label xlink:type="resource" xlink:label="ions_UpdatedEuropeanDistributionModelEmployeeSeveranceAndRetentionMember_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_UpdatedEuropeanDistributionModelEmployeeSeveranceAndRetentionMember_lbl" xml:lang="en-US" id="ions_UpdatedEuropeanDistributionModelEmployeeSeveranceAndRetentionMember_lbl">Termination of employees and retention of key employees for a specific period of time associated with an updated European Distribution model for TEGSEDI and WAYLIVRA.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="UpdatedEuropeanDistributionModelEmployeeSeveranceAndRetentionMember" xlink:to="ions_UpdatedEuropeanDistributionModelEmployeeSeveranceAndRetentionMember_lbl" xlink:title="label: UpdatedEuropeanDistributionModelEmployeeSeveranceAndRetentionMember to ions_UpdatedEuropeanDistributionModelEmployeeSeveranceAndRetentionMember_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_UpdatedEuropeanDistributionModelEmployeeSeveranceAndRetentionMember_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_UpdatedEuropeanDistributionModelEmployeeSeveranceAndRetentionMember_lbl1" xml:lang="en-US" id="ions_UpdatedEuropeanDistributionModelEmployeeSeveranceAndRetentionMember_lbl1">Updated European Distribution Model, Employee Severance and Retention [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="UpdatedEuropeanDistributionModelEmployeeSeveranceAndRetentionMember" xlink:to="ions_UpdatedEuropeanDistributionModelEmployeeSeveranceAndRetentionMember_lbl1" xlink:title="label: UpdatedEuropeanDistributionModelEmployeeSeveranceAndRetentionMember to ions_UpdatedEuropeanDistributionModelEmployeeSeveranceAndRetentionMember_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_UpdatedEuropeanDistributionModelEmployeeSeveranceAndRetentionMember_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_UpdatedEuropeanDistributionModelEmployeeSeveranceAndRetentionMember_lbl2" xml:lang="en-US" id="ions_UpdatedEuropeanDistributionModelEmployeeSeveranceAndRetentionMember_lbl2">Restructured European Operations [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="UpdatedEuropeanDistributionModelEmployeeSeveranceAndRetentionMember" xlink:to="ions_UpdatedEuropeanDistributionModelEmployeeSeveranceAndRetentionMember_lbl2" xlink:title="label: UpdatedEuropeanDistributionModelEmployeeSeveranceAndRetentionMember to ions_UpdatedEuropeanDistributionModelEmployeeSeveranceAndRetentionMember_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_SeveranceAndRetentionCostsTable" xlink:label="SeveranceAndRetentionCostsTable" xlink:title="SeveranceAndRetentionCostsTable" />
    <link:label xlink:type="resource" xlink:label="ions_SeveranceAndRetentionCostsTable_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_SeveranceAndRetentionCostsTable_lbl" xml:lang="en-US" id="ions_SeveranceAndRetentionCostsTable_lbl">Disclosure of information about severance and retention costs.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="SeveranceAndRetentionCostsTable" xlink:to="ions_SeveranceAndRetentionCostsTable_lbl" xlink:title="label: SeveranceAndRetentionCostsTable to ions_SeveranceAndRetentionCostsTable_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_SeveranceAndRetentionCostsTable_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_SeveranceAndRetentionCostsTable_lbl1" xml:lang="en-US" id="ions_SeveranceAndRetentionCostsTable_lbl1">Severance and Retention Costs [Table]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="SeveranceAndRetentionCostsTable" xlink:to="ions_SeveranceAndRetentionCostsTable_lbl1" xlink:title="label: SeveranceAndRetentionCostsTable to ions_SeveranceAndRetentionCostsTable_lbl1" />
    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_RestructuredEuropeanOperationsMember" xlink:label="RestructuredEuropeanOperationsMember" xlink:title="RestructuredEuropeanOperationsMember" />
    <link:label xlink:type="resource" xlink:label="ions_RestructuredEuropeanOperationsMember_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_RestructuredEuropeanOperationsMember_lbl" xml:lang="en-US" id="ions_RestructuredEuropeanOperationsMember_lbl">Termination of employees and retention of key employees for a specific period of time associated with the restructuring of the Company's European operations.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="RestructuredEuropeanOperationsMember" xlink:to="ions_RestructuredEuropeanOperationsMember_lbl" xlink:title="label: RestructuredEuropeanOperationsMember to ions_RestructuredEuropeanOperationsMember_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_RestructuredEuropeanOperationsMember_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_RestructuredEuropeanOperationsMember_lbl1" xml:lang="en-US" id="ions_RestructuredEuropeanOperationsMember_lbl1">Restructured European Operations [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="RestructuredEuropeanOperationsMember" xlink:to="ions_RestructuredEuropeanOperationsMember_lbl1" xlink:title="label: RestructuredEuropeanOperationsMember to ions_RestructuredEuropeanOperationsMember_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_RestructuredEuropeanOperationsMember_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_RestructuredEuropeanOperationsMember_lbl2" xml:lang="en-US" id="ions_RestructuredEuropeanOperationsMember_lbl2">Restructured European Operations [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="RestructuredEuropeanOperationsMember" xlink:to="ions_RestructuredEuropeanOperationsMember_lbl2" xlink:title="label: RestructuredEuropeanOperationsMember to ions_RestructuredEuropeanOperationsMember_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_RestructuredNorthAmericanTegsediOperationsMember" xlink:label="RestructuredNorthAmericanTegsediOperationsMember" xlink:title="RestructuredNorthAmericanTegsediOperationsMember" />
    <link:label xlink:type="resource" xlink:label="ions_RestructuredNorthAmericanTegsediOperationsMember_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_RestructuredNorthAmericanTegsediOperationsMember_lbl" xml:lang="en-US" id="ions_RestructuredNorthAmericanTegsediOperationsMember_lbl">Restructuring of the Akcea workforce in the Company's North American TEGSEDI Operations.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="RestructuredNorthAmericanTegsediOperationsMember" xlink:to="ions_RestructuredNorthAmericanTegsediOperationsMember_lbl" xlink:title="label: RestructuredNorthAmericanTegsediOperationsMember to ions_RestructuredNorthAmericanTegsediOperationsMember_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_RestructuredNorthAmericanTegsediOperationsMember_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_RestructuredNorthAmericanTegsediOperationsMember_lbl1" xml:lang="en-US" id="ions_RestructuredNorthAmericanTegsediOperationsMember_lbl1">Restructured North American TEGSEDI Operations [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="RestructuredNorthAmericanTegsediOperationsMember" xlink:to="ions_RestructuredNorthAmericanTegsediOperationsMember_lbl1" xlink:title="label: RestructuredNorthAmericanTegsediOperationsMember to ions_RestructuredNorthAmericanTegsediOperationsMember_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_RestructuredNorthAmericanTegsediOperationsMember_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_RestructuredNorthAmericanTegsediOperationsMember_lbl2" xml:lang="en-US" id="ions_RestructuredNorthAmericanTegsediOperationsMember_lbl2">Restructured North American TEGSEDI Operations [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="RestructuredNorthAmericanTegsediOperationsMember" xlink:to="ions_RestructuredNorthAmericanTegsediOperationsMember_lbl2" xlink:title="label: RestructuredNorthAmericanTegsediOperationsMember to ions_RestructuredNorthAmericanTegsediOperationsMember_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_SeveranceAndRetentionCostsLineItems" xlink:label="SeveranceAndRetentionCostsLineItems" xlink:title="SeveranceAndRetentionCostsLineItems" />
    <link:label xlink:type="resource" xlink:label="ions_SeveranceAndRetentionCostsLineItems_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_SeveranceAndRetentionCostsLineItems_lbl" xml:lang="en-US" id="ions_SeveranceAndRetentionCostsLineItems_lbl">Line items represent financial concepts included in a table. These concepts are used to disclose reportable information associated with domain members defined in one or many axes to the table.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="SeveranceAndRetentionCostsLineItems" xlink:to="ions_SeveranceAndRetentionCostsLineItems_lbl" xlink:title="label: SeveranceAndRetentionCostsLineItems to ions_SeveranceAndRetentionCostsLineItems_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_SeveranceAndRetentionCostsLineItems_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_SeveranceAndRetentionCostsLineItems_lbl1" xml:lang="en-US" id="ions_SeveranceAndRetentionCostsLineItems_lbl1">Severance and Retention Costs [Line Items]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="SeveranceAndRetentionCostsLineItems" xlink:to="ions_SeveranceAndRetentionCostsLineItems_lbl1" xlink:title="label: SeveranceAndRetentionCostsLineItems to ions_SeveranceAndRetentionCostsLineItems_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_SeveranceAndRetentionCostsLineItems_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_SeveranceAndRetentionCostsLineItems_lbl2" xml:lang="en-US" id="ions_SeveranceAndRetentionCostsLineItems_lbl2">Severance and Retention Costs [Abstract]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="SeveranceAndRetentionCostsLineItems" xlink:to="ions_SeveranceAndRetentionCostsLineItems_lbl2" xlink:title="label: SeveranceAndRetentionCostsLineItems to ions_SeveranceAndRetentionCostsLineItems_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_JohnMakrisEtAlVIonisPharmaceuticalsIncEtAlMember" xlink:label="JohnMakrisEtAlVIonisPharmaceuticalsIncEtAlMember" xlink:title="JohnMakrisEtAlVIonisPharmaceuticalsIncEtAlMember" />
    <link:label xlink:type="resource" xlink:label="ions_JohnMakrisEtAlVIonisPharmaceuticalsIncEtAlMember_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_JohnMakrisEtAlVIonisPharmaceuticalsIncEtAlMember_lbl" xml:lang="en-US" id="ions_JohnMakrisEtAlVIonisPharmaceuticalsIncEtAlMember_lbl">John Makris, et al. v. Ionis Pharmaceuticals, Inc., et al., C.A. No. 2021-0681, or the "Delaware Action."</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="JohnMakrisEtAlVIonisPharmaceuticalsIncEtAlMember" xlink:to="ions_JohnMakrisEtAlVIonisPharmaceuticalsIncEtAlMember_lbl" xlink:title="label: JohnMakrisEtAlVIonisPharmaceuticalsIncEtAlMember to ions_JohnMakrisEtAlVIonisPharmaceuticalsIncEtAlMember_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_JohnMakrisEtAlVIonisPharmaceuticalsIncEtAlMember_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_JohnMakrisEtAlVIonisPharmaceuticalsIncEtAlMember_lbl1" xml:lang="en-US" id="ions_JohnMakrisEtAlVIonisPharmaceuticalsIncEtAlMember_lbl1">John Makris, et al. v. Ionis Pharmaceuticals, Inc., et al. [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="JohnMakrisEtAlVIonisPharmaceuticalsIncEtAlMember" xlink:to="ions_JohnMakrisEtAlVIonisPharmaceuticalsIncEtAlMember_lbl1" xlink:title="label: JohnMakrisEtAlVIonisPharmaceuticalsIncEtAlMember to ions_JohnMakrisEtAlVIonisPharmaceuticalsIncEtAlMember_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_JohnMakrisEtAlVIonisPharmaceuticalsIncEtAlMember_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_JohnMakrisEtAlVIonisPharmaceuticalsIncEtAlMember_lbl2" xml:lang="en-US" id="ions_JohnMakrisEtAlVIonisPharmaceuticalsIncEtAlMember_lbl2">John Makris, et al. v. Ionis Pharmaceuticals, Inc., et al. [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="JohnMakrisEtAlVIonisPharmaceuticalsIncEtAlMember" xlink:to="ions_JohnMakrisEtAlVIonisPharmaceuticalsIncEtAlMember_lbl2" xlink:title="label: JohnMakrisEtAlVIonisPharmaceuticalsIncEtAlMember to ions_JohnMakrisEtAlVIonisPharmaceuticalsIncEtAlMember_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_PaymentsMadeUnderCollaborationAgreement" xlink:label="PaymentsMadeUnderCollaborationAgreement" xlink:title="PaymentsMadeUnderCollaborationAgreement" />
    <link:label xlink:type="resource" xlink:label="ions_PaymentsMadeUnderCollaborationAgreement_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_PaymentsMadeUnderCollaborationAgreement_lbl" xml:lang="en-US" id="ions_PaymentsMadeUnderCollaborationAgreement_lbl">Represents the cash outflow for payments made under the collaboration agreement for the reimbursement of support received in connection with the Company's Huntington's disease program.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="PaymentsMadeUnderCollaborationAgreement" xlink:to="ions_PaymentsMadeUnderCollaborationAgreement_lbl" xlink:title="label: PaymentsMadeUnderCollaborationAgreement to ions_PaymentsMadeUnderCollaborationAgreement_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_PaymentsMadeUnderCollaborationAgreement_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_PaymentsMadeUnderCollaborationAgreement_lbl1" xml:lang="en-US" id="ions_PaymentsMadeUnderCollaborationAgreement_lbl1">Payments made under collaboration agreement</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="PaymentsMadeUnderCollaborationAgreement" xlink:to="ions_PaymentsMadeUnderCollaborationAgreement_lbl1" xlink:title="label: PaymentsMadeUnderCollaborationAgreement to ions_PaymentsMadeUnderCollaborationAgreement_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_PaymentsMadeUnderCollaborationAgreement_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_PaymentsMadeUnderCollaborationAgreement_lbl2" xml:lang="en-US" id="ions_PaymentsMadeUnderCollaborationAgreement_lbl2">Payment of license fee</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="PaymentsMadeUnderCollaborationAgreement" xlink:to="ions_PaymentsMadeUnderCollaborationAgreement_lbl2" xlink:title="label: PaymentsMadeUnderCollaborationAgreement to ions_PaymentsMadeUnderCollaborationAgreement_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_InvestmentInEquitySecuritiesFvNi" xlink:label="InvestmentInEquitySecuritiesFvNi" xlink:title="InvestmentInEquitySecuritiesFvNi" />
    <link:label xlink:type="resource" xlink:label="ions_InvestmentInEquitySecuritiesFvNi_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_InvestmentInEquitySecuritiesFvNi_lbl" xml:lang="en-US" id="ions_InvestmentInEquitySecuritiesFvNi_lbl">Acquisition of investment in equity security measured at fair value with change in fair value recognized in net income (FV-NI).</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="InvestmentInEquitySecuritiesFvNi" xlink:to="ions_InvestmentInEquitySecuritiesFvNi_lbl" xlink:title="label: InvestmentInEquitySecuritiesFvNi to ions_InvestmentInEquitySecuritiesFvNi_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_InvestmentInEquitySecuritiesFvNi_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_InvestmentInEquitySecuritiesFvNi_lbl1" xml:lang="en-US" id="ions_InvestmentInEquitySecuritiesFvNi_lbl1">Investment in Equity Securities, FV-NI</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="InvestmentInEquitySecuritiesFvNi" xlink:to="ions_InvestmentInEquitySecuritiesFvNi_lbl1" xlink:title="label: InvestmentInEquitySecuritiesFvNi to ions_InvestmentInEquitySecuritiesFvNi_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_InvestmentInEquitySecuritiesFvNi_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_InvestmentInEquitySecuritiesFvNi_lbl2" xml:lang="en-US" id="ions_InvestmentInEquitySecuritiesFvNi_lbl2">Equity investment</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="InvestmentInEquitySecuritiesFvNi" xlink:to="ions_InvestmentInEquitySecuritiesFvNi_lbl2" xlink:title="label: InvestmentInEquitySecuritiesFvNi to ions_InvestmentInEquitySecuritiesFvNi_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_CumulativePaymentsMade" xlink:label="CumulativePaymentsMade" xlink:title="CumulativePaymentsMade" />
    <link:label xlink:type="resource" xlink:label="ions_CumulativePaymentsMade_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_CumulativePaymentsMade_lbl" xml:lang="en-US" id="ions_CumulativePaymentsMade_lbl">Cumulative amount of payments made under the collaboration agreement as of the end of the reporting period.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="CumulativePaymentsMade" xlink:to="ions_CumulativePaymentsMade_lbl" xlink:title="label: CumulativePaymentsMade to ions_CumulativePaymentsMade_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_CumulativePaymentsMade_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_CumulativePaymentsMade_lbl1" xml:lang="en-US" id="ions_CumulativePaymentsMade_lbl1">Cumulative payments made</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="CumulativePaymentsMade" xlink:to="ions_CumulativePaymentsMade_lbl1" xlink:title="label: CumulativePaymentsMade to ions_CumulativePaymentsMade_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_CumulativePaymentsMade_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_CumulativePaymentsMade_lbl2" xml:lang="en-US" id="ions_CumulativePaymentsMade_lbl2">Cumulative payments made</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="CumulativePaymentsMade" xlink:to="ions_CumulativePaymentsMade_lbl2" xlink:title="label: CumulativePaymentsMade to ions_CumulativePaymentsMade_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_LockUpAgreementTermOfTradingRestriction" xlink:label="LockUpAgreementTermOfTradingRestriction" xlink:title="LockUpAgreementTermOfTradingRestriction" />
    <link:label xlink:type="resource" xlink:label="ions_LockUpAgreementTermOfTradingRestriction_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_LockUpAgreementTermOfTradingRestriction_lbl" xml:lang="en-US" id="ions_LockUpAgreementTermOfTradingRestriction_lbl">Period after completion of initial public offering by an equity investee and restriction to sell equity holding in the investee, in 'PnYnMnDTnHnMnS' format, for example, 'P1Y5M13D' represents reported fact of one year, five months, and thirteen days.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="LockUpAgreementTermOfTradingRestriction" xlink:to="ions_LockUpAgreementTermOfTradingRestriction_lbl" xlink:title="label: LockUpAgreementTermOfTradingRestriction to ions_LockUpAgreementTermOfTradingRestriction_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_LockUpAgreementTermOfTradingRestriction_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_LockUpAgreementTermOfTradingRestriction_lbl1" xml:lang="en-US" id="ions_LockUpAgreementTermOfTradingRestriction_lbl1">Lock up Agreement, Term of Trading Restriction</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="LockUpAgreementTermOfTradingRestriction" xlink:to="ions_LockUpAgreementTermOfTradingRestriction_lbl1" xlink:title="label: LockUpAgreementTermOfTradingRestriction to ions_LockUpAgreementTermOfTradingRestriction_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_LockUpAgreementTermOfTradingRestriction_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_LockUpAgreementTermOfTradingRestriction_lbl2" xml:lang="en-US" id="ions_LockUpAgreementTermOfTradingRestriction_lbl2">Trading restriction period under lock up agreement</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="LockUpAgreementTermOfTradingRestriction" xlink:to="ions_LockUpAgreementTermOfTradingRestriction_lbl2" xlink:title="label: LockUpAgreementTermOfTradingRestriction to ions_LockUpAgreementTermOfTradingRestriction_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20211231.xsd#ions_BicycleCollaborationMember" xlink:label="BicycleCollaborationMember" xlink:title="BicycleCollaborationMember" />
    <link:label xlink:type="resource" xlink:label="ions_BicycleCollaborationMember_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_BicycleCollaborationMember_lbl" xml:lang="en-US" id="ions_BicycleCollaborationMember_lbl">Collaboration agreement entered into with Bicycle Therapeutics in December 2020 and obtained an option to license its peptide technology to potentially increase the delivery capabilities of our Ligand Conjugated Antisense, or LICA, medicines.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="BicycleCollaborationMember" xlink:to="ions_BicycleCollaborationMember_lbl" xlink:title="label: BicycleCollaborationMember to ions_BicycleCollaborationMember_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_BicycleCollaborationMember_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_BicycleCollaborationMember_lbl1" xml:lang="en-US" id="ions_BicycleCollaborationMember_lbl1">Bicycle Collaboration [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="BicycleCollaborationMember" xlink:to="ions_BicycleCollaborationMember_lbl1" xlink:title="label: BicycleCollaborationMember to ions_BicycleCollaborationMember_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_BicycleCollaborationMember_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_BicycleCollaborationMember_lbl2" xml:lang="en-US" id="ions_BicycleCollaborationMember_lbl2">Bicycle License Agreement [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="BicycleCollaborationMember" xlink:to="ions_BicycleCollaborationMember_lbl2" xlink:title="label: BicycleCollaborationMember to ions_BicycleCollaborationMember_lbl2" />
  </link:labelLink>
</link:linkbase>
</XBRL>
</TEXT>
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<DOCUMENT>
<TYPE>EX-101.PRE
<SEQUENCE>16
<FILENAME>ions-20211231_pre.xml
<DESCRIPTION>XBRL TAXONOMY EXTENSION PRESENTATION LINKBASE
<TEXT>
<XBRL>
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<title></title>
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<span style="display: none;">v3.22.0.1</span><table class="report" border="0" cellspacing="2" id="idm139691007466104">
<tr>
<th class="tl" colspan="1" rowspan="2"><div style="width: 200px;"><strong>Document and Entity Information - USD ($)<br></strong></div></th>
<th class="th" colspan="1">12 Months Ended</th>
<th class="th" colspan="1"></th>
<th class="th" colspan="1"></th>
</tr>
<tr>
<th class="th"><div>Dec. 31, 2021</div></th>
<th class="th"><div>Feb. 16, 2022</div></th>
<th class="th"><div>Jun. 30, 2021</div></th>
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<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_dei_CoverAbstract', window );"><strong>Cover [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
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<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
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<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_dei_DocumentType', window );">Document Type</a></td>
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<td class="text">false<span></span>
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<td class="text">&#160;<span></span>
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<td class="text">&#160;<span></span>
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<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_dei_DocumentAnnualReport', window );">Document Annual Report</a></td>
<td class="text">true<span></span>
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<td class="text">&#160;<span></span>
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<td class="text">&#160;<span></span>
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<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_dei_DocumentPeriodEndDate', window );">Document Period End Date</a></td>
<td class="text">Dec. 31,  2021<span></span>
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<td class="text">&#160;<span></span>
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<td class="text">&#160;<span></span>
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<tr class="ro">
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<td class="text">--12-31<span></span>
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<td class="text">&#160;<span></span>
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<td class="text">&#160;<span></span>
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<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_dei_DocumentFiscalYearFocus', window );">Document Fiscal Year Focus</a></td>
<td class="text">2021<span></span>
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<td class="text">&#160;<span></span>
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<td class="text">&#160;<span></span>
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<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_dei_DocumentFiscalPeriodFocus', window );">Document Fiscal Period Focus</a></td>
<td class="text">FY<span></span>
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<td class="text">&#160;<span></span>
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<td class="text">&#160;<span></span>
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<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_dei_DocumentTransitionReport', window );">Document Transition Report</a></td>
<td class="text">false<span></span>
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<td class="text">&#160;<span></span>
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<td class="text">&#160;<span></span>
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<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_dei_EntityFileNumber', window );">Entity File Number</a></td>
<td class="text">000-19125<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
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</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_dei_EntityRegistrantName', window );">Entity Registrant Name</a></td>
<td class="text">Ionis Pharmaceuticals, Inc<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_dei_EntityCentralIndexKey', window );">Entity Central Index Key</a></td>
<td class="text">0000874015<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_dei_EntityIncorporationStateCountryCode', window );">Entity Incorporation, State or Country Code</a></td>
<td class="text">DE<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_dei_EntityTaxIdentificationNumber', window );">Entity Tax Identification Number</a></td>
<td class="text">33-0336973<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_dei_EntityAddressAddressLine1', window );">Entity Address, Address Line One</a></td>
<td class="text">2855 Gazelle Court<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_dei_EntityAddressCityOrTown', window );">Entity Address, City or Town</a></td>
<td class="text">Carlsbad<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_dei_EntityAddressStateOrProvince', window );">Entity Address, State or Province</a></td>
<td class="text">CA<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_dei_EntityAddressPostalZipCode', window );">Entity Address, Postal Zip Code</a></td>
<td class="text">92010<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_dei_CityAreaCode', window );">City Area Code</a></td>
<td class="text">760<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_dei_LocalPhoneNumber', window );">Local Phone Number</a></td>
<td class="text">931-9200<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_dei_Security12bTitle', window );">Title of 12(b) Security</a></td>
<td class="text">Common Stock, $.001 Par Value<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_dei_TradingSymbol', window );">Trading Symbol</a></td>
<td class="text">IONS<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_dei_SecurityExchangeName', window );">Security Exchange Name</a></td>
<td class="text">NASDAQ<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_dei_EntityWellKnownSeasonedIssuer', window );">Entity Well-known Seasoned Issuer</a></td>
<td class="text">Yes<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_dei_EntityVoluntaryFilers', window );">Entity Voluntary Filers</a></td>
<td class="text">No<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_dei_EntityCurrentReportingStatus', window );">Entity Current Reporting Status</a></td>
<td class="text">Yes<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_dei_EntityInteractiveDataCurrent', window );">Entity Interactive Data Current</a></td>
<td class="text">Yes<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_dei_EntityFilerCategory', window );">Entity Filer Category</a></td>
<td class="text">Large Accelerated Filer<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_dei_EntitySmallBusiness', window );">Entity Small Business</a></td>
<td class="text">false<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_dei_EntityEmergingGrowthCompany', window );">Entity Emerging Growth Company</a></td>
<td class="text">false<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_dei_IcfrAuditorAttestationFlag', window );">ICFR Auditor Attestation Flag</a></td>
<td class="text">true<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_dei_EntityShellCompany', window );">Entity Shell Company</a></td>
<td class="text">false<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_dei_EntityPublicFloat', window );">Entity Public Float</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 4,675,204,973<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_dei_EntityCommonStockSharesOutstanding', window );">Entity Common Stock, Shares Outstanding</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">141,688,727<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_dei_AuditorFirmId', window );">Auditor Firm ID</a></td>
<td class="text">42<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_dei_AuditorName', window );">Auditor Name</a></td>
<td class="text">Ernst & Young LLP<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_dei_AuditorLocation', window );">Auditor Location</a></td>
<td class="text">San Diego, California<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
</table>
<div style="display: none;">
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_dei_AmendmentFlag">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Boolean flag that is true when the XBRL content amends previously-filed or accepted submission.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">dei_AmendmentFlag</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>dei_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:booleanItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_dei_AuditorFirmId">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>PCAOB issued Audit Firm Identifier</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/presentationRef<br> -Publisher SEC<br> -Name Form 10-K<br> -Number 249<br> -Section 310<br><br>Reference 2: http://www.xbrl.org/2003/role/presentationRef<br> -Publisher SEC<br> -Name Form 20-F<br> -Number 249<br> -Section 220<br> -Subsection f<br><br>Reference 3: http://www.xbrl.org/2003/role/presentationRef<br> -Publisher SEC<br> -Name Form 40-F<br> -Number 249<br> -Section 240<br> -Subsection f<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">dei_AuditorFirmId</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>dei_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>dei:nonemptySequenceNumberItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_dei_AuditorLocation">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- References</a><div><p>Reference 1: http://www.xbrl.org/2003/role/presentationRef<br> -Publisher SEC<br> -Name Form 10-K<br> -Number 249<br> -Section 310<br><br>Reference 2: http://www.xbrl.org/2003/role/presentationRef<br> -Publisher SEC<br> -Name Form 20-F<br> -Number 249<br> -Section 220<br> -Subsection f<br><br>Reference 3: http://www.xbrl.org/2003/role/presentationRef<br> -Publisher SEC<br> -Name Form 40-F<br> -Number 249<br> -Section 240<br> -Subsection f<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">dei_AuditorLocation</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>dei_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>dei:internationalNameItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_dei_AuditorName">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- References</a><div><p>Reference 1: http://www.xbrl.org/2003/role/presentationRef<br> -Publisher SEC<br> -Name Form 10-K<br> -Number 249<br> -Section 310<br><br>Reference 2: http://www.xbrl.org/2003/role/presentationRef<br> -Publisher SEC<br> -Name Form 20-F<br> -Number 249<br> -Section 220<br> -Subsection f<br><br>Reference 3: http://www.xbrl.org/2003/role/presentationRef<br> -Publisher SEC<br> -Name Form 40-F<br> -Number 249<br> -Section 240<br> -Subsection f<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">dei_AuditorName</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>dei_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>dei:internationalNameItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_dei_CityAreaCode">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Area code of city</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">dei_CityAreaCode</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>dei_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:normalizedStringItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_dei_CoverAbstract">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Cover page.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">dei_CoverAbstract</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>dei_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:stringItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_dei_CurrentFiscalYearEndDate">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>End date of current fiscal year in the format --MM-DD.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">dei_CurrentFiscalYearEndDate</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>dei_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:gMonthDayItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_dei_DocumentAnnualReport">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Boolean flag that is true only for a form used as an annual report.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/presentationRef<br> -Publisher SEC<br> -Name Form 10-K<br> -Number 249<br> -Section 310<br><br>Reference 2: http://www.xbrl.org/2003/role/presentationRef<br> -Publisher SEC<br> -Name Form 20-F<br> -Number 249<br> -Section 220<br> -Subsection f<br><br>Reference 3: http://www.xbrl.org/2003/role/presentationRef<br> -Publisher SEC<br> -Name Form 40-F<br> -Number 249<br> -Section 240<br> -Subsection f<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">dei_DocumentAnnualReport</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>dei_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:booleanItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_dei_DocumentFiscalPeriodFocus">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Fiscal period values are FY, Q1, Q2, and Q3.  1st, 2nd and 3rd quarter 10-Q or 10-QT statements have value Q1, Q2, and Q3 respectively, with 10-K, 10-KT or other fiscal year statements having FY.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">dei_DocumentFiscalPeriodFocus</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>dei_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>dei:fiscalPeriodItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_dei_DocumentFiscalYearFocus">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>This is focus fiscal year of the document report in YYYY format. For a 2006 annual report, which may also provide financial information from prior periods, fiscal 2006 should be given as the fiscal year focus. Example: 2006.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">dei_DocumentFiscalYearFocus</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>dei_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:gYearItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_dei_DocumentPeriodEndDate">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>For the EDGAR submission types of Form 8-K: the date of the report, the date of the earliest event reported; for the EDGAR submission types of Form N-1A: the filing date; for all other submission types: the end of the reporting or transition period.  The format of the date is YYYY-MM-DD.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">dei_DocumentPeriodEndDate</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>dei_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:dateItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_dei_DocumentTransitionReport">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Boolean flag that is true only for a form used as a transition report.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/presentationRef<br> -Publisher SEC<br> -Name Forms 10-K, 10-Q, 20-F<br> -Number 240<br> -Section 13<br> -Subsection a-1<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">dei_DocumentTransitionReport</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>dei_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:booleanItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_dei_DocumentType">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The type of document being provided (such as 10-K, 10-Q, 485BPOS, etc). The document type is limited to the same value as the supporting SEC submission type, or the word 'Other'.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">dei_DocumentType</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>dei_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>dei:submissionTypeItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_dei_EntityAddressAddressLine1">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Address Line 1 such as Attn, Building Name, Street Name</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">dei_EntityAddressAddressLine1</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>dei_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:normalizedStringItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_dei_EntityAddressCityOrTown">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Name of the City or Town</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">dei_EntityAddressCityOrTown</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>dei_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:normalizedStringItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_dei_EntityAddressPostalZipCode">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Code for the postal or zip code</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">dei_EntityAddressPostalZipCode</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>dei_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:normalizedStringItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_dei_EntityAddressStateOrProvince">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Name of the state or province.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">dei_EntityAddressStateOrProvince</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>dei_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>dei:stateOrProvinceItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_dei_EntityCentralIndexKey">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>A unique 10-digit SEC-issued value to identify entities that have filed disclosures with the SEC. It is commonly abbreviated as CIK.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/presentationRef<br> -Publisher SEC<br> -Name Exchange Act<br> -Number 240<br> -Section 12<br> -Subsection b-2<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">dei_EntityCentralIndexKey</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>dei_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>dei:centralIndexKeyItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_dei_EntityCommonStockSharesOutstanding">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Indicate number of shares or other units outstanding of each of registrant's classes of capital or common stock or other ownership interests, if and as stated on cover of related periodic report. Where multiple classes or units exist define each class/interest by adding class of stock items such as Common Class A [Member], Common Class B [Member] or Partnership Interest [Member] onto the Instrument [Domain] of the Entity Listings, Instrument.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">dei_EntityCommonStockSharesOutstanding</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>dei_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:sharesItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_dei_EntityCurrentReportingStatus">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Indicate 'Yes' or 'No' whether registrants (1) have filed all reports required to be filed by Section 13 or 15(d) of the Securities Exchange Act of 1934 during the preceding 12 months (or for such shorter period that registrants were required to file such reports), and (2) have been subject to such filing requirements for the past 90 days. This information should be based on the registrant's current or most recent filing containing the related disclosure.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">dei_EntityCurrentReportingStatus</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>dei_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>dei:yesNoItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_dei_EntityEmergingGrowthCompany">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Indicate if registrant meets the emerging growth company criteria.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/presentationRef<br> -Publisher SEC<br> -Name Exchange Act<br> -Number 240<br> -Section 12<br> -Subsection b-2<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">dei_EntityEmergingGrowthCompany</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>dei_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:booleanItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_dei_EntityFileNumber">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Commission file number. The field allows up to 17 characters. The prefix may contain 1-3 digits, the sequence number may contain 1-8 digits, the optional suffix may contain 1-4 characters, and the fields are separated with a hyphen.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">dei_EntityFileNumber</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>dei_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>dei:fileNumberItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_dei_EntityFilerCategory">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Indicate whether the registrant is one of the following: Large Accelerated Filer, Accelerated Filer, Non-accelerated Filer. Definitions of these categories are stated in Rule 12b-2 of the Exchange Act. This information should be based on the registrant's current or most recent filing containing the related disclosure.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/presentationRef<br> -Publisher SEC<br> -Name Exchange Act<br> -Number 240<br> -Section 12<br> -Subsection b-2<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">dei_EntityFilerCategory</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>dei_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>dei:filerCategoryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_dei_EntityIncorporationStateCountryCode">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Two-character EDGAR code representing the state or country of incorporation.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">dei_EntityIncorporationStateCountryCode</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>dei_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>dei:edgarStateCountryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_dei_EntityInteractiveDataCurrent">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Boolean flag that is true when the registrant has submitted electronically every Interactive Data File required to be submitted pursuant to Rule 405 of Regulation S-T during the preceding 12 months (or for such shorter period that the registrant was required to submit such files).</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/presentationRef<br> -Publisher SEC<br> -Name Regulation S-T<br> -Number 232<br> -Section 405<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">dei_EntityInteractiveDataCurrent</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>dei_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>dei:yesNoItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_dei_EntityPublicFloat">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The aggregate market value of the voting and non-voting common equity held by non-affiliates computed by reference to the price at which the common equity was last sold, or the average bid and asked price of such common equity, as of the last business day of the registrant's most recently completed second fiscal quarter.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">dei_EntityPublicFloat</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>dei_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_dei_EntityRegistrantName">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The exact name of the entity filing the report as specified in its charter, which is required by forms filed with the SEC.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/presentationRef<br> -Publisher SEC<br> -Name Exchange Act<br> -Number 240<br> -Section 12<br> -Subsection b-2<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">dei_EntityRegistrantName</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>dei_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:normalizedStringItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_dei_EntityShellCompany">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Boolean flag that is true when the registrant is a shell company as defined in Rule 12b-2 of the Exchange Act.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/presentationRef<br> -Publisher SEC<br> -Name Exchange Act<br> -Number 240<br> -Section 12<br> -Subsection b-2<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">dei_EntityShellCompany</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>dei_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:booleanItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_dei_EntitySmallBusiness">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Indicates that the company is a Smaller Reporting Company (SRC).</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/presentationRef<br> -Publisher SEC<br> -Name Exchange Act<br> -Number 240<br> -Section 12<br> -Subsection b-2<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">dei_EntitySmallBusiness</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>dei_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:booleanItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_dei_EntityTaxIdentificationNumber">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The Tax Identification Number (TIN), also known as an Employer Identification Number (EIN), is a unique 9-digit value assigned by the IRS.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/presentationRef<br> -Publisher SEC<br> -Name Exchange Act<br> -Number 240<br> -Section 12<br> -Subsection b-2<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">dei_EntityTaxIdentificationNumber</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>dei_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>dei:employerIdItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_dei_EntityVoluntaryFilers">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Indicate 'Yes' or 'No' if the registrant is not required to file reports pursuant to Section 13 or Section 15(d) of the Act.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">dei_EntityVoluntaryFilers</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>dei_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>dei:yesNoItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_dei_EntityWellKnownSeasonedIssuer">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Indicate 'Yes' or 'No' if the registrant is a well-known seasoned issuer, as defined in Rule 405 of the Securities Act. Is used on Form Type: 10-K, 10-Q, 8-K, 20-F, 6-K, 10-K/A, 10-Q/A, 20-F/A, 6-K/A, N-CSR, N-Q, N-1A.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/presentationRef<br> -Publisher SEC<br> -Name Securities Act<br> -Number 230<br> -Section 405<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">dei_EntityWellKnownSeasonedIssuer</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>dei_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>dei:yesNoItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_dei_IcfrAuditorAttestationFlag">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- References</a><div><p>Reference 1: http://www.xbrl.org/2003/role/presentationRef<br> -Publisher SEC<br> -Name Form 10-K<br> -Number 249<br> -Section 310<br><br>Reference 2: http://www.xbrl.org/2003/role/presentationRef<br> -Publisher SEC<br> -Name Form 20-F<br> -Number 249<br> -Section 220<br> -Subsection f<br><br>Reference 3: http://www.xbrl.org/2003/role/presentationRef<br> -Publisher SEC<br> -Name Form 40-F<br> -Number 249<br> -Section 240<br> -Subsection f<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">dei_IcfrAuditorAttestationFlag</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>dei_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:booleanItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_dei_LocalPhoneNumber">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Local phone number for entity.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">dei_LocalPhoneNumber</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>dei_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:normalizedStringItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_dei_Security12bTitle">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Title of a 12(b) registered security.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/presentationRef<br> -Publisher SEC<br> -Name Exchange Act<br> -Number 240<br> -Section 12<br> -Subsection b<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">dei_Security12bTitle</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>dei_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>dei:securityTitleItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_dei_SecurityExchangeName">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Name of the Exchange on which a security is registered.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/presentationRef<br> -Publisher SEC<br> -Name Exchange Act<br> -Number 240<br> -Section 12<br> -Subsection d1-1<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">dei_SecurityExchangeName</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>dei_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>dei:edgarExchangeCodeItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_dei_TradingSymbol">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Trading symbol of an instrument as listed on an exchange.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">dei_TradingSymbol</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>dei_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>dei:tradingSymbolItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
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<span style="display: none;">v3.22.0.1</span><table class="report" border="0" cellspacing="2" id="idm139691007216472">
<tr>
<th class="tl" colspan="1" rowspan="1"><div style="width: 200px;"><strong>CONSOLIDATED BALANCE SHEETS - USD ($)<br> $ in Thousands</strong></div></th>
<th class="th"><div>Dec. 31, 2021</div></th>
<th class="th"><div>Dec. 31, 2020</div></th>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AssetsCurrentAbstract', window );"><strong>Current assets:</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_CashAndCashEquivalentsAtCarryingValue', window );">Cash and cash equivalents</a></td>
<td class="nump">$ 869,191<span></span>
</td>
<td class="nump">$ 397,664<span></span>
</td>
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<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleSecuritiesDebtSecuritiesCurrent', window );">Short-term investments</a></td>
<td class="nump">1,245,782<span></span>
</td>
<td class="nump">1,494,711<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ContractWithCustomerAssetNetCurrent', window );">Contracts receivable</a></td>
<td class="nump">61,896<span></span>
</td>
<td class="nump">76,204<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_InventoryNet', window );">Inventories</a></td>
<td class="nump">24,806<span></span>
</td>
<td class="nump">21,965<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_OtherAssetsCurrent', window );">Other current assets</a></td>
<td class="nump">143,374<span></span>
</td>
<td class="nump">140,163<span></span>
</td>
</tr>
<tr class="reu">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AssetsCurrent', window );">Total current assets</a></td>
<td class="nump">2,345,049<span></span>
</td>
<td class="nump">2,130,707<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_PropertyPlantAndEquipmentNet', window );">Property, plant and equipment, net</a></td>
<td class="nump">178,069<span></span>
</td>
<td class="nump">181,077<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_FiniteLivedIntangibleAssetsNet', window );">Patents, net</a></td>
<td class="nump">29,005<span></span>
</td>
<td class="nump">27,937<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_OtherAssetsNoncurrent', window );">Deposits and other assets</a></td>
<td class="nump">59,567<span></span>
</td>
<td class="nump">50,034<span></span>
</td>
</tr>
<tr class="reu">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_Assets', window );">Total assets</a></td>
<td class="nump">2,611,690<span></span>
</td>
<td class="nump">2,389,755<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_LiabilitiesCurrentAbstract', window );"><strong>Current liabilities:</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AccountsPayableCurrent', window );">Accounts payable</a></td>
<td class="nump">11,904<span></span>
</td>
<td class="nump">17,199<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_EmployeeRelatedLiabilitiesCurrent', window );">Accrued compensation</a></td>
<td class="nump">38,810<span></span>
</td>
<td class="nump">65,728<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AccruedLiabilitiesCurrent', window );">Accrued liabilities</a></td>
<td class="nump">88,560<span></span>
</td>
<td class="nump">90,161<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AccruedIncomeTaxesCurrent', window );">Income taxes payable</a></td>
<td class="nump">36<span></span>
</td>
<td class="nump">1,324<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ConvertibleDebtCurrent', window );">1 percent convertible senior notes, net</a></td>
<td class="nump">0<span></span>
</td>
<td class="nump">308,809<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_LongTermObligationsExcludingConvertibleDebtCurrent', window );">Current portion of long-term obligations</a></td>
<td class="nump">3,526<span></span>
</td>
<td class="nump">7,301<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ContractWithCustomerLiabilityCurrent', window );">Current portion of deferred contract revenue</a></td>
<td class="nump">97,714<span></span>
</td>
<td class="nump">108,376<span></span>
</td>
</tr>
<tr class="rou">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_LiabilitiesCurrent', window );">Total current liabilities</a></td>
<td class="nump">240,550<span></span>
</td>
<td class="nump">598,898<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ContractWithCustomerLiabilityNoncurrent', window );">Long-term deferred contract revenue</a></td>
<td class="nump">351,879<span></span>
</td>
<td class="nump">424,046<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_LongTermObligationsExcludingConvertibleDebtNoncurrent', window );">Long-term obligations, less current portion</a></td>
<td class="nump">26,378<span></span>
</td>
<td class="nump">23,409<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_LongTermLoansFromBank', window );">Long-term mortgage debt</a></td>
<td class="nump">59,713<span></span>
</td>
<td class="nump">59,984<span></span>
</td>
</tr>
<tr class="rou">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_Liabilities', window );">Total liabilities</a></td>
<td class="nump">1,839,953<span></span>
</td>
<td class="nump">1,646,473<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_StockholdersEquityAbstract', window );"><strong>Stockholders' equity:</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_CommonStockValue', window );">Common stock, $0.001 par value; 300,000,000 shares authorized, 141,210,015 and 140,365,594 shares issued and outstanding at December 31, 2021 and December 31, 2020, respectively</a></td>
<td class="nump">141<span></span>
</td>
<td class="nump">140<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AdditionalPaidInCapitalCommonStock', window );">Additional paid-in capital</a></td>
<td class="nump">1,964,167<span></span>
</td>
<td class="nump">1,895,519<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AccumulatedOtherComprehensiveIncomeLossNetOfTax', window );">Accumulated other comprehensive loss</a></td>
<td class="num">(32,668)<span></span>
</td>
<td class="num">(21,071)<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RetainedEarningsAccumulatedDeficit', window );">Accumulated deficit</a></td>
<td class="num">(1,159,903)<span></span>
</td>
<td class="num">(1,131,306)<span></span>
</td>
</tr>
<tr class="rou">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_StockholdersEquity', window );">Total stockholders' equity</a></td>
<td class="nump">771,737<span></span>
</td>
<td class="nump">743,282<span></span>
</td>
</tr>
<tr class="reu">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_LiabilitiesAndStockholdersEquity', window );">Total liabilities and stockholders' equity</a></td>
<td class="nump">2,611,690<span></span>
</td>
<td class="nump">2,389,755<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DebtInstrumentAxis=ions_ConvertibleSeniorNotes0PercentMember', window );">0 Percent Convertible Senior Notes [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_LiabilitiesCurrentAbstract', window );"><strong>Current liabilities:</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ConvertibleDebtNoncurrent', window );">Convertible senior notes, net</a></td>
<td class="nump">619,119<span></span>
</td>
<td class="nump">0<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DebtInstrumentAxis=ions_ConvertibleSeniorNotes0125PercentMember', window );">0.125 Percent Convertible Senior Notes [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_LiabilitiesCurrentAbstract', window );"><strong>Current liabilities:</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ConvertibleDebtNoncurrent', window );">Convertible senior notes, net</a></td>
<td class="nump">$ 542,314<span></span>
</td>
<td class="nump">$ 540,136<span></span>
</td>
</tr>
</table>
<div style="display: none;">
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_LongTermObligationsExcludingConvertibleDebtCurrent">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of long-term debt and lease obligations, excluding convertible debt, classified as current.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_LongTermObligationsExcludingConvertibleDebtCurrent</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_LongTermObligationsExcludingConvertibleDebtNoncurrent">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of long-term debt and lease obligations, excluding convertible debt, classified as noncurrent.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_LongTermObligationsExcludingConvertibleDebtNoncurrent</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_AccountsPayableCurrent">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Carrying value as of the balance sheet date of liabilities incurred (and for which invoices have typically been received) and payable to vendors for goods and services received that are used in an entity's business. Used to reflect the current portion of the liabilities (due within one year or within the normal operating cycle if longer).</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 210<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.5-02.19(a))<br> -URI http://asc.fasb.org/extlink&amp;oid=120391452&amp;loc=d3e13212-122682<br><br>Reference 2: http://www.xbrl.org/2003/role/exampleRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 852<br> -SubTopic 10<br> -Section 55<br> -Paragraph 10<br> -URI http://asc.fasb.org/extlink&amp;oid=84165509&amp;loc=d3e56426-112766<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_AccountsPayableCurrent</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_AccruedIncomeTaxesCurrent">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Carrying amount as of the balance sheet date of the unpaid sum of the known and estimated amounts payable to satisfy all currently due domestic and foreign income tax obligations.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 944<br> -SubTopic 210<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.7-03(a)(15)(b)(1))<br> -URI http://asc.fasb.org/extlink&amp;oid=120400017&amp;loc=d3e572229-122910<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 942<br> -SubTopic 210<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.9-03(15)(1))<br> -URI http://asc.fasb.org/extlink&amp;oid=120398452&amp;loc=d3e534808-122878<br><br>Reference 3: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 210<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.5-02(20))<br> -URI http://asc.fasb.org/extlink&amp;oid=120391452&amp;loc=d3e13212-122682<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_AccruedIncomeTaxesCurrent</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_AccruedLiabilitiesCurrent">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Carrying value as of the balance sheet date of obligations incurred and payable, pertaining to costs that are statutory in nature, are incurred on contractual obligations, or accumulate over time and for which invoices have not yet been received or will not be rendered. Examples include taxes, interest, rent and utilities. Used to reflect the current portion of the liabilities (due within one year or within the normal operating cycle if longer).</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 210<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.5-02.20)<br> -URI http://asc.fasb.org/extlink&amp;oid=120391452&amp;loc=d3e13212-122682<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_AccruedLiabilitiesCurrent</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_AccumulatedOtherComprehensiveIncomeLossNetOfTax">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Accumulated change in equity from transactions and other events and circumstances from non-owner sources, net of tax effect, at period end. Excludes Net Income (Loss), and accumulated changes in equity from transactions resulting from investments by owners and distributions to owners. Includes foreign currency translation items, certain pension adjustments, unrealized gains and losses on certain investments in debt and equity securities, other than temporary impairment (OTTI) losses related to factors other than credit losses on available-for-sale and held-to-maturity debt securities that an entity does not intend to sell and it is not more likely than not that the entity will be required to sell before recovery of the amortized cost basis, as well as changes in the fair value of derivatives related to the effective portion of a designated cash flow hedge.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 210<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.5-02(30)(a)(4))<br> -URI http://asc.fasb.org/extlink&amp;oid=120391452&amp;loc=d3e13212-122682<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 220<br> -SubTopic 10<br> -Section 45<br> -Paragraph 11<br> -URI http://asc.fasb.org/extlink&amp;oid=124509347&amp;loc=d3e637-108580<br><br>Reference 3: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 944<br> -SubTopic 210<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.7-03(a)(23)(a)(3))<br> -URI http://asc.fasb.org/extlink&amp;oid=120400017&amp;loc=d3e572229-122910<br><br>Reference 4: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 220<br> -SubTopic 10<br> -Section 45<br> -Paragraph 14A<br> -URI http://asc.fasb.org/extlink&amp;oid=124509347&amp;loc=SL7669686-108580<br><br>Reference 5: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 944<br> -SubTopic 40<br> -Section 65<br> -Paragraph 2<br> -Subparagraph (h)(2)<br> -URI http://asc.fasb.org/extlink&amp;oid=124501264&amp;loc=SL117420844-207641<br><br>Reference 6: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 944<br> -SubTopic 40<br> -Section 65<br> -Paragraph 2<br> -Subparagraph (g)(2)(ii)<br> -URI http://asc.fasb.org/extlink&amp;oid=124501264&amp;loc=SL117420844-207641<br><br>Reference 7: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 220<br> -SubTopic 10<br> -Section 45<br> -Paragraph 14<br> -URI http://asc.fasb.org/extlink&amp;oid=124509347&amp;loc=d3e681-108580<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_AccumulatedOtherComprehensiveIncomeLossNetOfTax</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
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<td><strong> Data Type:</strong></td>
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<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
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<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
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<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_AdditionalPaidInCapitalCommonStock">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Value received from shareholders in common stock-related transactions that are in excess of par value or stated value and amounts received from other stock-related transactions. Includes only common stock transactions (excludes preferred stock transactions). May be called contributed capital, capital in excess of par, capital surplus, or paid-in capital.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 210<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.5-02(30)(a)(1))<br> -URI http://asc.fasb.org/extlink&amp;oid=120391452&amp;loc=d3e13212-122682<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
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<td><strong> Name:</strong></td>
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<tr>
<td><strong> Period Type:</strong></td>
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<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Sum of the carrying amounts as of the balance sheet date of all assets that are recognized. Assets are probable future economic benefits obtained or controlled by an entity as a result of past transactions or events.</p></div>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_Assets</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
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<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
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<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
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<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
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</div></td></tr>
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<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_AssetsCurrent">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Sum of the carrying amounts as of the balance sheet date of all assets that are expected to be realized in cash, sold, or consumed within one year (or the normal operating cycle, if longer). Assets are probable future economic benefits obtained or controlled by an entity as a result of past transactions or events.</p></div>
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http://asc.fasb.org/extlink&amp;oid=120395691&amp;loc=d3e23780-122690<br><br>Reference 20: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 210<br> -SubTopic 10<br> -Section 45<br> -Paragraph 1<br> -URI http://asc.fasb.org/extlink&amp;oid=124098289&amp;loc=d3e6676-107765<br><br>Reference 21: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 470<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1B<br> -Subparagraph (SX 210.13-02(a)(4)(i))<br> -URI http://asc.fasb.org/extlink&amp;oid=124359900&amp;loc=SL124442552-122756<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_AssetsCurrent</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_AssetsCurrentAbstract">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_AssetsCurrentAbstract</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
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</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_AvailableForSaleSecuritiesDebtSecuritiesCurrent">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of investment in debt security measured at fair value with change in fair value recognized in other comprehensive income (available-for-sale), classified as current.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 326<br> -SubTopic 30<br> -Section 45<br> -Paragraph 1<br> -URI http://asc.fasb.org/extlink&amp;oid=124258926&amp;loc=SL82898722-210454<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 320<br> -SubTopic 10<br> -Section 45<br> -Paragraph 2<br> -URI http://asc.fasb.org/extlink&amp;oid=124260329&amp;loc=d3e26626-111562<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_AvailableForSaleSecuritiesDebtSecuritiesCurrent</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_CashAndCashEquivalentsAtCarryingValue">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of currency on hand as well as demand deposits with banks or financial institutions. Includes other kinds of accounts that have the general characteristics of demand deposits. Also includes short-term, highly liquid investments that are both readily convertible to known amounts of cash and so near their maturity that they present insignificant risk of changes in value because of changes in interest rates. Excludes cash and cash equivalents within disposal group and discontinued operation.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 230<br> -SubTopic 10<br> -Section 45<br> -Paragraph 4<br> -URI http://asc.fasb.org/extlink&amp;oid=123570139&amp;loc=d3e3044-108585<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 210<br> -SubTopic 10<br> -Section 45<br> -Paragraph 1<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=124098289&amp;loc=d3e6676-107765<br><br>Reference 3: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 210<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.5-02.1)<br> -URI http://asc.fasb.org/extlink&amp;oid=120391452&amp;loc=d3e13212-122682<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_CashAndCashEquivalentsAtCarryingValue</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_CommonStockValue">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Aggregate par or stated value of issued nonredeemable common stock (or common stock redeemable solely at the option of the issuer). This item includes treasury stock repurchased by the entity. Note: elements for number of nonredeemable common shares, par value and other disclosure concepts are in another section within stockholders' equity.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/exampleRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 852<br> -SubTopic 10<br> -Section 55<br> -Paragraph 10<br> -URI http://asc.fasb.org/extlink&amp;oid=84165509&amp;loc=d3e56426-112766<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 210<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.5-02(29))<br> -URI http://asc.fasb.org/extlink&amp;oid=120391452&amp;loc=d3e13212-122682<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_CommonStockValue</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_ContractWithCustomerAssetNetCurrent">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount, after allowance for credit loss, of right to consideration in exchange for good or service transferred to customer when right is conditioned on something other than passage of time, classified as current.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 606<br> -SubTopic 10<br> -Section 45<br> -Paragraph 1<br> -URI http://asc.fasb.org/extlink&amp;oid=123360276&amp;loc=SL49130531-203044<br><br>Reference 2: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 606<br> -SubTopic 10<br> -Section 45<br> -Paragraph 3<br> -URI http://asc.fasb.org/extlink&amp;oid=123360276&amp;loc=SL49130533-203044<br><br>Reference 3: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 606<br> -SubTopic 10<br> -Section 50<br> -Paragraph 8<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=123351226&amp;loc=SL49130549-203045<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ContractWithCustomerAssetNetCurrent</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_ContractWithCustomerLiabilityCurrent">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of obligation to transfer good or service to customer for which consideration has been received or is receivable, classified as current.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 606<br> -SubTopic 10<br> -Section 45<br> -Paragraph 1<br> -URI http://asc.fasb.org/extlink&amp;oid=123360276&amp;loc=SL49130531-203044<br><br>Reference 2: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 606<br> -SubTopic 10<br> -Section 45<br> -Paragraph 2<br> -URI http://asc.fasb.org/extlink&amp;oid=123360276&amp;loc=SL49130532-203044<br><br>Reference 3: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 606<br> -SubTopic 10<br> -Section 50<br> -Paragraph 8<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=123351226&amp;loc=SL49130549-203045<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ContractWithCustomerLiabilityCurrent</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_ContractWithCustomerLiabilityNoncurrent">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of obligation to transfer good or service to customer for which consideration has been received or is receivable, classified as noncurrent.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 606<br> -SubTopic 10<br> -Section 45<br> -Paragraph 2<br> -URI http://asc.fasb.org/extlink&amp;oid=123360276&amp;loc=SL49130532-203044<br><br>Reference 2: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 606<br> -SubTopic 10<br> -Section 45<br> -Paragraph 1<br> -URI http://asc.fasb.org/extlink&amp;oid=123360276&amp;loc=SL49130531-203044<br><br>Reference 3: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 606<br> -SubTopic 10<br> -Section 50<br> -Paragraph 8<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=123351226&amp;loc=SL49130549-203045<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ContractWithCustomerLiabilityNoncurrent</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_ConvertibleDebtCurrent">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The portion of the carrying value of long-term convertible debt as of the balance sheet date that is scheduled to be repaid within one year or in the normal operating cycle if longer. Convertible debt is a financial instrument which can be exchanged for a specified amount of another security, typically the entity's common stock, at the option of the issuer or the holder.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 210<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.5-02(19))<br> -URI http://asc.fasb.org/extlink&amp;oid=120391452&amp;loc=d3e13212-122682<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ConvertibleDebtCurrent</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_ConvertibleDebtNoncurrent">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Carrying amount of long-term convertible debt as of the balance sheet date, net of the amount due in the next twelve months or greater than the normal operating cycle, if longer. The debt is convertible into another form of financial instrument, typically the entity's common stock.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 210<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.5-02.22)<br> -URI http://asc.fasb.org/extlink&amp;oid=120391452&amp;loc=d3e13212-122682<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ConvertibleDebtNoncurrent</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_EmployeeRelatedLiabilitiesCurrent">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Total of the carrying values as of the balance sheet date of obligations incurred through that date and payable for obligations related to services received from employees, such as accrued salaries and bonuses, payroll taxes and fringe benefits. Used to reflect the current portion of the liabilities (due within one year or within the normal operating cycle if longer).</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 210<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.5-02.20)<br> -URI http://asc.fasb.org/extlink&amp;oid=120391452&amp;loc=d3e13212-122682<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
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</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
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</tr>
<tr>
<td><strong> Data Type:</strong></td>
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</tr>
<tr>
<td><strong> Balance Type:</strong></td>
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</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_FiniteLivedIntangibleAssetsNet">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount after amortization of assets, excluding financial assets and goodwill, lacking physical substance with a finite life.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 926<br> -SubTopic 20<br> -Section 50<br> -Paragraph 5<br> -URI http://asc.fasb.org/extlink&amp;oid=120154696&amp;loc=d3e54445-107959<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 350<br> -SubTopic 30<br> -Section 50<br> -Paragraph 2<br> -Subparagraph (a)(1)<br> -URI http://asc.fasb.org/extlink&amp;oid=66006027&amp;loc=d3e16323-109275<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
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</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
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</tr>
<tr>
<td><strong> Data Type:</strong></td>
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</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_InventoryNet">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount after valuation and LIFO reserves of inventory expected to be sold, or consumed within one year or operating cycle, if longer.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 210<br> -SubTopic 10<br> -Section 45<br> -Paragraph 1<br> -Subparagraph (b)<br> -URI http://asc.fasb.org/extlink&amp;oid=124098289&amp;loc=d3e6676-107765<br><br>Reference 2: http://www.xbrl.org/2003/role/exampleRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 852<br> -SubTopic 10<br> -Section 55<br> -Paragraph 10<br> -URI http://asc.fasb.org/extlink&amp;oid=84165509&amp;loc=d3e56426-112766<br><br>Reference 3: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 210<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.5-02.6(a))<br> -URI http://asc.fasb.org/extlink&amp;oid=120391452&amp;loc=d3e13212-122682<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_InventoryNet</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_Liabilities">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Sum of the carrying amounts as of the balance sheet date of all liabilities that are recognized. Liabilities are probable future sacrifices of economic benefits arising from present obligations of an entity to transfer assets or provide services to other entities in the future.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 210<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.5-02.19-26)<br> -URI http://asc.fasb.org/extlink&amp;oid=120391452&amp;loc=d3e13212-122682<br><br>Reference 2: http://www.xbrl.org/2009/role/commonPracticeRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 852<br> -SubTopic 10<br> -Section 50<br> -Paragraph 7<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=124433192&amp;loc=SL2890621-112765<br><br>Reference 3: http://www.xbrl.org/2003/role/exampleRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 280<br> -SubTopic 10<br> -Section 50<br> -Paragraph 30<br> -Subparagraph (d)<br> -URI 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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_Liabilities</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_LiabilitiesAndStockholdersEquity">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of liabilities and equity items, including the portion of equity attributable to noncontrolling interests, if any.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2009/role/commonPracticeRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 323<br> -SubTopic 10<br> -Section 50<br> -Paragraph 3<br> -Subparagraph (c)<br> -URI http://asc.fasb.org/extlink&amp;oid=114001798&amp;loc=d3e33918-111571<br><br>Reference 2: http://www.xbrl.org/2003/role/exampleRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 852<br> -SubTopic 10<br> -Section 55<br> -Paragraph 10<br> -URI http://asc.fasb.org/extlink&amp;oid=84165509&amp;loc=d3e56426-112766<br><br>Reference 3: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 942<br> -SubTopic 210<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.9-03(23))<br> -URI http://asc.fasb.org/extlink&amp;oid=120398452&amp;loc=d3e534808-122878<br><br>Reference 4: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 944<br> -SubTopic 210<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.7-03(a)(25))<br> -URI http://asc.fasb.org/extlink&amp;oid=120400017&amp;loc=d3e572229-122910<br><br>Reference 5: http://www.xbrl.org/2009/role/commonPracticeRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 235<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.4-08(g)(1)(ii))<br> -URI http://asc.fasb.org/extlink&amp;oid=120395691&amp;loc=d3e23780-122690<br><br>Reference 6: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 210<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.5-02(32))<br> -URI http://asc.fasb.org/extlink&amp;oid=120391452&amp;loc=d3e13212-122682<br><br>Reference 7: http://www.xbrl.org/2009/role/commonPracticeRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 825<br> -SubTopic 10<br> -Section 50<br> -Paragraph 28<br> -Subparagraph (f)<br> -URI http://asc.fasb.org/extlink&amp;oid=123596393&amp;loc=d3e14064-108612<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_LiabilitiesAndStockholdersEquity</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_LiabilitiesCurrent">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Total obligations incurred as part of normal operations that are expected to be paid during the following twelve months or within one business cycle, if longer.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/exampleRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 852<br> -SubTopic 10<br> -Section 55<br> -Paragraph 10<br> -URI http://asc.fasb.org/extlink&amp;oid=84165509&amp;loc=d3e56426-112766<br><br>Reference 2: http://www.xbrl.org/2009/role/commonPracticeRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 852<br> -SubTopic 10<br> -Section 50<br> -Paragraph 7<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=124433192&amp;loc=SL2890621-112765<br><br>Reference 3: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 470<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1B<br> -Subparagraph (SX 210.13-02(a)(4)(iii)(A))<br> -URI 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Standards Codification<br> -Topic 470<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1A<br> -Subparagraph (SX 210.13-01(a)(5))<br> -URI http://asc.fasb.org/extlink&amp;oid=124359900&amp;loc=SL124442526-122756<br><br>Reference 14: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 810<br> -SubTopic 10<br> -Section 50<br> -Paragraph 3<br> -Subparagraph (bb)<br> -URI http://asc.fasb.org/extlink&amp;oid=123419778&amp;loc=d3e5710-111685<br><br>Reference 15: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 470<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1B<br> -Subparagraph (SX 210.13-02(a)(5))<br> -URI http://asc.fasb.org/extlink&amp;oid=124359900&amp;loc=SL124442552-122756<br><br>Reference 16: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 470<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1A<br> -Subparagraph (SX 210.13-01(a)(4)(iii)(A))<br> -URI http://asc.fasb.org/extlink&amp;oid=124359900&amp;loc=SL124442526-122756<br><br>Reference 17: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 470<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1A<br> -Subparagraph (SX 210.13-01(a)(4)(i))<br> -URI http://asc.fasb.org/extlink&amp;oid=124359900&amp;loc=SL124442526-122756<br><br>Reference 18: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 470<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1A<br> -Subparagraph (SX 210.13-01(a)(4)(iv))<br> -URI http://asc.fasb.org/extlink&amp;oid=124359900&amp;loc=SL124442526-122756<br><br>Reference 19: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 825<br> -SubTopic 10<br> -Section 50<br> -Paragraph 28<br> -Subparagraph (f)<br> -URI http://asc.fasb.org/extlink&amp;oid=123596393&amp;loc=d3e14064-108612<br><br>Reference 20: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 210<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.5-02.21)<br> -URI http://asc.fasb.org/extlink&amp;oid=120391452&amp;loc=d3e13212-122682<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_LiabilitiesCurrent</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_LiabilitiesCurrentAbstract">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_LiabilitiesCurrentAbstract</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
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<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:stringItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_LongTermLoansFromBank">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Carrying value as of the balance sheet date of loans from a bank with maturities initially due after one year or beyond the operating cycle if longer, excluding current portion.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 210<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.5-02(22))<br> -URI http://asc.fasb.org/extlink&amp;oid=120391452&amp;loc=d3e13212-122682<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 942<br> -SubTopic 210<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.9-03(16))<br> -URI http://asc.fasb.org/extlink&amp;oid=120398452&amp;loc=d3e534808-122878<br><br>Reference 3: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 944<br> -SubTopic 210<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.7-03(a)(16)(a)(2))<br> -URI http://asc.fasb.org/extlink&amp;oid=120400017&amp;loc=d3e572229-122910<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_LongTermLoansFromBank</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_OtherAssetsCurrent">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of current assets classified as other.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 210<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.5-02.8)<br> -URI http://asc.fasb.org/extlink&amp;oid=120391452&amp;loc=d3e13212-122682<br><br>Reference 2: http://www.xbrl.org/2003/role/exampleRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 852<br> -SubTopic 10<br> -Section 55<br> -Paragraph 10<br> -URI http://asc.fasb.org/extlink&amp;oid=84165509&amp;loc=d3e56426-112766<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_OtherAssetsCurrent</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_OtherAssetsNoncurrent">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of noncurrent assets classified as other.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 210<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.5-02.17)<br> -URI http://asc.fasb.org/extlink&amp;oid=120391452&amp;loc=d3e13212-122682<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_OtherAssetsNoncurrent</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_PropertyPlantAndEquipmentNet">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount after accumulated depreciation, depletion and amortization of physical assets used in the normal conduct of business to produce goods and services and not intended for resale. Examples include, but are not limited to, land, buildings, machinery and equipment, office equipment, and furniture and fixtures.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 210<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.5-02(14))<br> -URI http://asc.fasb.org/extlink&amp;oid=120391452&amp;loc=d3e13212-122682<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 360<br> -SubTopic 10<br> -Section 50<br> -Paragraph 1<br> -URI http://asc.fasb.org/extlink&amp;oid=6391035&amp;loc=d3e2868-110229<br><br>Reference 3: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 944<br> -SubTopic 210<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.7-03(a)(8))<br> -URI http://asc.fasb.org/extlink&amp;oid=120400017&amp;loc=d3e572229-122910<br><br>Reference 4: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 942<br> -SubTopic 360<br> -Section 50<br> -Paragraph 1<br> -URI http://asc.fasb.org/extlink&amp;oid=124429447&amp;loc=SL124453093-239630<br><br>Reference 5: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 210<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.5-02(13))<br> -URI http://asc.fasb.org/extlink&amp;oid=120391452&amp;loc=d3e13212-122682<br><br>Reference 6: http://www.xbrl.org/2003/role/exampleRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 852<br> -SubTopic 10<br> -Section 55<br> -Paragraph 10<br> -URI http://asc.fasb.org/extlink&amp;oid=84165509&amp;loc=d3e56426-112766<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_PropertyPlantAndEquipmentNet</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_RetainedEarningsAccumulatedDeficit">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The cumulative amount of the reporting entity's undistributed earnings or deficit.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 210<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.5-02(30)(a)(3))<br> -URI http://asc.fasb.org/extlink&amp;oid=120391452&amp;loc=d3e13212-122682<br><br>Reference 2: http://www.xbrl.org/2003/role/exampleRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 852<br> -SubTopic 10<br> -Section 55<br> -Paragraph 10<br> -URI http://asc.fasb.org/extlink&amp;oid=84165509&amp;loc=d3e56426-112766<br><br>Reference 3: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 718<br> -SubTopic 10<br> -Section 65<br> -Paragraph 15<br> -Subparagraph (g)(2)<br> -URI http://asc.fasb.org/extlink&amp;oid=121322162&amp;loc=SL121327923-165333<br><br>Reference 4: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 944<br> -SubTopic 210<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.7-03(a)(23)(a)(4))<br> -URI http://asc.fasb.org/extlink&amp;oid=120400017&amp;loc=d3e572229-122910<br><br>Reference 5: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 944<br> -SubTopic 40<br> -Section 65<br> -Paragraph 2<br> -Subparagraph (h)(2)<br> -URI http://asc.fasb.org/extlink&amp;oid=124501264&amp;loc=SL117420844-207641<br><br>Reference 6: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 505<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.3-04)<br> -URI http://asc.fasb.org/extlink&amp;oid=120397183&amp;loc=d3e187085-122770<br><br>Reference 7: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 944<br> -SubTopic 40<br> -Section 65<br> -Paragraph 2<br> -Subparagraph (g)(2)(i)<br> -URI http://asc.fasb.org/extlink&amp;oid=124501264&amp;loc=SL117420844-207641<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_RetainedEarningsAccumulatedDeficit</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_StockholdersEquity">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Total of all stockholders' equity (deficit) items, net of receivables from officers, directors, owners, and affiliates of the entity which are attributable to the parent. The amount of the economic entity's stockholders' equity attributable to the parent excludes the amount of stockholders' equity which is allocable to that ownership interest in subsidiary equity which is not attributable to the parent (noncontrolling interest, minority interest). This excludes temporary equity and is sometimes called permanent equity.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2009/role/commonPracticeRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 235<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.4-08(g)(1)(ii))<br> -URI http://asc.fasb.org/extlink&amp;oid=120395691&amp;loc=d3e23780-122690<br><br>Reference 2: http://www.xbrl.org/2003/role/exampleRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 852<br> -SubTopic 10<br> -Section 55<br> -Paragraph 10<br> -URI http://asc.fasb.org/extlink&amp;oid=84165509&amp;loc=d3e56426-112766<br><br>Reference 3: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 310<br> -SubTopic 10<br> -Section S99<br> -Paragraph 2<br> -Subparagraph (SAB Topic 4.E)<br> -URI http://asc.fasb.org/extlink&amp;oid=122038336&amp;loc=d3e74512-122707<br><br>Reference 4: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 210<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.5-02(31))<br> -URI http://asc.fasb.org/extlink&amp;oid=120391452&amp;loc=d3e13212-122682<br><br>Reference 5: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 210<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.5-02(29))<br> -URI http://asc.fasb.org/extlink&amp;oid=120391452&amp;loc=d3e13212-122682<br><br>Reference 6: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 210<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.5-02(30))<br> -URI http://asc.fasb.org/extlink&amp;oid=120391452&amp;loc=d3e13212-122682<br><br>Reference 7: http://www.xbrl.org/2009/role/commonPracticeRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 825<br> -SubTopic 10<br> -Section 50<br> -Paragraph 28<br> -Subparagraph (f)<br> -URI http://asc.fasb.org/extlink&amp;oid=123596393&amp;loc=d3e14064-108612<br><br>Reference 8: http://www.xbrl.org/2009/role/commonPracticeRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 323<br> -SubTopic 10<br> -Section 50<br> -Paragraph 3<br> -Subparagraph (c)<br> -URI http://asc.fasb.org/extlink&amp;oid=114001798&amp;loc=d3e33918-111571<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
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<span style="display: none;">v3.22.0.1</span><table class="report" border="0" cellspacing="2" id="idm139691017456664">
<tr>
<th class="tl" colspan="1" rowspan="1"><div style="width: 200px;"><strong>CONSOLIDATED BALANCE SHEETS (Parenthetical) - $ / shares<br></strong></div></th>
<th class="th"><div>Dec. 31, 2021</div></th>
<th class="th"><div>Dec. 31, 2020</div></th>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_StockholdersEquityAbstract', window );"><strong>Stockholders' equity:</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
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</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_CommonStockParOrStatedValuePerShare', window );">Common stock, par value (in dollars per share)</a></td>
<td class="nump">$ 0.001<span></span>
</td>
<td class="nump">$ 0.001<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_CommonStockSharesAuthorized', window );">Common stock, shares authorized (in shares)</a></td>
<td class="nump">300,000,000<span></span>
</td>
<td class="nump">300,000,000<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_CommonStockSharesIssued', window );">Common stock, shares issued (in shares)</a></td>
<td class="nump">141,210,015<span></span>
</td>
<td class="nump">140,365,594<span></span>
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<td class="nump">141,210,015<span></span>
</td>
<td class="nump">140,365,594<span></span>
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<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DebtInstrumentAxis=ions_ConvertibleSeniorNotes1PercentMember', window );">1 Percent Convertible Senior Notes [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
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<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_LiabilitiesAndStockholdersEquityAbstract', window );"><strong>LIABILITIES AND STOCKHOLDERS' EQUITY</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
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<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DebtInstrumentInterestRateStatedPercentage', window );">Interest rate on convertible senior notes</a></td>
<td class="nump">1.00%<span></span>
</td>
<td class="nump">1.00%<span></span>
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<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DebtInstrumentAxis=ions_ConvertibleSeniorNotes0PercentMember', window );">0 Percent Convertible Senior Notes [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
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<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_LiabilitiesAndStockholdersEquityAbstract', window );"><strong>LIABILITIES AND STOCKHOLDERS' EQUITY</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DebtInstrumentInterestRateStatedPercentage', window );">Interest rate on convertible senior notes</a></td>
<td class="nump">0.00%<span></span>
</td>
<td class="text">&#160;<span></span>
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<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DebtInstrumentAxis=ions_ConvertibleSeniorNotes0125PercentMember', window );">0.125 Percent Convertible Senior Notes [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
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<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_LiabilitiesAndStockholdersEquityAbstract', window );"><strong>LIABILITIES AND STOCKHOLDERS' EQUITY</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
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<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DebtInstrumentInterestRateStatedPercentage', window );">Interest rate on convertible senior notes</a></td>
<td class="nump">0.125%<span></span>
</td>
<td class="nump">0.125%<span></span>
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<div style="display: none;">
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Face amount or stated value per share of common stock.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 210<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.5-02(29))<br> -URI http://asc.fasb.org/extlink&amp;oid=120391452&amp;loc=d3e13212-122682<br></p></div>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The maximum number of common shares permitted to be issued by an entity's charter and bylaws.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 210<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.5-02(29))<br> -URI http://asc.fasb.org/extlink&amp;oid=120391452&amp;loc=d3e13212-122682<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
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<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Total number of common shares of an entity that have been sold or granted to shareholders (includes common shares that were issued, repurchased and remain in the treasury). These shares represent capital invested by the firm's shareholders and owners, and may be all or only a portion of the number of shares authorized. Shares issued include shares outstanding and shares held in the treasury.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 210<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.5-02(29))<br> -URI http://asc.fasb.org/extlink&amp;oid=120391452&amp;loc=d3e13212-122682<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Number of shares of common stock outstanding. Common stock represent the ownership interest in a corporation.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 505<br> -SubTopic 10<br> -Section 50<br> -Paragraph 2<br> -URI http://asc.fasb.org/extlink&amp;oid=123467817&amp;loc=d3e21463-112644<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 210<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.5-02(29))<br> -URI http://asc.fasb.org/extlink&amp;oid=120391452&amp;loc=d3e13212-122682<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_CommonStockSharesOutstanding</td>
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<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
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<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:sharesItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
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<td><strong> Period Type:</strong></td>
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<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Contractual interest rate for funds borrowed, under the debt agreement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 470<br> -SubTopic 20<br> -Section 50<br> -Paragraph 1B<br> -Subparagraph (b)<br> -URI http://asc.fasb.org/extlink&amp;oid=123466505&amp;loc=SL123495323-112611<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 210<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.5-02.22(a)(1))<br> -URI http://asc.fasb.org/extlink&amp;oid=120391452&amp;loc=d3e13212-122682<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_DebtInstrumentInterestRateStatedPercentage</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
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<tr>
<td><strong> Balance Type:</strong></td>
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<td><strong> Period Type:</strong></td>
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</tr>
</table></div>
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<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_LiabilitiesAndStockholdersEquityAbstract">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_LiabilitiesAndStockholdersEquityAbstract</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
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<td><strong> Data Type:</strong></td>
<td>xbrli:stringItemType</td>
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<td><strong> Balance Type:</strong></td>
<td>na</td>
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<tr>
<td><strong> Period Type:</strong></td>
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</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_StockholdersEquityAbstract">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_StockholdersEquityAbstract</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
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<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:stringItemType</td>
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<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
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<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_DebtInstrumentAxis=ions_ConvertibleSeniorNotes1PercentMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_DebtInstrumentAxis=ions_ConvertibleSeniorNotes1PercentMember</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td></td>
</tr>
</table></div>
</div></td></tr>
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<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_DebtInstrumentAxis=ions_ConvertibleSeniorNotes0PercentMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_DebtInstrumentAxis=ions_ConvertibleSeniorNotes0PercentMember</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td></td>
</tr>
</table></div>
</div></td></tr>
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<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_DebtInstrumentAxis=ions_ConvertibleSeniorNotes0125PercentMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_DebtInstrumentAxis=ions_ConvertibleSeniorNotes0125PercentMember</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td></td>
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<tr>
<td><strong> Data Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td></td>
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<tr>
<td><strong> Period Type:</strong></td>
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<DOCUMENT>
<TYPE>XML
<SEQUENCE>34
<FILENAME>R4.htm
<DESCRIPTION>IDEA: XBRL DOCUMENT
<TEXT>
<html>
<head>
<title></title>
<link rel="stylesheet" type="text/css" href="report.css">
<script type="text/javascript" src="Show.js">/* Do Not Remove This Comment */</script><script type="text/javascript">
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<span style="display: none;">v3.22.0.1</span><table class="report" border="0" cellspacing="2" id="idm139691008265912">
<tr>
<th class="tl" colspan="1" rowspan="2"><div style="width: 200px;"><strong>CONSOLIDATED STATEMENTS OF OPERATIONS - USD ($)<br> shares in Thousands, $ in Thousands</strong></div></th>
<th class="th" colspan="3">12 Months Ended</th>
</tr>
<tr>
<th class="th"><div>Dec. 31, 2021</div></th>
<th class="th"><div>Dec. 31, 2020</div></th>
<th class="th"><div>Dec. 31, 2019</div></th>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RevenuesAbstract', window );"><strong>Revenue:</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax', window );">Revenue</a></td>
<td class="nump">$ 810,456<span></span>
</td>
<td class="nump">$ 729,264<span></span>
</td>
<td class="nump">$ 1,122,599<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_CostsAndExpensesAbstract', window );"><strong>Expenses:</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_CostOfGoodsAndServicesSold', window );">Cost of sales</a></td>
<td class="nump">10,842<span></span>
</td>
<td class="nump">11,947<span></span>
</td>
<td class="nump">4,384<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_ResearchDevelopmentAndPatentExpense', window );">Research, development and patent</a></td>
<td class="nump">643,453<span></span>
</td>
<td class="nump">535,077<span></span>
</td>
<td class="nump">465,688<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_SellingGeneralAndAdministrativeExpense', window );">Selling, general and administrative</a></td>
<td class="nump">186,347<span></span>
</td>
<td class="nump">354,322<span></span>
</td>
<td class="nump">286,644<span></span>
</td>
</tr>
<tr class="reu">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_CostsAndExpenses', window );">Total operating expenses</a></td>
<td class="nump">840,642<span></span>
</td>
<td class="nump">901,346<span></span>
</td>
<td class="nump">756,716<span></span>
</td>
</tr>
<tr class="rou">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_OperatingIncomeLoss', window );">Income (loss) from operations</a></td>
<td class="num">(30,186)<span></span>
</td>
<td class="num">(172,082)<span></span>
</td>
<td class="nump">365,883<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_NonoperatingIncomeExpenseAbstract', window );"><strong>Other income (expense):</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_InvestmentIncomeNet', window );">Investment income</a></td>
<td class="nump">10,044<span></span>
</td>
<td class="nump">30,562<span></span>
</td>
<td class="nump">52,013<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_InterestExpense', window );">Interest expense</a></td>
<td class="num">(9,349)<span></span>
</td>
<td class="num">(9,510)<span></span>
</td>
<td class="num">(12,440)<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_GainLossOnInvestments', window );">Gain on investments</a></td>
<td class="nump">10,103<span></span>
</td>
<td class="nump">16,540<span></span>
</td>
<td class="nump">192<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_GainsLossesOnExtinguishmentOfDebt', window );">Loss on early retirement of debt</a></td>
<td class="num">(8,627)<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="num">(66,196)<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_OtherNonoperatingIncomeExpense', window );">Other expenses</a></td>
<td class="num">(1,133)<span></span>
</td>
<td class="num">(62)<span></span>
</td>
<td class="num">(686)<span></span>
</td>
</tr>
<tr class="reu">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_IncomeLossFromContinuingOperationsBeforeIncomeTaxesExtraordinaryItemsNoncontrollingInterest', window );">Income (loss) before income tax benefit (expense)</a></td>
<td class="num">(29,148)<span></span>
</td>
<td class="num">(134,552)<span></span>
</td>
<td class="nump">338,766<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_IncomeTaxExpenseBenefit', window );">Income tax benefit (expense)</a></td>
<td class="nump">551<span></span>
</td>
<td class="num">(345,191)<span></span>
</td>
<td class="num">(51,507)<span></span>
</td>
</tr>
<tr class="reu">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ProfitLoss', window );">Net income (loss)</a></td>
<td class="num">(28,597)<span></span>
</td>
<td class="num">(479,743)<span></span>
</td>
<td class="nump">287,259<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_NetIncomeLossAttributableToNoncontrollingInterest', window );">Net (income) loss attributable to noncontrolling interest in Akcea Therapeutics, Inc.</a></td>
<td class="nump">0<span></span>
</td>
<td class="nump">35,480<span></span>
</td>
<td class="num">(9,116)<span></span>
</td>
</tr>
<tr class="reu">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_NetIncomeLoss', window );">Net income (loss) attributable to Ionis Pharmaceuticals, Inc. common stockholders</a></td>
<td class="num">$ (28,597)<span></span>
</td>
<td class="num">$ (444,263)<span></span>
</td>
<td class="nump">$ 278,143<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_EarningsPerShareBasic', window );">Basic net income (loss) per share (in dollars per share)</a></td>
<td class="num">$ (0.20)<span></span>
</td>
<td class="num">$ (3.18)<span></span>
</td>
<td class="nump">$ 2.00<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_WeightedAverageNumberOfSharesOutstandingBasic', window );">Shares used in computing basic net income (loss) per share (in shares)</a></td>
<td class="nump">141,021<span></span>
</td>
<td class="nump">139,612<span></span>
</td>
<td class="nump">139,998<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_EarningsPerShareDiluted', window );">Diluted net income (loss) per share (in dollars per share)</a></td>
<td class="num">$ (0.20)<span></span>
</td>
<td class="num">$ (3.18)<span></span>
</td>
<td class="nump">$ 1.90<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_WeightedAverageNumberOfDilutedSharesOutstanding', window );">Shares used in computing diluted net income (loss) per share (in shares)</a></td>
<td class="nump">141,021<span></span>
</td>
<td class="nump">139,612<span></span>
</td>
<td class="nump">153,164<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_srt_ProductOrServiceAxis=ions_CommercialMember', window );">Commercial Revenue [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RevenuesAbstract', window );"><strong>Revenue:</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax', window );">Revenue</a></td>
<td class="nump">$ 342,395<span></span>
</td>
<td class="nump">$ 364,699<span></span>
</td>
<td class="nump">$ 352,450<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_srt_ProductOrServiceAxis=ions_SpinrazaRoyaltiesMember', window );">SPINRAZA Royalties [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RevenuesAbstract', window );"><strong>Revenue:</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax', window );">Revenue</a></td>
<td class="nump">267,776<span></span>
</td>
<td class="nump">286,583<span></span>
</td>
<td class="nump">292,992<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_srt_ProductOrServiceAxis=us-gaap_ProductMember', window );">TEGSEDI and WAYLIVRA Revenue, Net [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RevenuesAbstract', window );"><strong>Revenue:</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax', window );">Revenue</a></td>
<td class="nump">55,500<span></span>
</td>
<td class="nump">69,999<span></span>
</td>
<td class="nump">42,253<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_srt_ProductOrServiceAxis=ions_LicensingAndOtherRoyaltiesMember', window );">Licensing and Other Royalty Revenue [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RevenuesAbstract', window );"><strong>Revenue:</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax', window );">Revenue</a></td>
<td class="nump">19,119<span></span>
</td>
<td class="nump">8,117<span></span>
</td>
<td class="nump">17,205<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_srt_ProductOrServiceAxis=ions_ResearchAndDevelopmentRevenueUnderCollaborativeAgreementsMember', window );">Research and Development Revenue Under Collaborative Agreements [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RevenuesAbstract', window );"><strong>Revenue:</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax', window );">Revenue</a></td>
<td class="nump">$ 468,061<span></span>
</td>
<td class="nump">$ 364,565<span></span>
</td>
<td class="nump">$ 770,149<span></span>
</td>
</tr>
</table>
<div style="display: none;">
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_ResearchDevelopmentAndPatentExpense">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The aggregate costs incurred (1) in a planned search or critical investigation aimed at discovery of new knowledge with the hope that such knowledge will be useful in developing a new product or service, a new process or technique, or in bringing about a significant improvement to an existing product or process; or (2) to translate research findings or other knowledge into a plan or design for a new product or process or for a significant improvement to an existing product or process whether intended for sale or the entity's use, during the reporting period charged to research and development projects. Also includes charges for amortization and write-downs of capitalized patent costs, as well as legal fees for patent litigation and patent defense.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
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<tr>
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</tr>
<tr>
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</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
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<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_CostOfGoodsAndServicesSold">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The aggregate costs related to goods produced and sold and services rendered by an entity during the reporting period. This excludes costs incurred during the reporting period related to financial services rendered and other revenue generating activities.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 924<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SAB Topic 11.L)<br> -URI http://asc.fasb.org/extlink&amp;oid=6472922&amp;loc=d3e499488-122856<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 220<br> -SubTopic 10<br> -Section S99<br> -Paragraph 2<br> -Subparagraph (SX 210.5-03.2(a),(d))<br> -URI http://asc.fasb.org/extlink&amp;oid=123367319&amp;loc=SL114868664-224227<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
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<tr>
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<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Total costs of sales and operating expenses for the period.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 220<br> -SubTopic 10<br> -Section S99<br> -Paragraph 2<br> -Subparagraph (SX 210.5-03)<br> -URI http://asc.fasb.org/extlink&amp;oid=123367319&amp;loc=SL114868664-224227<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_CostsAndExpenses</td>
</tr>
<tr>
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<td><strong> Period Type:</strong></td>
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<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_CostsAndExpensesAbstract">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_CostsAndExpensesAbstract</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
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<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:stringItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
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<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_EarningsPerShareBasic">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The amount of net income (loss) for the period per each share of common stock or unit outstanding during the reporting period.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 815<br> -SubTopic 40<br> -Section 65<br> -Paragraph 1<br> -Subparagraph (e)(4)<br> -URI http://asc.fasb.org/extlink&amp;oid=123482062&amp;loc=SL123482106-238011<br><br>Reference 2: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 250<br> -SubTopic 10<br> -Section 50<br> -Paragraph 3<br> -URI http://asc.fasb.org/extlink&amp;oid=124431687&amp;loc=d3e22583-107794<br><br>Reference 3: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 250<br> -SubTopic 10<br> -Section 50<br> -Paragraph 11<br> -Subparagraph (b)<br> -URI http://asc.fasb.org/extlink&amp;oid=124431687&amp;loc=d3e22694-107794<br><br>Reference 4: 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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_EarningsPerShareBasic</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>dtr-types:perShareItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_EarningsPerShareDiluted">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The amount of net income (loss) for the period available to each share of common stock or common unit outstanding during the reporting period and to each share or unit that would have been outstanding assuming the issuance of common shares or units for all dilutive potential common shares or units outstanding during the reporting period.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/exampleRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 260<br> -SubTopic 10<br> -Section 55<br> -Paragraph 52<br> -URI http://asc.fasb.org/extlink&amp;oid=125512782&amp;loc=d3e4984-109258<br><br>Reference 2: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 250<br> -SubTopic 10<br> -Section 50<br> -Paragraph 7<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=124431687&amp;loc=d3e22644-107794<br><br>Reference 3: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 260<br> -SubTopic 10<br> -Section 55<br> -Paragraph 15<br> -URI http://asc.fasb.org/extlink&amp;oid=125512782&amp;loc=d3e3842-109258<br><br>Reference 4: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 260<br> -SubTopic 10<br> -Section 45<br> -Paragraph 2<br> -URI http://asc.fasb.org/extlink&amp;oid=125511455&amp;loc=d3e1252-109256<br><br>Reference 5: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 250<br> -SubTopic 10<br> -Section 50<br> -Paragraph 11<br> -Subparagraph (b)<br> -URI http://asc.fasb.org/extlink&amp;oid=124431687&amp;loc=d3e22694-107794<br><br>Reference 6: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 250<br> -SubTopic 10<br> -Section 50<br> -Paragraph 4<br> -URI http://asc.fasb.org/extlink&amp;oid=124431687&amp;loc=d3e22595-107794<br><br>Reference 7: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 250<br> -SubTopic 10<br> -Section 50<br> -Paragraph 3<br> -URI http://asc.fasb.org/extlink&amp;oid=124431687&amp;loc=d3e22583-107794<br><br>Reference 8: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 260<br> -SubTopic 10<br> -Section 45<br> -Paragraph 60B<br> -Subparagraph (d)<br> -URI http://asc.fasb.org/extlink&amp;oid=125511455&amp;loc=SL5780133-109256<br><br>Reference 9: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 815<br> -SubTopic 40<br> -Section 65<br> -Paragraph 1<br> -Subparagraph (f)<br> -URI http://asc.fasb.org/extlink&amp;oid=123482062&amp;loc=SL123482106-238011<br><br>Reference 10: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 942<br> -SubTopic 220<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.9-04(27))<br> -URI http://asc.fasb.org/extlink&amp;oid=120399700&amp;loc=SL114874048-224260<br><br>Reference 11: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 260<br> -SubTopic 10<br> -Section 50<br> -Paragraph 1<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=124432515&amp;loc=d3e3550-109257<br><br>Reference 12: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 944<br> -SubTopic 220<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.7-04(23))<br> -URI http://asc.fasb.org/extlink&amp;oid=120400993&amp;loc=SL114874131-224263<br><br>Reference 13: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 250<br> -SubTopic 10<br> -Section 50<br> -Paragraph 11<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=124431687&amp;loc=d3e22694-107794<br><br>Reference 14: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 260<br> -SubTopic 10<br> -Section 45<br> -Paragraph 7<br> -URI http://asc.fasb.org/extlink&amp;oid=125511455&amp;loc=d3e1337-109256<br><br>Reference 15: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 815<br> -SubTopic 40<br> -Section 65<br> -Paragraph 1<br> -Subparagraph (e)(4)<br> -URI http://asc.fasb.org/extlink&amp;oid=123482062&amp;loc=SL123482106-238011<br><br>Reference 16: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 220<br> -SubTopic 10<br> -Section S99<br> -Paragraph 2<br> -Subparagraph (SX 210.5-03(25))<br> -URI http://asc.fasb.org/extlink&amp;oid=123367319&amp;loc=SL114868664-224227<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_EarningsPerShareDiluted</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>dtr-types:perShareItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_GainLossOnInvestments">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of realized and unrealized gain (loss) on investment.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 320<br> -SubTopic 10<br> -Section 50<br> -Paragraph 10<br> -Subparagraph (c)<br> -URI http://asc.fasb.org/extlink&amp;oid=123581744&amp;loc=d3e27405-111563<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 220<br> -SubTopic 10<br> -Section S99<br> -Paragraph 2<br> -Subparagraph (SX 210.5-03.7(c),9(a))<br> -URI http://asc.fasb.org/extlink&amp;oid=123367319&amp;loc=SL114868664-224227<br><br>Reference 3: http://www.xbrl.org/2003/role/recommendedDisclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 230<br> -SubTopic 10<br> -Section 45<br> -Paragraph 28<br> -Subparagraph (b)<br> -URI http://asc.fasb.org/extlink&amp;oid=123570139&amp;loc=d3e3602-108585<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_GainLossOnInvestments</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_GainsLossesOnExtinguishmentOfDebt">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Difference between the fair value of payments made and the carrying amount of debt which is extinguished prior to maturity.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 470<br> -SubTopic 50<br> -Section 40<br> -Paragraph 4<br> -URI http://asc.fasb.org/extlink&amp;oid=123467658&amp;loc=d3e12355-112629<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 470<br> -SubTopic 50<br> -Section 40<br> -Paragraph 2<br> -URI http://asc.fasb.org/extlink&amp;oid=123467658&amp;loc=d3e12317-112629<br><br>Reference 3: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 230<br> -SubTopic 10<br> -Section 45<br> -Paragraph 28<br> -Subparagraph (b)<br> -URI http://asc.fasb.org/extlink&amp;oid=123570139&amp;loc=d3e3602-108585<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_GainsLossesOnExtinguishmentOfDebt</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_IncomeLossFromContinuingOperationsBeforeIncomeTaxesExtraordinaryItemsNoncontrollingInterest">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of income (loss) from continuing operations, including income (loss) from equity method investments, before deduction of income tax expense (benefit), and income (loss) attributable to noncontrolling interest.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 280<br> -SubTopic 10<br> -Section 50<br> -Paragraph 32<br> -Subparagraph (c)<br> -URI http://asc.fasb.org/extlink&amp;oid=123359005&amp;loc=d3e8933-108599<br><br>Reference 2: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 280<br> -SubTopic 10<br> -Section 50<br> -Paragraph 30<br> -Subparagraph (b)<br> -URI http://asc.fasb.org/extlink&amp;oid=123359005&amp;loc=d3e8906-108599<br><br>Reference 3: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 280<br> -SubTopic 10<br> -Section 50<br> -Paragraph 32<br> -Subparagraph (f)<br> -URI http://asc.fasb.org/extlink&amp;oid=123359005&amp;loc=d3e8933-108599<br><br>Reference 4: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 940<br> -SubTopic 20<br> -Section 25<br> -Paragraph 1<br> -URI http://asc.fasb.org/extlink&amp;oid=123384075&amp;loc=d3e41242-110953<br><br>Reference 5: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 280<br> -SubTopic 10<br> -Section 50<br> -Paragraph 22<br> -URI http://asc.fasb.org/extlink&amp;oid=123359005&amp;loc=d3e8736-108599<br><br>Reference 6: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 220<br> -SubTopic 10<br> -Section S99<br> -Paragraph 2<br> -Subparagraph (SX 210.5-03(10))<br> -URI http://asc.fasb.org/extlink&amp;oid=123367319&amp;loc=SL114868664-224227<br><br>Reference 7: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 944<br> -SubTopic 220<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.7-04(8))<br> -URI http://asc.fasb.org/extlink&amp;oid=120400993&amp;loc=SL114874131-224263<br><br>Reference 8: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 942<br> -SubTopic 235<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.9-05(b)(2))<br> -URI http://asc.fasb.org/extlink&amp;oid=120399901&amp;loc=d3e537907-122884<br><br>Reference 9: http://www.xbrl.org/2003/role/exampleRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 280<br> -SubTopic 10<br> -Section 50<br> -Paragraph 31<br> -URI http://asc.fasb.org/extlink&amp;oid=123359005&amp;loc=d3e8924-108599<br><br>Reference 10: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 942<br> -SubTopic 220<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.9-04(15))<br> -URI http://asc.fasb.org/extlink&amp;oid=120399700&amp;loc=SL114874048-224260<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_IncomeLossFromContinuingOperationsBeforeIncomeTaxesExtraordinaryItemsNoncontrollingInterest</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_IncomeTaxExpenseBenefit">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of current income tax expense (benefit) and deferred income tax expense (benefit) pertaining to continuing operations.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SAB TOPIC 6.I.7)<br> -URI http://asc.fasb.org/extlink&amp;oid=122134291&amp;loc=d3e330036-122817<br><br>Reference 2: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section 50<br> -Paragraph 10<br> -URI http://asc.fasb.org/extlink&amp;oid=121826272&amp;loc=d3e32672-109319<br><br>Reference 3: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 280<br> -SubTopic 10<br> -Section 50<br> -Paragraph 22<br> -Subparagraph (h)<br> -URI http://asc.fasb.org/extlink&amp;oid=123359005&amp;loc=d3e8736-108599<br><br>Reference 4: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 235<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.4-08(h))<br> -URI http://asc.fasb.org/extlink&amp;oid=120395691&amp;loc=d3e23780-122690<br><br>Reference 5: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 250<br> -SubTopic 10<br> -Section 50<br> -Paragraph 9<br> -URI http://asc.fasb.org/extlink&amp;oid=124431687&amp;loc=d3e22663-107794<br><br>Reference 6: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 20<br> -Section 45<br> -Paragraph 2<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=123586238&amp;loc=d3e38679-109324<br><br>Reference 7: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 944<br> -SubTopic 220<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.7-04(9))<br> -URI http://asc.fasb.org/extlink&amp;oid=120400993&amp;loc=SL114874131-224263<br><br>Reference 8: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 250<br> -SubTopic 10<br> -Section 50<br> -Paragraph 8<br> -URI http://asc.fasb.org/extlink&amp;oid=124431687&amp;loc=d3e22658-107794<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_IncomeTaxExpenseBenefit</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_InterestExpense">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of the cost of borrowed funds accounted for as interest expense.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 835<br> -SubTopic 20<br> -Section 50<br> -Paragraph 1<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=6450988&amp;loc=d3e26243-108391<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 835<br> -SubTopic 30<br> -Section 45<br> -Paragraph 3<br> -URI http://asc.fasb.org/extlink&amp;oid=124435984&amp;loc=d3e28555-108399<br><br>Reference 3: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 280<br> -SubTopic 10<br> -Section 50<br> -Paragraph 22<br> -Subparagraph (d)<br> -URI http://asc.fasb.org/extlink&amp;oid=123359005&amp;loc=d3e8736-108599<br><br>Reference 4: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 220<br> -SubTopic 10<br> -Section S99<br> -Paragraph 2<br> -Subparagraph (210.5-03(11))<br> -URI http://asc.fasb.org/extlink&amp;oid=123367319&amp;loc=SL114868664-224227<br><br>Reference 5: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 942<br> -SubTopic 220<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.9-04.9)<br> -URI http://asc.fasb.org/extlink&amp;oid=120399700&amp;loc=SL114874048-224260<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_InterestExpense</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_InvestmentIncomeNet">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount after accretion (amortization) of discount (premium), and investment expense, of interest income and dividend income on nonoperating securities.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 220<br> -SubTopic 10<br> -Section S99<br> -Paragraph 2<br> -Subparagraph (SX 210.5-03.7(a),(b))<br> -URI http://asc.fasb.org/extlink&amp;oid=123367319&amp;loc=SL114868664-224227<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 220<br> -SubTopic 10<br> -Section S99<br> -Paragraph 2<br> -Subparagraph (SX 210.5-03.8)<br> -URI http://asc.fasb.org/extlink&amp;oid=123367319&amp;loc=SL114868664-224227<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_InvestmentIncomeNet</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_NetIncomeLoss">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The portion of profit or loss for the period, net of income taxes, which is attributable to the parent.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 942<br> -SubTopic 220<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.9-04(22))<br> -URI http://asc.fasb.org/extlink&amp;oid=120399700&amp;loc=SL114874048-224260<br><br>Reference 2: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 280<br> -SubTopic 10<br> -Section 50<br> -Paragraph 32<br> -Subparagraph (f)<br> -URI http://asc.fasb.org/extlink&amp;oid=123359005&amp;loc=d3e8933-108599<br><br>Reference 3: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 250<br> -SubTopic 10<br> -Section 50<br> -Paragraph 4<br> -URI 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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_NetIncomeLoss</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
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<tr>
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<td>xbrli:monetaryItemType</td>
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<tr>
<td><strong> Balance Type:</strong></td>
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<td><strong> Period Type:</strong></td>
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</tr>
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</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_NetIncomeLossAttributableToNoncontrollingInterest">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of Net Income (Loss) attributable to noncontrolling interest.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 220<br> -SubTopic 10<br> -Section 45<br> -Paragraph 1B<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=124509347&amp;loc=SL7669625-108580<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 810<br> -SubTopic 10<br> -Section 50<br> -Paragraph 1A<br> -Subparagraph (a)(2)<br> -URI http://asc.fasb.org/extlink&amp;oid=109239629&amp;loc=SL4573702-111684<br><br>Reference 3: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 250<br> -SubTopic 10<br> -Section 50<br> -Paragraph 8<br> -URI http://asc.fasb.org/extlink&amp;oid=124431687&amp;loc=d3e22658-107794<br><br>Reference 4: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 220<br> -SubTopic 10<br> -Section 45<br> -Paragraph 1A<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=124509347&amp;loc=SL7669619-108580<br><br>Reference 5: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 810<br> -SubTopic 10<br> -Section 55<br> -Paragraph 4J<br> -URI http://asc.fasb.org/extlink&amp;oid=120409616&amp;loc=SL4591551-111686<br><br>Reference 6: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 250<br> -SubTopic 10<br> -Section 50<br> -Paragraph 9<br> -URI http://asc.fasb.org/extlink&amp;oid=124431687&amp;loc=d3e22663-107794<br><br>Reference 7: http://www.xbrl.org/2009/role/commonPracticeRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 220<br> -SubTopic 10<br> -Section 50<br> -Paragraph 6<br> -URI http://asc.fasb.org/extlink&amp;oid=124431353&amp;loc=SL124452729-227067<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_NetIncomeLossAttributableToNoncontrollingInterest</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
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<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
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<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_NonoperatingIncomeExpenseAbstract</td>
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<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
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<td><strong> Data Type:</strong></td>
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<tr>
<td><strong> Balance Type:</strong></td>
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<tr>
<td><strong> Period Type:</strong></td>
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</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_OperatingIncomeLoss">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The net result for the period of deducting operating expenses from operating revenues.</p></div>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_OperatingIncomeLoss</td>
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<tr>
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<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
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<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
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</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_OtherNonoperatingIncomeExpense">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of income (expense) related to nonoperating activities, classified as other.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 220<br> -SubTopic 10<br> -Section S99<br> -Paragraph 2<br> -Subparagraph (SX 210.5-03.9)<br> -URI http://asc.fasb.org/extlink&amp;oid=123367319&amp;loc=SL114868664-224227<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_OtherNonoperatingIncomeExpense</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
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</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
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</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_ProfitLoss">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The consolidated profit or loss for the period, net of income taxes, including the portion attributable to the noncontrolling interest.</p></div>
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10<br> -Section S99<br> -Paragraph 1A<br> -Subparagraph (SX 210.13-01(a)(5))<br> -URI http://asc.fasb.org/extlink&amp;oid=124359900&amp;loc=SL124442526-122756<br><br>Reference 11: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 470<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1B<br> -Subparagraph (SX 210.13-02(a)(4)(iv))<br> -URI http://asc.fasb.org/extlink&amp;oid=124359900&amp;loc=SL124442552-122756<br><br>Reference 12: http://www.xbrl.org/2009/role/commonPracticeRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 220<br> -SubTopic 10<br> -Section 50<br> -Paragraph 6<br> -URI http://asc.fasb.org/extlink&amp;oid=124431353&amp;loc=SL124452729-227067<br><br>Reference 13: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 280<br> -SubTopic 10<br> -Section 50<br> -Paragraph 30<br> -Subparagraph (b)<br> -URI 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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ProfitLoss</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount, excluding tax collected from customer, of revenue from satisfaction of performance obligation by transferring promised good or service to customer. Tax collected from customer is tax assessed by governmental authority that is both imposed on and concurrent with specific revenue-producing transaction, including, but not limited to, sales, use, value added and excise.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 280<br> -SubTopic 10<br> -Section 50<br> -Paragraph 30<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=123359005&amp;loc=d3e8906-108599<br><br>Reference 2: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 280<br> -SubTopic 10<br> -Section 50<br> -Paragraph 40<br> -URI http://asc.fasb.org/extlink&amp;oid=123359005&amp;loc=d3e9031-108599<br><br>Reference 3: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 280<br> -SubTopic 10<br> -Section 50<br> -Paragraph 41<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=123359005&amp;loc=d3e9038-108599<br><br>Reference 4: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 280<br> -SubTopic 10<br> -Section 50<br> -Paragraph 32<br> -Subparagraph (b)<br> -URI http://asc.fasb.org/extlink&amp;oid=123359005&amp;loc=d3e8933-108599<br><br>Reference 5: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 280<br> -SubTopic 10<br> -Section 50<br> -Paragraph 32<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=123359005&amp;loc=d3e8933-108599<br><br>Reference 6: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 606<br> -SubTopic 10<br> -Section 50<br> -Paragraph 4<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=123351226&amp;loc=SL49130543-203045<br><br>Reference 7: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 280<br> -SubTopic 10<br> -Section 50<br> -Paragraph 22<br> -Subparagraph (b)<br> -URI http://asc.fasb.org/extlink&amp;oid=123359005&amp;loc=d3e8736-108599<br><br>Reference 8: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 280<br> -SubTopic 10<br> -Section 50<br> -Paragraph 22<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=123359005&amp;loc=d3e8736-108599<br><br>Reference 9: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 280<br> -SubTopic 10<br> -Section 50<br> -Paragraph 42<br> -URI http://asc.fasb.org/extlink&amp;oid=123359005&amp;loc=d3e9054-108599<br><br>Reference 10: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 606<br> -SubTopic 10<br> -Section 50<br> -Paragraph 5<br> -URI http://asc.fasb.org/extlink&amp;oid=123351226&amp;loc=SL49130545-203045<br><br>Reference 11: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 924<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SAB Topic 11.L)<br> -URI http://asc.fasb.org/extlink&amp;oid=6472922&amp;loc=d3e499488-122856<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_RevenuesAbstract">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_RevenuesAbstract</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:stringItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_SellingGeneralAndAdministrativeExpense">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The aggregate total costs related to selling a firm's product and services, as well as all other general and administrative expenses. Direct selling expenses (for example, credit, warranty, and advertising) are expenses that can be directly linked to the sale of specific products. Indirect selling expenses are expenses that cannot be directly linked to the sale of specific products, for example telephone expenses, Internet, and postal charges. General and administrative expenses include salaries of non-sales personnel, rent, utilities, communication, etc.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 220<br> -SubTopic 10<br> -Section S99<br> -Paragraph 2<br> -Subparagraph (SX 210.5-03.4)<br> -URI http://asc.fasb.org/extlink&amp;oid=123367319&amp;loc=SL114868664-224227<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_SellingGeneralAndAdministrativeExpense</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_WeightedAverageNumberOfDilutedSharesOutstanding">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The average number of shares or units issued and outstanding that are used in calculating diluted EPS or earnings per unit (EPU), determined based on the timing of issuance of shares or units in the period.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 260<br> -SubTopic 10<br> -Section 50<br> -Paragraph 1<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=124432515&amp;loc=d3e3550-109257<br><br>Reference 2: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 260<br> -SubTopic 10<br> -Section 45<br> -Paragraph 16<br> -URI http://asc.fasb.org/extlink&amp;oid=125511455&amp;loc=d3e1505-109256<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_WeightedAverageNumberOfDilutedSharesOutstanding</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:sharesItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_WeightedAverageNumberOfSharesOutstandingBasic">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Number of [basic] shares or units, after adjustment for contingently issuable shares or units and other shares or units not deemed outstanding, determined by relating the portion of time within a reporting period that common shares or units have been outstanding to the total time in that period.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 260<br> -SubTopic 10<br> -Section 50<br> -Paragraph 1<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=124432515&amp;loc=d3e3550-109257<br><br>Reference 2: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 260<br> -SubTopic 10<br> -Section 45<br> -Paragraph 10<br> -URI http://asc.fasb.org/extlink&amp;oid=125511455&amp;loc=d3e1448-109256<br></p></div>
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<tr>
<td><strong> Name:</strong></td>
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<span style="display: none;">v3.22.0.1</span><table class="report" border="0" cellspacing="2" id="idm139691007174856">
<tr>
<th class="tl" colspan="1" rowspan="2"><div style="width: 200px;"><strong>CONSOLIDATED STATEMENTS OF COMPREHENSIVE INCOME (LOSS) - USD ($)<br> $ in Thousands</strong></div></th>
<th class="th" colspan="3">12 Months Ended</th>
</tr>
<tr>
<th class="th"><div>Dec. 31, 2021</div></th>
<th class="th"><div>Dec. 31, 2020</div></th>
<th class="th"><div>Dec. 31, 2019</div></th>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_StatementOfIncomeAndComprehensiveIncomeAbstract', window );"><strong>CONSOLIDATED STATEMENTS OF COMPREHENSIVE INCOME (LOSS) [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
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<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ProfitLoss', window );">Net income (loss)</a></td>
<td class="num">$ (28,597)<span></span>
</td>
<td class="num">$ (479,743)<span></span>
</td>
<td class="nump">$ 287,259<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_OtherComprehensiveIncomeUnrealizedHoldingGainLossOnSecuritiesArisingDuringPeriodNetOfTax', window );">Unrealized gains (losses) on investments, net of tax</a></td>
<td class="num">(11,486)<span></span>
</td>
<td class="nump">3,729<span></span>
</td>
<td class="nump">6,633<span></span>
</td>
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<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_OtherComprehensiveIncomeForeignCurrencyTransactionAndTranslationGainLossArisingDuringPeriodNetOfTax', window );">Currency translation adjustment</a></td>
<td class="num">(111)<span></span>
</td>
<td class="nump">617<span></span>
</td>
<td class="nump">93<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_OtherComprehensiveIncomeLossAdjustmentsFromPurchaseOfNoncontrollingInterestOfSubsidiary', window );">Adjustments to other comprehensive loss from purchase of noncontrolling interest of Akcea Therapeutics, Inc.</a></td>
<td class="nump">0<span></span>
</td>
<td class="num">(127)<span></span>
</td>
<td class="nump">0<span></span>
</td>
</tr>
<tr class="rou">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ComprehensiveIncomeNetOfTaxIncludingPortionAttributableToNoncontrollingInterest', window );">Comprehensive income (loss)</a></td>
<td class="num">(40,194)<span></span>
</td>
<td class="num">(475,524)<span></span>
</td>
<td class="nump">293,985<span></span>
</td>
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<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ComprehensiveIncomeNetOfTaxAttributableToNoncontrollingInterest', window );">Comprehensive income (loss) attributable to noncontrolling interest in Akcea Therapeutics, Inc.</a></td>
<td class="nump">0<span></span>
</td>
<td class="num">(35,480)<span></span>
</td>
<td class="nump">9,116<span></span>
</td>
</tr>
<tr class="rou">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ComprehensiveIncomeNetOfTax', window );">Comprehensive income (loss) attributable to Ionis Pharmaceuticals, Inc. common stockholders</a></td>
<td class="num">$ (40,194)<span></span>
</td>
<td class="num">$ (440,044)<span></span>
</td>
<td class="nump">$ 284,869<span></span>
</td>
</tr>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Adjustments to other comprehensive income (loss) from purchase of noncontrolling interest of subsidiary.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_OtherComprehensiveIncomeLossAdjustmentsFromPurchaseOfNoncontrollingInterestOfSubsidiary</td>
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<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_ComprehensiveIncomeNetOfTax">
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount after tax of increase (decrease) in equity from transactions and other events and circumstances from net income and other comprehensive income, attributable to parent entity. Excludes changes in equity resulting from investments by owners and distributions to owners.</p></div>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ComprehensiveIncomeNetOfTax</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
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<td><strong> Balance Type:</strong></td>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount after tax of increase (decrease) in equity from transactions and other events and circumstances from net income (loss) and other comprehensive income (loss), attributable to noncontrolling interests. Excludes changes in equity resulting from investments by owners and distributions to owners.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 220<br> -SubTopic 10<br> -Section 45<br> -Paragraph 1B<br> -Subparagraph (b)<br> -URI http://asc.fasb.org/extlink&amp;oid=124509347&amp;loc=SL7669625-108580<br><br>Reference 2: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 944<br> -SubTopic 220<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.7-04(21))<br> -URI http://asc.fasb.org/extlink&amp;oid=120400993&amp;loc=SL114874131-224263<br><br>Reference 3: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 942<br> -SubTopic 220<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.9-04(25))<br> -URI http://asc.fasb.org/extlink&amp;oid=120399700&amp;loc=SL114874048-224260<br><br>Reference 4: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 810<br> -SubTopic 10<br> -Section 55<br> -Paragraph 4K<br> -URI http://asc.fasb.org/extlink&amp;oid=120409616&amp;loc=SL4591552-111686<br><br>Reference 5: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 220<br> -SubTopic 10<br> -Section 45<br> -Paragraph 1A<br> -Subparagraph (c)<br> -URI http://asc.fasb.org/extlink&amp;oid=124509347&amp;loc=SL7669619-108580<br><br>Reference 6: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 810<br> -SubTopic 10<br> -Section 45<br> -Paragraph 21<br> -URI http://asc.fasb.org/extlink&amp;oid=123454820&amp;loc=SL4613674-111683<br><br>Reference 7: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 220<br> -SubTopic 10<br> -Section S99<br> -Paragraph 2<br> -Subparagraph (SX 210.5-03(23))<br> -URI http://asc.fasb.org/extlink&amp;oid=123367319&amp;loc=SL114868664-224227<br><br>Reference 8: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 810<br> -SubTopic 10<br> -Section 45<br> -Paragraph 20<br> -URI http://asc.fasb.org/extlink&amp;oid=123454820&amp;loc=SL4569643-111683<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ComprehensiveIncomeNetOfTaxAttributableToNoncontrollingInterest</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
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<td><strong> Balance Type:</strong></td>
<td>debit</td>
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<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
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</div></td></tr>
</table>
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<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount after tax of increase (decrease) in equity from transactions and other events and circumstances from net income and other comprehensive income. Excludes changes in equity resulting from investments by owners and distributions to owners.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 810<br> -SubTopic 10<br> -Section 55<br> -Paragraph 4K<br> -URI http://asc.fasb.org/extlink&amp;oid=120409616&amp;loc=SL4591552-111686<br><br>Reference 2: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 220<br> -SubTopic 10<br> -Section 45<br> -Paragraph 1A<br> -Subparagraph (c)<br> -URI http://asc.fasb.org/extlink&amp;oid=124509347&amp;loc=SL7669619-108580<br><br>Reference 3: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 944<br> -SubTopic 220<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.7-04(20))<br> -URI http://asc.fasb.org/extlink&amp;oid=120400993&amp;loc=SL114874131-224263<br><br>Reference 4: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 810<br> -SubTopic 10<br> -Section 45<br> -Paragraph 19<br> -URI http://asc.fasb.org/extlink&amp;oid=123454820&amp;loc=SL4569616-111683<br><br>Reference 5: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 220<br> -SubTopic 10<br> -Section 45<br> -Paragraph 1B<br> -Subparagraph (b)<br> -URI http://asc.fasb.org/extlink&amp;oid=124509347&amp;loc=SL7669625-108580<br><br>Reference 6: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 220<br> -SubTopic 10<br> -Section S99<br> -Paragraph 2<br> -Subparagraph (SX 210.5-03(22))<br> -URI http://asc.fasb.org/extlink&amp;oid=123367319&amp;loc=SL114868664-224227<br><br>Reference 7: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 942<br> -SubTopic 220<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.9-04(24))<br> -URI http://asc.fasb.org/extlink&amp;oid=120399700&amp;loc=SL114874048-224260<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount after tax, before reclassification adjustments of gain (loss) on foreign currency translation adjustments, foreign currency transactions designated and effective as economic hedges of a net investment in a foreign entity and intra-entity foreign currency transactions that are of a long-term-investment nature.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 830<br> -SubTopic 20<br> -Section 35<br> -Paragraph 3<br> -URI http://asc.fasb.org/extlink&amp;oid=123602790&amp;loc=d3e30304-110892<br><br>Reference 2: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 830<br> -SubTopic 10<br> -Section 45<br> -Paragraph 9<br> -URI http://asc.fasb.org/extlink&amp;oid=120253306&amp;loc=d3e28129-110885<br><br>Reference 3: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 830<br> -SubTopic 30<br> -Section 45<br> -Paragraph 12<br> -URI http://asc.fasb.org/extlink&amp;oid=118261656&amp;loc=d3e32022-110900<br><br>Reference 4: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 220<br> -SubTopic 10<br> -Section 45<br> -Paragraph 10A<br> -Subparagraph (a-c)<br> -URI http://asc.fasb.org/extlink&amp;oid=124509347&amp;loc=SL7669646-108580<br><br>Reference 5: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 220<br> -SubTopic 10<br> -Section 45<br> -Paragraph 11<br> -URI http://asc.fasb.org/extlink&amp;oid=124509347&amp;loc=d3e637-108580<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
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<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount, after tax and before adjustment, of unrealized holding gain (loss) on investment in debt security measured at fair value with change in fair value recognized in other comprehensive income (available-for-sale). Excludes unrealized gain (loss) on investment in debt security measured at amortized cost (held-to-maturity) from transfer to available-for-sale.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 220<br> -SubTopic 10<br> -Section 45<br> -Paragraph 10A<br> -Subparagraph (e)<br> -URI http://asc.fasb.org/extlink&amp;oid=124509347&amp;loc=SL7669646-108580<br><br>Reference 2: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 220<br> -SubTopic 10<br> -Section 45<br> -Paragraph 11<br> -URI http://asc.fasb.org/extlink&amp;oid=124509347&amp;loc=d3e637-108580<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The consolidated profit or loss for the period, net of income taxes, including the portion attributable to the noncontrolling interest.</p></div>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
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<span style="display: none;">v3.22.0.1</span><table class="report" border="0" cellspacing="2" id="idm139691008815976">
<tr>
<th class="tl" colspan="1" rowspan="1"><div style="width: 200px;"><strong>CONSOLIDATED STATEMENTS OF STOCKHOLDERS' EQUITY - USD ($)<br> shares in Thousands, $ in Thousands</strong></div></th>
<th class="th"><div>Common Stock [Member]</div></th>
<th class="th"><div>Additional Paid In Capital [Member]</div></th>
<th class="th"><div>Accumulated Other Comprehensive Loss [Member]</div></th>
<th class="th"><div>Accumulated Deficit [Member]</div></th>
<th class="th"><div>Total Ionis Stockholders' Equity [Member]</div></th>
<th class="th"><div>Noncontrolling Interest in Akcea Therapeutics, Inc. [Member]</div></th>
<th class="th"><div>Total</div></th>
</tr>
<tr class="rc">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_StockholdersEquityIncludingPortionAttributableToNoncontrollingInterest', window );">Balance at Dec. 31, 2018</a></td>
<td class="nump">$ 138<span></span>
</td>
<td class="nump">$ 1,833,668<span></span>
</td>
<td class="num">$ (32,016)<span></span>
</td>
<td class="num">$ (840,251)<span></span>
</td>
<td class="nump">$ 961,539<span></span>
</td>
<td class="nump">$ 139,084<span></span>
</td>
<td class="nump">$ 1,100,623<span></span>
</td>
</tr>
<tr class="rc">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_SharesIssued', window );">Balance (in shares) at Dec. 31, 2018</a></td>
<td class="nump">137,929<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_IncreaseDecreaseInStockholdersEquityRollForward', window );"><strong>Increase (Decrease) in Stockholders' Equity [Roll Forward]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_NetIncomeLoss', window );">Net loss</a></td>
<td class="nump">$ 0<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="nump">278,143<span></span>
</td>
<td class="nump">278,143<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="nump">278,143<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_OtherComprehensiveIncomeAvailableforsaleSecuritiesAdjustmentNetOfTaxPortionAttributableToParent', window );">Change in unrealized gains (losses), net of tax</a></td>
<td class="nump">0<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="nump">6,633<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="nump">6,633<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="nump">6,633<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_OtherComprehensiveIncomeForeignCurrencyTransactionAndTranslationGainLossArisingDuringPeriodNetOfTax', window );">Foreign currency translation</a></td>
<td class="nump">0<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="nump">93<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="nump">93<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="nump">93<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_StockIssuedDuringPeriodValueShareBasedCompensationGross', window );">Issuance of common stock in connection with employee stock plans</a></td>
<td class="nump">$ 3<span></span>
</td>
<td class="nump">119,654<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="nump">119,657<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="nump">119,657<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_StockIssuedDuringPeriodSharesShareBasedCompensation', window );">Issuance of common stock in connection with employee stock plans (in shares)</a></td>
<td class="nump">3,100<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AdjustmentsToAdditionalPaidInCapitalWarrantIssued', window );">Issuance of warrants</a></td>
<td class="nump">$ 0<span></span>
</td>
<td class="nump">56,110<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="nump">56,110<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="nump">56,110<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AdjustmentsToAdditionalPaidInCapitalOther', window );">Purchase of note hedges, net of tax</a></td>
<td class="nump">0<span></span>
</td>
<td class="num">(85,860)<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="num">(85,860)<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="num">(85,860)<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_StockRepurchasedAndRetiredDuringPeriodValue', window );">Repurchases and retirements of common stock</a></td>
<td class="num">$ (1)<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="num">(34,387)<span></span>
</td>
<td class="num">(34,388)<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="num">(34,388)<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_StockRepurchasedAndRetiredDuringPeriodShares', window );">Repurchases and retirements of common stock (in shares)</a></td>
<td class="num">(535)<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AdjustmentsToAdditionalPaidInCapitalSharebasedCompensationRequisiteServicePeriodRecognitionValue', window );">Stock-based compensation expense</a></td>
<td class="nump">$ 0<span></span>
</td>
<td class="nump">146,574<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="nump">146,574<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="nump">146,574<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AdjustmentsRelatedToTaxWithholdingForShareBasedCompensation', window );">Payments of tax withholdings related to vesting of employee stock awards and exercise of employee stock options</a></td>
<td class="nump">$ 0<span></span>
</td>
<td class="num">(19,242)<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="num">(19,242)<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="num">(19,242)<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_SharesPaidForTaxWithholdingForShareBasedCompensation', window );">Payments of tax withholdings related to vesting of employee stock awards and exercise of employee stock options (in shares)</a></td>
<td class="num">(154)<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_MinorityInterestPeriodIncreaseDecrease', window );">Noncontrolling interest in Akcea Therapeutics, Inc.</a></td>
<td class="nump">$ 0<span></span>
</td>
<td class="num">(65,254)<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="num">(65,254)<span></span>
</td>
<td class="nump">74,370<span></span>
</td>
<td class="nump">9,116<span></span>
</td>
</tr>
<tr class="rc">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_StockholdersEquityIncludingPortionAttributableToNoncontrollingInterest', window );">Balance at Dec. 31, 2019</a></td>
<td class="nump">$ 140<span></span>
</td>
<td class="nump">1,985,650<span></span>
</td>
<td class="num">(25,290)<span></span>
</td>
<td class="num">(596,495)<span></span>
</td>
<td class="nump">1,364,005<span></span>
</td>
<td class="nump">213,454<span></span>
</td>
<td class="nump">1,577,459<span></span>
</td>
</tr>
<tr class="rc">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_SharesIssued', window );">Balance (in shares) at Dec. 31, 2019</a></td>
<td class="nump">140,340<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_IncreaseDecreaseInStockholdersEquityRollForward', window );"><strong>Increase (Decrease) in Stockholders' Equity [Roll Forward]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_NetIncomeLoss', window );">Net loss</a></td>
<td class="nump">$ 0<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="num">(444,263)<span></span>
</td>
<td class="num">(444,263)<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="num">(444,263)<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_OtherComprehensiveIncomeAvailableforsaleSecuritiesAdjustmentNetOfTaxPortionAttributableToParent', window );">Change in unrealized gains (losses), net of tax</a></td>
<td class="nump">0<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="nump">3,729<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="nump">3,729<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="nump">3,729<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_OtherComprehensiveIncomeForeignCurrencyTransactionAndTranslationGainLossArisingDuringPeriodNetOfTax', window );">Foreign currency translation</a></td>
<td class="nump">0<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="nump">617<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="nump">617<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="nump">617<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_StockIssuedDuringPeriodValueShareBasedCompensationGross', window );">Issuance of common stock in connection with employee stock plans</a></td>
<td class="nump">$ 1<span></span>
</td>
<td class="nump">52,033<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="nump">52,034<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="nump">52,034<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_StockIssuedDuringPeriodSharesShareBasedCompensation', window );">Issuance of common stock in connection with employee stock plans (in shares)</a></td>
<td class="nump">1,721<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_MinorityInterestDecreaseFromRedemptions', window );">Purchase of noncontrolling interest of Akcea Therapeutics, Inc., including cash payments for cancellation of Akcea Therapeutics, Inc. equity awards</a></td>
<td class="nump">$ 0<span></span>
</td>
<td class="num">(324,022)<span></span>
</td>
<td class="nump">301<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="num">(323,721)<span></span>
</td>
<td class="num">(220,965)<span></span>
</td>
<td class="num">(544,686)<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_StockRepurchasedAndRetiredDuringPeriodValue', window );">Repurchases and retirements of common stock</a></td>
<td class="num">$ (1)<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="num">(90,548)<span></span>
</td>
<td class="num">(90,549)<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="num">(90,549)<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_StockRepurchasedAndRetiredDuringPeriodShares', window );">Repurchases and retirements of common stock (in shares)</a></td>
<td class="num">(1,478)<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AdjustmentsToAdditionalPaidInCapitalSharebasedCompensationRequisiteServicePeriodRecognitionValue', window );">Stock-based compensation expense</a></td>
<td class="nump">$ 0<span></span>
</td>
<td class="nump">230,117<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="nump">230,117<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="nump">230,117<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AdjustmentsRelatedToTaxWithholdingForShareBasedCompensation', window );">Payments of tax withholdings related to vesting of employee stock awards and exercise of employee stock options</a></td>
<td class="nump">$ 0<span></span>
</td>
<td class="num">(13,410)<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="num">(13,410)<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="num">(13,410)<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_SharesPaidForTaxWithholdingForShareBasedCompensation', window );">Payments of tax withholdings related to vesting of employee stock awards and exercise of employee stock options (in shares)</a></td>
<td class="num">(217)<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_AdjustmentsToAdditionalPaidInCapitalDeferredTaxLiabilityAdjustment', window );">Deferred tax liability adjustment due to purchase of noncontrolling interest of Akcea Therapeutics, Inc.</a></td>
<td class="nump">$ 0<span></span>
</td>
<td class="nump">7,714<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="nump">7,714<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="nump">7,714<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_MinorityInterestPeriodIncreaseDecrease', window );">Noncontrolling interest in Akcea Therapeutics, Inc.</a></td>
<td class="nump">0<span></span>
</td>
<td class="num">(42,563)<span></span>
</td>
<td class="num">(428)<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="num">(42,991)<span></span>
</td>
<td class="nump">7,511<span></span>
</td>
<td class="num">(35,480)<span></span>
</td>
</tr>
<tr class="rc">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_StockholdersEquityIncludingPortionAttributableToNoncontrollingInterest', window );">Balance at Dec. 31, 2020</a></td>
<td class="nump">$ 140<span></span>
</td>
<td class="nump">1,895,519<span></span>
</td>
<td class="num">(21,071)<span></span>
</td>
<td class="num">(1,131,306)<span></span>
</td>
<td class="nump">743,282<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="nump">743,282<span></span>
</td>
</tr>
<tr class="rc">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_SharesIssued', window );">Balance (in shares) at Dec. 31, 2020</a></td>
<td class="nump">140,366<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_IncreaseDecreaseInStockholdersEquityRollForward', window );"><strong>Increase (Decrease) in Stockholders' Equity [Roll Forward]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_NetIncomeLoss', window );">Net loss</a></td>
<td class="nump">$ 0<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="num">(28,597)<span></span>
</td>
<td class="num">(28,597)<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="num">(28,597)<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_OtherComprehensiveIncomeAvailableforsaleSecuritiesAdjustmentNetOfTaxPortionAttributableToParent', window );">Change in unrealized gains (losses), net of tax</a></td>
<td class="nump">0<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="num">(11,486)<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="num">(11,486)<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="num">(11,486)<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_OtherComprehensiveIncomeForeignCurrencyTransactionAndTranslationGainLossArisingDuringPeriodNetOfTax', window );">Foreign currency translation</a></td>
<td class="nump">0<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="num">(111)<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="num">(111)<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="num">(111)<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_StockIssuedDuringPeriodValueShareBasedCompensationGross', window );">Issuance of common stock in connection with employee stock plans</a></td>
<td class="nump">$ 1<span></span>
</td>
<td class="nump">11,563<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="nump">11,564<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="nump">11,564<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_StockIssuedDuringPeriodSharesShareBasedCompensation', window );">Issuance of common stock in connection with employee stock plans (in shares)</a></td>
<td class="nump">1,132<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AdjustmentsToAdditionalPaidInCapitalWarrantIssued', window );">Issuance of warrants</a></td>
<td class="nump">$ 0<span></span>
</td>
<td class="nump">89,752<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="nump">89,752<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="nump">89,752<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AdjustmentsToAdditionalPaidInCapitalOther', window );">Purchase of note hedges, net of tax</a></td>
<td class="nump">0<span></span>
</td>
<td class="num">(136,620)<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="num">(136,620)<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="num">(136,620)<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AdjustmentsToAdditionalPaidInCapitalSharebasedCompensationRequisiteServicePeriodRecognitionValue', window );">Stock-based compensation expense</a></td>
<td class="nump">0<span></span>
</td>
<td class="nump">120,678<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="nump">120,678<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="nump">120,678<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AdjustmentsRelatedToTaxWithholdingForShareBasedCompensation', window );">Payments of tax withholdings related to vesting of employee stock awards and exercise of employee stock options</a></td>
<td class="nump">$ 0<span></span>
</td>
<td class="num">(16,725)<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="num">(16,725)<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="num">(16,725)<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_SharesPaidForTaxWithholdingForShareBasedCompensation', window );">Payments of tax withholdings related to vesting of employee stock awards and exercise of employee stock options (in shares)</a></td>
<td class="num">(288)<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rc">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_StockholdersEquityIncludingPortionAttributableToNoncontrollingInterest', window );">Balance at Dec. 31, 2021</a></td>
<td class="nump">$ 141<span></span>
</td>
<td class="nump">$ 1,964,167<span></span>
</td>
<td class="num">$ (32,668)<span></span>
</td>
<td class="num">$ (1,159,903)<span></span>
</td>
<td class="nump">$ 771,737<span></span>
</td>
<td class="nump">$ 0<span></span>
</td>
<td class="nump">$ 771,737<span></span>
</td>
</tr>
<tr class="rc">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_SharesIssued', window );">Balance (in shares) at Dec. 31, 2021</a></td>
<td class="nump">141,210<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
</table>
<div style="display: none;">
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_AdjustmentsToAdditionalPaidInCapitalDeferredTaxLiabilityAdjustment">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of increase (decrease) in additional paid in capital (APIC) due to deferred tax liability adjustment associated with the purchase of noncontrolling interest of Akcea Therapeutics, Inc.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_AdjustmentsToAdditionalPaidInCapitalDeferredTaxLiabilityAdjustment</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_AdjustmentsRelatedToTaxWithholdingForShareBasedCompensation">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of decrease to equity for grantee's tax withholding obligation for award under share-based payment arrangement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_AdjustmentsRelatedToTaxWithholdingForShareBasedCompensation</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_AdjustmentsToAdditionalPaidInCapitalOther">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of other increase (decrease) in additional paid in capital (APIC).</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_AdjustmentsToAdditionalPaidInCapitalOther</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_AdjustmentsToAdditionalPaidInCapitalSharebasedCompensationRequisiteServicePeriodRecognitionValue">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of increase to additional paid-in capital (APIC) for recognition of cost for award under share-based payment arrangement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 718<br> -SubTopic 20<br> -Section 55<br> -Paragraph 12<br> -URI http://asc.fasb.org/extlink&amp;oid=122142933&amp;loc=d3e11149-113907<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 718<br> -SubTopic 10<br> -Section 50<br> -Paragraph 1<br> -Subparagraph (b)<br> -URI http://asc.fasb.org/extlink&amp;oid=120381028&amp;loc=d3e5047-113901<br><br>Reference 3: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 718<br> -SubTopic 20<br> -Section 55<br> -Paragraph 13<br> -URI http://asc.fasb.org/extlink&amp;oid=122142933&amp;loc=d3e11178-113907<br><br>Reference 4: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 718<br> -SubTopic 10<br> -Section 35<br> -Paragraph 2<br> -URI http://asc.fasb.org/extlink&amp;oid=123468992&amp;loc=d3e4534-113899<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_AdjustmentsToAdditionalPaidInCapitalSharebasedCompensationRequisiteServicePeriodRecognitionValue</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_AdjustmentsToAdditionalPaidInCapitalWarrantIssued">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of increase in additional paid in capital (APIC) resulting from the issuance of warrants. Includes allocation of proceeds of debt securities issued with detachable stock purchase warrants.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 470<br> -SubTopic 20<br> -Section 25<br> -Paragraph 2<br> -URI http://asc.fasb.org/extlink&amp;oid=123466302&amp;loc=d3e4724-112606<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 505<br> -SubTopic 10<br> -Section 50<br> -Paragraph 2<br> -URI http://asc.fasb.org/extlink&amp;oid=123467817&amp;loc=d3e21463-112644<br><br>Reference 3: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 505<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.3-04)<br> -URI http://asc.fasb.org/extlink&amp;oid=120397183&amp;loc=d3e187085-122770<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_AdjustmentsToAdditionalPaidInCapitalWarrantIssued</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_IncreaseDecreaseInStockholdersEquityRollForward">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>A roll forward is a reconciliation of a concept from the beginning of a period to the end of a period.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_IncreaseDecreaseInStockholdersEquityRollForward</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:stringItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_MinorityInterestDecreaseFromRedemptions">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Decrease in noncontrolling interest (for example, but not limited to, redeeming or purchasing the interests of noncontrolling shareholders, issuance of shares (interests) by the non-wholly owned subsidiary to the parent entity for other than cash, and a buyback of shares (interest) by the non-wholly owned subsidiary from the noncontrolling interests).</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 810<br> -SubTopic 10<br> -Section 45<br> -Paragraph 23<br> -URI http://asc.fasb.org/extlink&amp;oid=123454820&amp;loc=SL4569655-111683<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 810<br> -SubTopic 10<br> -Section 45<br> -Paragraph 24<br> -URI http://asc.fasb.org/extlink&amp;oid=123454820&amp;loc=SL4616395-111683<br><br>Reference 3: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 505<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.3-04)<br> -URI http://asc.fasb.org/extlink&amp;oid=120397183&amp;loc=d3e187085-122770<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_MinorityInterestDecreaseFromRedemptions</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_MinorityInterestPeriodIncreaseDecrease">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Net Increase or Decrease in balance of noncontrolling interest in the subsidiary during the reporting period.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 810<br> -SubTopic 10<br> -Section 45<br> -Paragraph 16<br> -URI http://asc.fasb.org/extlink&amp;oid=123454820&amp;loc=SL4568740-111683<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_MinorityInterestPeriodIncreaseDecrease</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_NetIncomeLoss">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The portion of profit or loss for the period, net of income taxes, which is attributable to the parent.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 942<br> -SubTopic 220<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.9-04(22))<br> -URI http://asc.fasb.org/extlink&amp;oid=120399700&amp;loc=SL114874048-224260<br><br>Reference 2: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 280<br> -SubTopic 10<br> -Section 50<br> -Paragraph 32<br> -Subparagraph (f)<br> -URI http://asc.fasb.org/extlink&amp;oid=123359005&amp;loc=d3e8933-108599<br><br>Reference 3: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 250<br> -SubTopic 10<br> -Section 50<br> -Paragraph 4<br> -URI 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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_NetIncomeLoss</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_OtherComprehensiveIncomeAvailableforsaleSecuritiesAdjustmentNetOfTaxPortionAttributableToParent">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount after tax and reclassification adjustments, of appreciation (loss) in value of unsold available-for-sale securities, attributable to parent entity. Excludes amounts related to other than temporary impairment (OTTI) loss.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 810<br> -SubTopic 10<br> -Section 50<br> -Paragraph 1A<br> -Subparagraph (c)(3)<br> -URI http://asc.fasb.org/extlink&amp;oid=109239629&amp;loc=SL4573702-111684<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 810<br> -SubTopic 10<br> -Section 45<br> -Paragraph 19<br> -URI http://asc.fasb.org/extlink&amp;oid=123454820&amp;loc=SL4569616-111683<br><br>Reference 3: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 810<br> -SubTopic 10<br> -Section 45<br> -Paragraph 20<br> -URI http://asc.fasb.org/extlink&amp;oid=123454820&amp;loc=SL4569643-111683<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_OtherComprehensiveIncomeAvailableforsaleSecuritiesAdjustmentNetOfTaxPortionAttributableToParent</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_OtherComprehensiveIncomeForeignCurrencyTransactionAndTranslationGainLossArisingDuringPeriodNetOfTax">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount after tax, before reclassification adjustments of gain (loss) on foreign currency translation adjustments, foreign currency transactions designated and effective as economic hedges of a net investment in a foreign entity and intra-entity foreign currency transactions that are of a long-term-investment nature.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 830<br> -SubTopic 20<br> -Section 35<br> -Paragraph 3<br> -URI http://asc.fasb.org/extlink&amp;oid=123602790&amp;loc=d3e30304-110892<br><br>Reference 2: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 830<br> -SubTopic 10<br> -Section 45<br> -Paragraph 9<br> -URI http://asc.fasb.org/extlink&amp;oid=120253306&amp;loc=d3e28129-110885<br><br>Reference 3: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 830<br> -SubTopic 30<br> -Section 45<br> -Paragraph 12<br> -URI http://asc.fasb.org/extlink&amp;oid=118261656&amp;loc=d3e32022-110900<br><br>Reference 4: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 220<br> -SubTopic 10<br> -Section 45<br> -Paragraph 10A<br> -Subparagraph (a-c)<br> -URI http://asc.fasb.org/extlink&amp;oid=124509347&amp;loc=SL7669646-108580<br><br>Reference 5: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 220<br> -SubTopic 10<br> -Section 45<br> -Paragraph 11<br> -URI http://asc.fasb.org/extlink&amp;oid=124509347&amp;loc=d3e637-108580<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_OtherComprehensiveIncomeForeignCurrencyTransactionAndTranslationGainLossArisingDuringPeriodNetOfTax</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_SharesIssued">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Number of shares of stock issued as of the balance sheet date, including shares that had been issued and were previously outstanding but which are now held in the treasury.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 505<br> -SubTopic 10<br> -Section 50<br> -Paragraph 2<br> -URI http://asc.fasb.org/extlink&amp;oid=123467817&amp;loc=d3e21463-112644<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_SharesIssued</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:sharesItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_SharesPaidForTaxWithholdingForShareBasedCompensation">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Number of shares used to settle grantee's tax withholding obligation for award under share-based payment arrangement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_SharesPaidForTaxWithholdingForShareBasedCompensation</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:sharesItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_StockIssuedDuringPeriodSharesShareBasedCompensation">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Number, after forfeiture, of shares or units issued under share-based payment arrangement. Excludes shares or units issued under employee stock ownership plan (ESOP).</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 505<br> -SubTopic 10<br> -Section 50<br> -Paragraph 2<br> -URI http://asc.fasb.org/extlink&amp;oid=123467817&amp;loc=d3e21463-112644<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 505<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.3-04)<br> -URI http://asc.fasb.org/extlink&amp;oid=120397183&amp;loc=d3e187085-122770<br><br>Reference 3: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 210<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.5-02(28))<br> -URI http://asc.fasb.org/extlink&amp;oid=120391452&amp;loc=d3e13212-122682<br><br>Reference 4: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 210<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.5-02(29))<br> -URI http://asc.fasb.org/extlink&amp;oid=120391452&amp;loc=d3e13212-122682<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_StockIssuedDuringPeriodSharesShareBasedCompensation</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:sharesItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_StockIssuedDuringPeriodValueShareBasedCompensationGross">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Value, before forfeiture, of shares issued under share-based payment arrangement. Excludes employee stock ownership plan (ESOP).</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_StockIssuedDuringPeriodValueShareBasedCompensationGross</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_StockRepurchasedAndRetiredDuringPeriodShares">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Number of shares that have been repurchased and retired during the period.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 210<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.5-02(28))<br> -URI http://asc.fasb.org/extlink&amp;oid=120391452&amp;loc=d3e13212-122682<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 505<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.3-04)<br> -URI http://asc.fasb.org/extlink&amp;oid=120397183&amp;loc=d3e187085-122770<br><br>Reference 3: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 210<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.5-02(29))<br> -URI http://asc.fasb.org/extlink&amp;oid=120391452&amp;loc=d3e13212-122682<br><br>Reference 4: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 505<br> -SubTopic 10<br> -Section 50<br> -Paragraph 2<br> -URI http://asc.fasb.org/extlink&amp;oid=123467817&amp;loc=d3e21463-112644<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_StockRepurchasedAndRetiredDuringPeriodShares</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:sharesItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_StockRepurchasedAndRetiredDuringPeriodValue">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Equity impact of the value of stock that has been repurchased and retired during the period. The excess of the purchase price over par value can be charged against retained earnings (once the excess is fully allocated to additional paid in capital).</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 210<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.5-02(28))<br> -URI http://asc.fasb.org/extlink&amp;oid=120391452&amp;loc=d3e13212-122682<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 210<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.5-02(29))<br> -URI http://asc.fasb.org/extlink&amp;oid=120391452&amp;loc=d3e13212-122682<br><br>Reference 3: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 505<br> -SubTopic 10<br> -Section 50<br> -Paragraph 2<br> -URI http://asc.fasb.org/extlink&amp;oid=123467817&amp;loc=d3e21463-112644<br><br>Reference 4: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 505<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.3-04)<br> -URI http://asc.fasb.org/extlink&amp;oid=120397183&amp;loc=d3e187085-122770<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_StockRepurchasedAndRetiredDuringPeriodValue</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_StockholdersEquityIncludingPortionAttributableToNoncontrollingInterest">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of stockholders' equity (deficit), net of receivables from officers, directors, owners, and affiliates of the entity, attributable to both the parent and noncontrolling interests. Amount excludes temporary equity. Alternate caption for the concept is permanent equity.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 250<br> -SubTopic 10<br> -Section 45<br> -Paragraph 24<br> -URI http://asc.fasb.org/extlink&amp;oid=124436220&amp;loc=d3e21930-107793<br><br>Reference 2: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 505<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.3-04)<br> -URI http://asc.fasb.org/extlink&amp;oid=120397183&amp;loc=d3e187085-122770<br><br>Reference 3: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 250<br> -SubTopic 10<br> -Section 45<br> -Paragraph 23<br> -Subparagraph (b)<br> -URI http://asc.fasb.org/extlink&amp;oid=124436220&amp;loc=d3e21914-107793<br><br>Reference 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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_StockholdersEquityIncludingPortionAttributableToNoncontrollingInterest</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
</div>
</body>
</html>
</TEXT>
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<span style="display: none;">v3.22.0.1</span><table class="report" border="0" cellspacing="2" id="idm139691008554424">
<tr>
<th class="tl" colspan="1" rowspan="2"><div style="width: 200px;"><strong>CONSOLIDATED STATEMENTS OF CASH FLOWS - USD ($)<br> $ in Thousands</strong></div></th>
<th class="th" colspan="3">12 Months Ended</th>
</tr>
<tr>
<th class="th"><div>Dec. 31, 2021</div></th>
<th class="th"><div>Dec. 31, 2020</div></th>
<th class="th"><div>Dec. 31, 2019</div></th>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_NetCashProvidedByUsedInOperatingActivitiesAbstract', window );"><strong>Operating activities:</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ProfitLoss', window );">Net income (loss)</a></td>
<td class="num">$ (28,597)<span></span>
</td>
<td class="num">$ (479,743)<span></span>
</td>
<td class="nump">$ 287,259<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AdjustmentsToReconcileNetIncomeLossToCashProvidedByUsedInOperatingActivitiesAbstract', window );"><strong>Adjustments to reconcile net income (loss) to net cash used in operating activities:</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_Depreciation', window );">Depreciation</a></td>
<td class="nump">15,487<span></span>
</td>
<td class="nump">13,365<span></span>
</td>
<td class="nump">12,540<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_OperatingLeaseRightOfUseAssetAmortizationExpense', window );">Amortization of right-of-use operating lease assets</a></td>
<td class="nump">1,721<span></span>
</td>
<td class="nump">1,731<span></span>
</td>
<td class="nump">1,542<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AmortizationOfIntangibleAssets', window );">Amortization of patents</a></td>
<td class="nump">2,352<span></span>
</td>
<td class="nump">2,064<span></span>
</td>
<td class="nump">1,912<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AccretionAmortizationOfDiscountsAndPremiumsInvestments', window );">Amortization of premium (discount) on investments, net</a></td>
<td class="nump">17,776<span></span>
</td>
<td class="nump">11,521<span></span>
</td>
<td class="num">(7,485)<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AmortizationOfFinancingCosts', window );">Amortization of debt issuance costs</a></td>
<td class="nump">4,958<span></span>
</td>
<td class="nump">3,255<span></span>
</td>
<td class="nump">2,945<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedCompensation', window );">Stock-based compensation expense</a></td>
<td class="nump">120,678<span></span>
</td>
<td class="nump">230,117<span></span>
</td>
<td class="nump">146,574<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_GainsLossesOnExtinguishmentOfDebt', window );">Loss on early retirement of debt</a></td>
<td class="nump">8,627<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="nump">66,196<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RealizedInvestmentGainsLosses', window );">Gain on investments</a></td>
<td class="num">(1,092)<span></span>
</td>
<td class="num">(16,540)<span></span>
</td>
<td class="num">(192)<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DeferredIncomeTaxesAndTaxCredits', window );">Deferred income taxes, including changes in valuation allowance</a></td>
<td class="nump">0<span></span>
</td>
<td class="nump">341,729<span></span>
</td>
<td class="nump">911<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ImpairmentOfIntangibleAssetsFinitelived', window );">Non-cash losses related to patents</a></td>
<td class="nump">2,707<span></span>
</td>
<td class="nump">1,948<span></span>
</td>
<td class="nump">2,226<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_IncreaseDecreaseInOperatingCapitalAbstract', window );"><strong>Changes in operating assets and liabilities:</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_IncreaseDecreaseInContractWithCustomerAsset', window );">Contracts receivable</a></td>
<td class="nump">14,308<span></span>
</td>
<td class="num">(13,170)<span></span>
</td>
<td class="num">(47,674)<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_IncreaseDecreaseInInventories', window );">Inventories</a></td>
<td class="num">(2,841)<span></span>
</td>
<td class="num">(1,261)<span></span>
</td>
<td class="num">(5,411)<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_IncreaseDecreaseInOtherOperatingAssets', window );">Other current and long-term assets</a></td>
<td class="num">(877)<span></span>
</td>
<td class="num">(9,975)<span></span>
</td>
<td class="num">(44,659)<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_IncreaseDecreaseInIncomeTaxesReceivablePayable', window );">Long-term income taxes receivable (payable)</a></td>
<td class="nump">1,008<span></span>
</td>
<td class="num">(89)<span></span>
</td>
<td class="nump">8,418<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_IncreaseDecreaseInAccountsPayable', window );">Accounts payable</a></td>
<td class="num">(6,000)<span></span>
</td>
<td class="num">(2,755)<span></span>
</td>
<td class="num">(16,343)<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_IncreaseDecreaseInIncomeTaxesPayableNetOfIncomeTaxesReceivable', window );">Income taxes</a></td>
<td class="num">(1,288)<span></span>
</td>
<td class="num">(31,190)<span></span>
</td>
<td class="nump">31,656<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_IncreaseDecreaseInOtherEmployeeRelatedLiabilities', window );">Accrued compensation</a></td>
<td class="num">(26,918)<span></span>
</td>
<td class="nump">28,371<span></span>
</td>
<td class="nump">8,089<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_IncreaseDecreaseInOtherAccountsPayableAndAccruedLiabilities', window );">Accrued liabilities and other current liabilities</a></td>
<td class="num">(8,381)<span></span>
</td>
<td class="nump">32,424<span></span>
</td>
<td class="nump">16,406<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_IncreaseDecreaseInContractWithCustomerLiability', window );">Deferred contract revenue</a></td>
<td class="num">(82,829)<span></span>
</td>
<td class="num">(75,910)<span></span>
</td>
<td class="num">(119,283)<span></span>
</td>
</tr>
<tr class="rou">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_NetCashProvidedByUsedInOperatingActivities', window );">Net cash used in operating activities</a></td>
<td class="nump">30,799<span></span>
</td>
<td class="nump">35,892<span></span>
</td>
<td class="nump">345,627<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_NetCashProvidedByUsedInInvestingActivitiesAbstract', window );"><strong>Investing activities:</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_PaymentsToAcquireAvailableForSaleSecuritiesDebt', window );">Purchases of short-term investments</a></td>
<td class="num">(1,124,193)<span></span>
</td>
<td class="num">(1,570,410)<span></span>
</td>
<td class="num">(1,946,726)<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ProceedsFromSaleAndMaturityOfAvailableForSaleSecurities', window );">Proceeds from sale of short-term investments</a></td>
<td class="nump">1,344,185<span></span>
</td>
<td class="nump">1,885,935<span></span>
</td>
<td class="nump">1,951,734<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_PaymentsToAcquirePropertyPlantAndEquipment', window );">Purchases of property, plant and equipment</a></td>
<td class="num">(11,955)<span></span>
</td>
<td class="num">(35,120)<span></span>
</td>
<td class="num">(30,905)<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_PaymentsToAcquireIntangibleAssets', window );">Acquisition of licenses and other assets, net</a></td>
<td class="num">(5,946)<span></span>
</td>
<td class="num">(5,928)<span></span>
</td>
<td class="num">(5,377)<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_PaymentsToAcquireOtherInvestments', window );">Purchases of strategic investments</a></td>
<td class="num">(7,185)<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="num">(10,000)<span></span>
</td>
</tr>
<tr class="reu">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_NetCashProvidedByUsedInInvestingActivities', window );">Net cash provided by (used in) investing activities</a></td>
<td class="nump">194,906<span></span>
</td>
<td class="nump">274,477<span></span>
</td>
<td class="num">(41,274)<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_NetCashProvidedByUsedInFinancingActivitiesAbstract', window );"><strong>Financing activities:</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ProceedsFromIssuanceOfSharesUnderIncentiveAndShareBasedCompensationPlansIncludingStockOptions', window );">Proceeds from equity, net</a></td>
<td class="nump">11,565<span></span>
</td>
<td class="nump">52,036<span></span>
</td>
<td class="nump">119,657<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_PaymentsRelatedToTaxWithholdingForShareBasedCompensation', window );">Payments of tax withholdings related to vesting of employee stock awards and exercise of employee stock options</a></td>
<td class="num">(16,725)<span></span>
</td>
<td class="num">(13,411)<span></span>
</td>
<td class="num">(19,242)<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_EarlyRepaymentOfConvertibleDebt', window );">Repurchase of $247.9 million principal amount of 1 percent convertible senior notes</a></td>
<td class="num">(256,963)<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="nump">0<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RepaymentsOfConvertibleDebt', window );">Repayment of remaining principal amount of 1 percent convertible senior notes at maturity</a></td>
<td class="num">(61,967)<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="nump">0<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ProceedsFromIssuanceOfWarrants', window );">Proceeds from issuance of warrants</a></td>
<td class="nump">89,752<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="nump">56,110<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_PaymentsForHedgeFinancingActivities', window );">Purchase of note hedges</a></td>
<td class="num">(136,620)<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="num">(108,684)<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_PaymentsForRepurchaseOfCommonStock', window );">Repurchases and retirements of common stock</a></td>
<td class="nump">0<span></span>
</td>
<td class="num">(90,548)<span></span>
</td>
<td class="num">(34,392)<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_PaymentsToMinorityShareholders', window );">Purchase of noncontrolling interest of Akcea Therapeutics, Inc., including cash payments for cancellation of Akcea Therapeutics, Inc. equity awards</a></td>
<td class="nump">0<span></span>
</td>
<td class="num">(544,686)<span></span>
</td>
<td class="nump">0<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RepaymentsOfLongTermLinesOfCredit', window );">Principal payments on line of credit</a></td>
<td class="nump">0<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="num">(12,500)<span></span>
</td>
</tr>
<tr class="rou">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_NetCashProvidedByUsedInFinancingActivities', window );">Net cash provided by (used in) financing activities</a></td>
<td class="nump">245,933<span></span>
</td>
<td class="num">(596,609)<span></span>
</td>
<td class="nump">100,021<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_EffectOfExchangeRateOnCashAndCashEquivalents', window );">Effects of exchange rates on cash</a></td>
<td class="num">(111)<span></span>
</td>
<td class="nump">617<span></span>
</td>
<td class="nump">93<span></span>
</td>
</tr>
<tr class="rou">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_CashCashEquivalentsRestrictedCashAndRestrictedCashEquivalentsPeriodIncreaseDecreaseIncludingExchangeRateEffect', window );">Net increase (decrease) in cash and cash equivalents</a></td>
<td class="nump">471,527<span></span>
</td>
<td class="num">(285,623)<span></span>
</td>
<td class="nump">404,467<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_CashCashEquivalentsRestrictedCashAndRestrictedCashEquivalents', window );">Cash and cash equivalents at beginning of year</a></td>
<td class="nump">397,664<span></span>
</td>
<td class="nump">683,287<span></span>
</td>
<td class="nump">278,820<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_CashCashEquivalentsRestrictedCashAndRestrictedCashEquivalents', window );">Cash and cash equivalents at end of year</a></td>
<td class="nump">869,191<span></span>
</td>
<td class="nump">397,664<span></span>
</td>
<td class="nump">683,287<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_SupplementalCashFlowInformationAbstract', window );"><strong>Supplemental disclosures of cash flow information:</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_InterestPaidNet', window );">Interest paid</a></td>
<td class="nump">4,778<span></span>
</td>
<td class="nump">6,247<span></span>
</td>
<td class="nump">9,870<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_IncomeTaxesPaid', window );">Income taxes paid</a></td>
<td class="nump">38<span></span>
</td>
<td class="nump">25,855<span></span>
</td>
<td class="nump">9,041<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_CashFlowNoncashInvestingAndFinancingActivitiesDisclosureAbstract', window );"><strong>Supplemental disclosures of non-cash investing and financing activities:</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RightOfUseAssetObtainedInExchangeForOperatingLeaseLiability', window );">Right-of-use assets obtained in exchange for lease liabilities</a></td>
<td class="nump">6,641<span></span>
</td>
<td class="nump">2,149<span></span>
</td>
<td class="nump">14,178<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_NonCashCapitalAndPatentExpenditures', window );">Amounts accrued for capital and patent expenditures</a></td>
<td class="nump">705<span></span>
</td>
<td class="nump">4,059<span></span>
</td>
<td class="nump">3,126<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_NotesIssued1', window );">0.125 percent convertible senior notes principal issued related to our December 2019 debt exchange/issuance</a></td>
<td class="nump">0<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="nump">439,326<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_NotesReduction', window );">1 percent convertible senior notes principal extinguished related to our December 2019 debt exchange</a></td>
<td class="nump">0<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="nump">375,590<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DebtInstrumentAxis=ions_ConvertibleSeniorNotes0PercentMember', window );">0 Percent Convertible Senior Notes [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_NetCashProvidedByUsedInFinancingActivitiesAbstract', window );"><strong>Financing activities:</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ProceedsFromConvertibleDebt', window );">Proceeds from the issuance of convertible senior notes</a></td>
<td class="nump">632,500<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="nump">0<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_PaymentsOfDebtIssuanceCosts', window );">Convertible senior notes issuance costs</a></td>
<td class="num">(15,609)<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="nump">0<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DebtInstrumentAxis=ions_ConvertibleSeniorNotes0125PercentMember', window );">0.125 Percent Convertible Senior Notes [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_NetCashProvidedByUsedInFinancingActivitiesAbstract', window );"><strong>Financing activities:</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ProceedsFromConvertibleDebt', window );">Proceeds from the issuance of convertible senior notes</a></td>
<td class="nump">0<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="nump">109,500<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_PaymentsOfDebtIssuanceCosts', window );">Convertible senior notes issuance costs</a></td>
<td class="nump">$ 0<span></span>
</td>
<td class="nump">$ 0<span></span>
</td>
<td class="num">$ (10,428)<span></span>
</td>
</tr>
</table>
<div style="display: none;">
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_EarlyRepaymentOfConvertibleDebt">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The cash outflow from the extinguishment of a long-term debt instrument which can be exchanged for a specified amount of another security, typically the entity's common stock, at the option of the issuer or the holder.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_EarlyRepaymentOfConvertibleDebt</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_IncreaseDecreaseInIncomeTaxesReceivablePayable">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The increase (decrease) during the reporting period in income taxes receivable (payable), which represents the amount due from tax authorities for refunds of overpayments or recoveries of income taxes paid or the amount due for taxes based on the reporting entity's earnings or attributable to the entity's income earning process (business presence) within a given jurisdiction.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_IncreaseDecreaseInIncomeTaxesReceivablePayable</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_NonCashCapitalAndPatentExpenditures">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Future cash outflow to pay for purchases of fixed assets and patents that have been incurred.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_NonCashCapitalAndPatentExpenditures</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_AccretionAmortizationOfDiscountsAndPremiumsInvestments">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The sum of the periodic adjustments of the differences between securities' face values and purchase prices that are charged against earnings. This is called accretion if the security was purchased at a discount and amortization if it was purchased at premium. As a noncash item, this element is an adjustment to net income when calculating cash provided by or used in operations using the indirect method.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 230<br> -SubTopic 10<br> -Section 45<br> -Paragraph 28<br> -URI http://asc.fasb.org/extlink&amp;oid=123570139&amp;loc=d3e3602-108585<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_AccretionAmortizationOfDiscountsAndPremiumsInvestments</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_AdjustmentsToReconcileNetIncomeLossToCashProvidedByUsedInOperatingActivitiesAbstract">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_AdjustmentsToReconcileNetIncomeLossToCashProvidedByUsedInOperatingActivitiesAbstract</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:stringItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_AmortizationOfFinancingCosts">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of amortization expense attributable to debt issuance costs.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2009/role/commonPracticeRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 230<br> -SubTopic 10<br> -Section 45<br> -Paragraph 28<br> -Subparagraph (b)<br> -URI http://asc.fasb.org/extlink&amp;oid=123570139&amp;loc=d3e3602-108585<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 220<br> -SubTopic 10<br> -Section S99<br> -Paragraph 2<br> -Subparagraph (SX 210.5-03(8))<br> -URI http://asc.fasb.org/extlink&amp;oid=123367319&amp;loc=SL114868664-224227<br><br>Reference 3: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 470<br> -SubTopic 20<br> -Section 50<br> -Paragraph 1F<br> -Subparagraph (b)(2)<br> -URI http://asc.fasb.org/extlink&amp;oid=123466505&amp;loc=SL123495355-112611<br><br>Reference 4: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 835<br> -SubTopic 30<br> -Section 45<br> -Paragraph 3<br> -URI http://asc.fasb.org/extlink&amp;oid=124435984&amp;loc=d3e28555-108399<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_AmortizationOfFinancingCosts</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_AmortizationOfIntangibleAssets">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The aggregate expense charged against earnings to allocate the cost of intangible assets (nonphysical assets not used in production) in a systematic and rational manner to the periods expected to benefit from such assets. As a noncash expense, this element is added back to net income when calculating cash provided by or used in operations using the indirect method.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 230<br> -SubTopic 10<br> -Section 45<br> -Paragraph 28<br> -Subparagraph (b)<br> -URI http://asc.fasb.org/extlink&amp;oid=123570139&amp;loc=d3e3602-108585<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 350<br> -SubTopic 30<br> -Section 50<br> -Paragraph 2<br> -Subparagraph (a)(2)<br> -URI http://asc.fasb.org/extlink&amp;oid=66006027&amp;loc=d3e16323-109275<br><br>Reference 3: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 350<br> -SubTopic 30<br> -Section 45<br> -Paragraph 2<br> -URI http://asc.fasb.org/extlink&amp;oid=6388964&amp;loc=d3e16225-109274<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_AmortizationOfIntangibleAssets</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_CashCashEquivalentsRestrictedCashAndRestrictedCashEquivalents">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of cash and cash equivalents, and cash and cash equivalents restricted to withdrawal or usage. Excludes amount for disposal group and discontinued operations. Cash includes, but is not limited to, currency on hand, demand deposits with banks or financial institutions, and other accounts with general characteristics of demand deposits. Cash equivalents include, but are not limited to, short-term, highly liquid investments that are both readily convertible to known amounts of cash and so near their maturity that they present insignificant risk of changes in value because of changes in interest rates.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 230<br> -SubTopic 10<br> -Section 45<br> -Paragraph 24<br> -URI http://asc.fasb.org/extlink&amp;oid=123570139&amp;loc=d3e3521-108585<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 230<br> -SubTopic 10<br> -Section 45<br> -Paragraph 4<br> -URI http://asc.fasb.org/extlink&amp;oid=123570139&amp;loc=d3e3044-108585<br><br>Reference 3: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 230<br> -SubTopic 10<br> -Section 50<br> -Paragraph 8<br> -URI http://asc.fasb.org/extlink&amp;oid=123431023&amp;loc=SL98516268-108586<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_CashCashEquivalentsRestrictedCashAndRestrictedCashEquivalents</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_CashCashEquivalentsRestrictedCashAndRestrictedCashEquivalentsPeriodIncreaseDecreaseIncludingExchangeRateEffect">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of increase (decrease) in cash, cash equivalents, and cash and cash equivalents restricted to withdrawal or usage; including effect from exchange rate change. Cash includes, but is not limited to, currency on hand, demand deposits with banks or financial institutions, and other accounts with general characteristics of demand deposits. Cash equivalents include, but are not limited to, short-term, highly liquid investments that are both readily convertible to known amounts of cash and so near their maturity that they present insignificant risk of changes in value because of changes in interest rates.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 830<br> -SubTopic 230<br> -Section 45<br> -Paragraph 1<br> -URI http://asc.fasb.org/extlink&amp;oid=123444420&amp;loc=d3e33268-110906<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 230<br> -SubTopic 10<br> -Section 45<br> -Paragraph 24<br> -URI http://asc.fasb.org/extlink&amp;oid=123570139&amp;loc=d3e3521-108585<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_CashCashEquivalentsRestrictedCashAndRestrictedCashEquivalentsPeriodIncreaseDecreaseIncludingExchangeRateEffect</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_CashFlowNoncashInvestingAndFinancingActivitiesDisclosureAbstract">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_CashFlowNoncashInvestingAndFinancingActivitiesDisclosureAbstract</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:stringItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_DeferredIncomeTaxesAndTaxCredits">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of deferred income tax expense (benefit) and income tax credits.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 230<br> -SubTopic 10<br> -Section 45<br> -Paragraph 28<br> -URI http://asc.fasb.org/extlink&amp;oid=123570139&amp;loc=d3e3602-108585<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_DeferredIncomeTaxesAndTaxCredits</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_Depreciation">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The amount of expense recognized in the current period that reflects the allocation of the cost of tangible assets over the assets' useful lives. Includes production and non-production related depreciation.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 360<br> -SubTopic 10<br> -Section 50<br> -Paragraph 1<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=6391035&amp;loc=d3e2868-110229<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 230<br> -SubTopic 10<br> -Section 45<br> -Paragraph 28<br> -Subparagraph (b)<br> -URI http://asc.fasb.org/extlink&amp;oid=123570139&amp;loc=d3e3602-108585<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_Depreciation</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_EffectOfExchangeRateOnCashAndCashEquivalents">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of increase (decrease) from the effect of exchange rate changes on cash and cash equivalent balances held in foreign currencies.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 830<br> -SubTopic 230<br> -Section 45<br> -Paragraph 1<br> -URI http://asc.fasb.org/extlink&amp;oid=123444420&amp;loc=d3e33268-110906<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_EffectOfExchangeRateOnCashAndCashEquivalents</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_GainsLossesOnExtinguishmentOfDebt">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Difference between the fair value of payments made and the carrying amount of debt which is extinguished prior to maturity.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 470<br> -SubTopic 50<br> -Section 40<br> -Paragraph 4<br> -URI http://asc.fasb.org/extlink&amp;oid=123467658&amp;loc=d3e12355-112629<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 470<br> -SubTopic 50<br> -Section 40<br> -Paragraph 2<br> -URI http://asc.fasb.org/extlink&amp;oid=123467658&amp;loc=d3e12317-112629<br><br>Reference 3: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 230<br> -SubTopic 10<br> -Section 45<br> -Paragraph 28<br> -Subparagraph (b)<br> -URI http://asc.fasb.org/extlink&amp;oid=123570139&amp;loc=d3e3602-108585<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_GainsLossesOnExtinguishmentOfDebt</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_ImpairmentOfIntangibleAssetsFinitelived">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The amount of impairment loss recognized in the period resulting from the write-down of the carrying amount of a finite-lived intangible asset to fair value.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2009/role/commonPracticeRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 230<br> -SubTopic 10<br> -Section 45<br> -Paragraph 28<br> -Subparagraph (b)<br> -URI http://asc.fasb.org/extlink&amp;oid=123570139&amp;loc=d3e3602-108585<br><br>Reference 2: http://www.xbrl.org/2009/role/commonPracticeRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 350<br> -SubTopic 30<br> -Section 50<br> -Paragraph 3<br> -Subparagraph (b)<br> -URI http://asc.fasb.org/extlink&amp;oid=66006027&amp;loc=d3e16373-109275<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ImpairmentOfIntangibleAssetsFinitelived</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_IncomeTaxesPaid">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The amount of cash paid during the current period to foreign, federal, state, and local authorities as taxes on income.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 230<br> -SubTopic 10<br> -Section 50<br> -Paragraph 2<br> -URI http://asc.fasb.org/extlink&amp;oid=123431023&amp;loc=d3e4297-108586<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 230<br> -SubTopic 10<br> -Section 45<br> -Paragraph 25<br> -Subparagraph (f)<br> -URI http://asc.fasb.org/extlink&amp;oid=123570139&amp;loc=d3e3536-108585<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_IncomeTaxesPaid</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_IncreaseDecreaseInAccountsPayable">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The increase (decrease) during the reporting period in the aggregate amount of liabilities incurred (and for which invoices have typically been received) and payable to vendors for goods and services received that are used in an entity's business.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 230<br> -SubTopic 10<br> -Section 45<br> -Paragraph 28<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=123570139&amp;loc=d3e3602-108585<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_IncreaseDecreaseInAccountsPayable</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_IncreaseDecreaseInContractWithCustomerAsset">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of increase (decrease) in right to consideration in exchange for good or service transferred to customer when right is conditioned on something other than passage of time.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2009/role/commonPracticeRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 230<br> -SubTopic 10<br> -Section 45<br> -Paragraph 28<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=123570139&amp;loc=d3e3602-108585<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_IncreaseDecreaseInContractWithCustomerAsset</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_IncreaseDecreaseInContractWithCustomerLiability">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of increase (decrease) in obligation to transfer good or service to customer for which consideration has been received or is receivable.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2009/role/commonPracticeRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 230<br> -SubTopic 10<br> -Section 45<br> -Paragraph 28<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=123570139&amp;loc=d3e3602-108585<br><br>Reference 2: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 912<br> -SubTopic 310<br> -Section 45<br> -Paragraph 11<br> -Subparagraph (b)<br> -URI http://asc.fasb.org/extlink&amp;oid=123371682&amp;loc=d3e55415-109406<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_IncreaseDecreaseInContractWithCustomerLiability</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_IncreaseDecreaseInIncomeTaxesPayableNetOfIncomeTaxesReceivable">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The increase (decrease) during the reporting period in the amounts payable to taxing authorities for taxes that are based on the reporting entity's earnings, net of amounts receivable from taxing authorities for refunds of overpayments or recoveries of income taxes.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2009/role/commonPracticeRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 230<br> -SubTopic 10<br> -Section 45<br> -Paragraph 28<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=123570139&amp;loc=d3e3602-108585<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_IncreaseDecreaseInIncomeTaxesPayableNetOfIncomeTaxesReceivable</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_IncreaseDecreaseInInventories">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The increase (decrease) during the reporting period in the aggregate value of all inventory held by the reporting entity, associated with underlying transactions that are classified as operating activities.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 230<br> -SubTopic 10<br> -Section 45<br> -Paragraph 28<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=123570139&amp;loc=d3e3602-108585<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_IncreaseDecreaseInInventories</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_IncreaseDecreaseInOperatingCapitalAbstract">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_IncreaseDecreaseInOperatingCapitalAbstract</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:stringItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_IncreaseDecreaseInOtherAccountsPayableAndAccruedLiabilities">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The increase (decrease) during the reporting period in other obligations or expenses incurred but not yet paid.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 230<br> -SubTopic 10<br> -Section 45<br> -Paragraph 28<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=123570139&amp;loc=d3e3602-108585<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_IncreaseDecreaseInOtherAccountsPayableAndAccruedLiabilities</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_IncreaseDecreaseInOtherEmployeeRelatedLiabilities">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of increase (decrease) in employer-related costs classified as other and current.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 230<br> -SubTopic 10<br> -Section 45<br> -Paragraph 28<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=123570139&amp;loc=d3e3602-108585<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_IncreaseDecreaseInOtherEmployeeRelatedLiabilities</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_IncreaseDecreaseInOtherOperatingAssets">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of increase (decrease) in operating assets classified as other.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 230<br> -SubTopic 10<br> -Section 45<br> -Paragraph 28<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=123570139&amp;loc=d3e3602-108585<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_IncreaseDecreaseInOtherOperatingAssets</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_InterestPaidNet">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of cash paid for interest, excluding capitalized interest, classified as operating activity. Includes, but is not limited to, payment to settle zero-coupon bond for accreted interest of debt discount and debt instrument with insignificant coupon interest rate in relation to effective interest rate of borrowing attributable to accreted interest of debt discount.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 230<br> -SubTopic 10<br> -Section 50<br> -Paragraph 2<br> -URI http://asc.fasb.org/extlink&amp;oid=123431023&amp;loc=d3e4297-108586<br><br>Reference 2: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 230<br> -SubTopic 10<br> -Section 45<br> -Paragraph 17<br> -Subparagraph (d)<br> -URI http://asc.fasb.org/extlink&amp;oid=123570139&amp;loc=d3e3367-108585<br><br>Reference 3: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 230<br> -SubTopic 10<br> -Section 45<br> -Paragraph 25<br> -Subparagraph (e)<br> -URI http://asc.fasb.org/extlink&amp;oid=123570139&amp;loc=d3e3536-108585<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_InterestPaidNet</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_NetCashProvidedByUsedInFinancingActivities">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of cash inflow (outflow) from financing activities, including discontinued operations. Financing activity cash flows include obtaining resources from owners and providing them with a return on, and a return of, their investment; borrowing money and repaying amounts borrowed, or settling the obligation; and obtaining and paying for other resources obtained from creditors on long-term credit.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 230<br> -SubTopic 10<br> -Section 45<br> -Paragraph 24<br> -URI http://asc.fasb.org/extlink&amp;oid=123570139&amp;loc=d3e3521-108585<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_NetCashProvidedByUsedInFinancingActivities</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_NetCashProvidedByUsedInFinancingActivitiesAbstract">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_NetCashProvidedByUsedInFinancingActivitiesAbstract</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:stringItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_NetCashProvidedByUsedInInvestingActivities">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of cash inflow (outflow) from investing activities, including discontinued operations. Investing activity cash flows include making and collecting loans and acquiring and disposing of debt or equity instruments and property, plant, and equipment and other productive assets.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 230<br> -SubTopic 10<br> -Section 45<br> -Paragraph 24<br> -URI http://asc.fasb.org/extlink&amp;oid=123570139&amp;loc=d3e3521-108585<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_NetCashProvidedByUsedInInvestingActivities</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_NetCashProvidedByUsedInInvestingActivitiesAbstract">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_NetCashProvidedByUsedInInvestingActivitiesAbstract</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:stringItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_NetCashProvidedByUsedInOperatingActivities">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of cash inflow (outflow) from operating activities, including discontinued operations. Operating activity cash flows include transactions, adjustments, and changes in value not defined as investing or financing activities.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 230<br> -SubTopic 10<br> -Section 45<br> -Paragraph 25<br> -URI http://asc.fasb.org/extlink&amp;oid=123570139&amp;loc=d3e3536-108585<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 230<br> -SubTopic 10<br> -Section 45<br> -Paragraph 24<br> -URI http://asc.fasb.org/extlink&amp;oid=123570139&amp;loc=d3e3521-108585<br><br>Reference 3: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 230<br> -SubTopic 10<br> -Section 45<br> -Paragraph 28<br> -URI http://asc.fasb.org/extlink&amp;oid=123570139&amp;loc=d3e3602-108585<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_NetCashProvidedByUsedInOperatingActivities</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_NetCashProvidedByUsedInOperatingActivitiesAbstract">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_NetCashProvidedByUsedInOperatingActivitiesAbstract</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:stringItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
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</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_NotesIssued1">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The fair value of notes issued in noncash investing and financing activities.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 230<br> -SubTopic 10<br> -Section 50<br> -Paragraph 4<br> -URI http://asc.fasb.org/extlink&amp;oid=123431023&amp;loc=d3e4313-108586<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 230<br> -SubTopic 10<br> -Section 50<br> -Paragraph 5<br> -URI http://asc.fasb.org/extlink&amp;oid=123431023&amp;loc=d3e4332-108586<br><br>Reference 3: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 230<br> -SubTopic 10<br> -Section 50<br> -Paragraph 3<br> -URI http://asc.fasb.org/extlink&amp;oid=123431023&amp;loc=d3e4304-108586<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_NotesIssued1</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
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<tr>
<td><strong> Balance Type:</strong></td>
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<tr>
<td><strong> Period Type:</strong></td>
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</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_NotesReduction">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The value of notes retired (or transferred to another entity) in noncash investing or financing transactions.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 230<br> -SubTopic 10<br> -Section 50<br> -Paragraph 5<br> -URI http://asc.fasb.org/extlink&amp;oid=123431023&amp;loc=d3e4332-108586<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 230<br> -SubTopic 10<br> -Section 50<br> -Paragraph 3<br> -URI http://asc.fasb.org/extlink&amp;oid=123431023&amp;loc=d3e4304-108586<br><br>Reference 3: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 230<br> -SubTopic 10<br> -Section 50<br> -Paragraph 4<br> -URI http://asc.fasb.org/extlink&amp;oid=123431023&amp;loc=d3e4313-108586<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_NotesReduction</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_OperatingLeaseRightOfUseAssetAmortizationExpense">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of amortization expense for right-of-use asset from operating lease.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2009/role/commonPracticeRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 230<br> -SubTopic 10<br> -Section 45<br> -Paragraph 28<br> -Subparagraph (b)<br> -URI http://asc.fasb.org/extlink&amp;oid=123570139&amp;loc=d3e3602-108585<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_OperatingLeaseRightOfUseAssetAmortizationExpense</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_PaymentsForHedgeFinancingActivities">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The cash outflow for a financial contract that meets the hedge criteria as either cash flow hedge, fair value hedge or hedge of net investment in foreign operations.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2009/role/commonPracticeRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 230<br> -SubTopic 10<br> -Section 45<br> -Paragraph 15<br> -URI http://asc.fasb.org/extlink&amp;oid=123570139&amp;loc=d3e3291-108585<br><br>Reference 2: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 230<br> -SubTopic 10<br> -Section 45<br> -Paragraph 27<br> -URI http://asc.fasb.org/extlink&amp;oid=123570139&amp;loc=d3e3581-108585<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_PaymentsForHedgeFinancingActivities</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_PaymentsForRepurchaseOfCommonStock">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The cash outflow to reacquire common stock during the period.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 230<br> -SubTopic 10<br> -Section 45<br> -Paragraph 15<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=123570139&amp;loc=d3e3291-108585<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_PaymentsForRepurchaseOfCommonStock</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_PaymentsOfDebtIssuanceCosts">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The cash outflow paid to third parties in connection with debt origination, which will be amortized over the remaining maturity period of the associated long-term debt.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 230<br> -SubTopic 10<br> -Section 45<br> -Paragraph 15<br> -Subparagraph (e)<br> -URI http://asc.fasb.org/extlink&amp;oid=123570139&amp;loc=d3e3291-108585<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_PaymentsOfDebtIssuanceCosts</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_PaymentsRelatedToTaxWithholdingForShareBasedCompensation">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of cash outflow to satisfy grantee's tax withholding obligation for award under share-based payment arrangement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 230<br> -SubTopic 10<br> -Section 45<br> -Paragraph 15<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=123570139&amp;loc=d3e3291-108585<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_PaymentsRelatedToTaxWithholdingForShareBasedCompensation</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_PaymentsToAcquireAvailableForSaleSecuritiesDebt">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of cash outflow to acquire investment in debt security measured at fair value with change in fair value recognized in other comprehensive income (available-for-sale).</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 230<br> -SubTopic 10<br> -Section 45<br> -Paragraph 13<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=123570139&amp;loc=d3e3213-108585<br><br>Reference 2: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 230<br> -SubTopic 10<br> -Section 45<br> -Paragraph 11<br> -URI http://asc.fasb.org/extlink&amp;oid=123570139&amp;loc=d3e3151-108585<br><br>Reference 3: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 320<br> -SubTopic 10<br> -Section 45<br> -Paragraph 11<br> -URI http://asc.fasb.org/extlink&amp;oid=124260329&amp;loc=d3e26853-111562<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_PaymentsToAcquireAvailableForSaleSecuritiesDebt</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_PaymentsToAcquireIntangibleAssets">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The cash outflow to acquire asset without physical form usually arising from contractual or other legal rights, excluding goodwill.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 230<br> -SubTopic 10<br> -Section 45<br> -Paragraph 13<br> -Subparagraph (c)<br> -URI http://asc.fasb.org/extlink&amp;oid=123570139&amp;loc=d3e3213-108585<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_PaymentsToAcquireIntangibleAssets</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_PaymentsToAcquireOtherInvestments">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of cash outflow to acquire investments classified as other.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 230<br> -SubTopic 10<br> -Section 45<br> -Paragraph 13<br> -URI http://asc.fasb.org/extlink&amp;oid=123570139&amp;loc=d3e3213-108585<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_PaymentsToAcquireOtherInvestments</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_PaymentsToAcquirePropertyPlantAndEquipment">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The cash outflow associated with the acquisition of long-lived, physical assets that are used in the normal conduct of business to produce goods and services and not intended for resale; includes cash outflows to pay for construction of self-constructed assets.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 230<br> -SubTopic 10<br> -Section 45<br> -Paragraph 13<br> -Subparagraph (c)<br> -URI http://asc.fasb.org/extlink&amp;oid=123570139&amp;loc=d3e3213-108585<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_PaymentsToAcquirePropertyPlantAndEquipment</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_PaymentsToMinorityShareholders">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of cash outflow to a noncontrolling interest. Includes, but not limited to, reduction of noncontrolling interest ownership. Excludes dividends paid to the noncontrolling interest.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 230<br> -SubTopic 10<br> -Section 45<br> -Paragraph 15<br> -URI http://asc.fasb.org/extlink&amp;oid=123570139&amp;loc=d3e3291-108585<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_PaymentsToMinorityShareholders</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_ProceedsFromConvertibleDebt">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The cash inflow from the issuance of a long-term debt instrument which can be exchanged for a specified amount of another security, typically the entity's common stock, at the option of the issuer or the holder.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 230<br> -SubTopic 10<br> -Section 45<br> -Paragraph 14<br> -Subparagraph (b)<br> -URI http://asc.fasb.org/extlink&amp;oid=123570139&amp;loc=d3e3255-108585<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ProceedsFromConvertibleDebt</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_ProceedsFromIssuanceOfSharesUnderIncentiveAndShareBasedCompensationPlansIncludingStockOptions">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of cash inflow from issuance of shares under share-based payment arrangement. Includes, but is not limited to, option exercised.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 718<br> -SubTopic 10<br> -Section 50<br> -Paragraph 2A<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=120381028&amp;loc=SL79508275-113901<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 230<br> -SubTopic 10<br> -Section 45<br> -Paragraph 14<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=123570139&amp;loc=d3e3255-108585<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ProceedsFromIssuanceOfSharesUnderIncentiveAndShareBasedCompensationPlansIncludingStockOptions</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_ProceedsFromIssuanceOfWarrants">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The cash inflow from issuance of rights to purchase common shares at predetermined price (usually issued together with corporate debt).</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 230<br> -SubTopic 10<br> -Section 45<br> -Paragraph 14<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=123570139&amp;loc=d3e3255-108585<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ProceedsFromIssuanceOfWarrants</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_ProceedsFromSaleAndMaturityOfAvailableForSaleSecurities">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of cash inflow from sale, maturity, prepayment and call of investment in debt security measured at fair value with change in fair value recognized in other comprehensive income (available-for-sale).</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 230<br> -SubTopic 10<br> -Section 45<br> -Paragraph 11<br> -URI http://asc.fasb.org/extlink&amp;oid=123570139&amp;loc=d3e3151-108585<br><br>Reference 2: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 230<br> -SubTopic 10<br> -Section 45<br> -Paragraph 12<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=123570139&amp;loc=d3e3179-108585<br><br>Reference 3: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 320<br> -SubTopic 10<br> -Section 45<br> -Paragraph 11<br> -URI http://asc.fasb.org/extlink&amp;oid=124260329&amp;loc=d3e26853-111562<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ProceedsFromSaleAndMaturityOfAvailableForSaleSecurities</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_ProfitLoss">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The consolidated profit or loss for the period, net of income taxes, including the portion attributable to the noncontrolling interest.</p></div>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ProfitLoss</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_RealizedInvestmentGainsLosses">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of realized gain (loss) on investment.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 944<br> -SubTopic 220<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.7-04.3(a))<br> -URI http://asc.fasb.org/extlink&amp;oid=120400993&amp;loc=SL114874131-224263<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_RealizedInvestmentGainsLosses</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_RepaymentsOfConvertibleDebt">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The cash outflow from the repayment of a long-term debt instrument which can be exchanged for a specified amount of another security, typically the entity's common stock, at the option of the issuer or the holder.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 230<br> -SubTopic 10<br> -Section 45<br> -Paragraph 15<br> -Subparagraph (b)<br> -URI http://asc.fasb.org/extlink&amp;oid=123570139&amp;loc=d3e3291-108585<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_RepaymentsOfConvertibleDebt</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_RepaymentsOfLongTermLinesOfCredit">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The cash outflow for the settlement of obligation drawn from a contractual arrangement with the lender, including letter of credit, standby letter of credit and revolving credit arrangements, under which borrowings can be made up to a specific amount at any point in time with maturities due beyond one year or the operating cycle, if longer.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 230<br> -SubTopic 10<br> -Section 45<br> -Paragraph 15<br> -Subparagraph (b)<br> -URI http://asc.fasb.org/extlink&amp;oid=123570139&amp;loc=d3e3291-108585<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_RepaymentsOfLongTermLinesOfCredit</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
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<tr>
<td><strong> Balance Type:</strong></td>
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<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
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<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_RightOfUseAssetObtainedInExchangeForOperatingLeaseLiability">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of increase in right-of-use asset obtained in exchange for operating lease liability.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/exampleRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 842<br> -SubTopic 20<br> -Section 55<br> -Paragraph 53<br> -URI http://asc.fasb.org/extlink&amp;oid=123414884&amp;loc=SL77918982-209971<br><br>Reference 2: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 842<br> -SubTopic 20<br> -Section 50<br> -Paragraph 4<br> -Subparagraph (g)(2)<br> -URI http://asc.fasb.org/extlink&amp;oid=123408670&amp;loc=SL77918686-209980<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_RightOfUseAssetObtainedInExchangeForOperatingLeaseLiability</td>
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<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
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<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_ShareBasedCompensation">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of noncash expense for share-based payment arrangement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 230<br> -SubTopic 10<br> -Section 45<br> -Paragraph 28<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=123570139&amp;loc=d3e3602-108585<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ShareBasedCompensation</td>
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<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
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<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
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<td><strong> Balance Type:</strong></td>
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<td><strong> Period Type:</strong></td>
<td>duration</td>
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<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_SupplementalCashFlowInformationAbstract</td>
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<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
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<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_DebtInstrumentAxis=ions_ConvertibleSeniorNotes0PercentMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_DebtInstrumentAxis=ions_ConvertibleSeniorNotes0PercentMember</td>
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<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
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<td><strong> Data Type:</strong></td>
<td>na</td>
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<td><strong> Balance Type:</strong></td>
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<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_DebtInstrumentAxis=ions_ConvertibleSeniorNotes0125PercentMember</td>
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<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
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<td></td>
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<span style="display: none;">v3.22.0.1</span><table class="report" border="0" cellspacing="2" id="idm139691007438232">
<tr>
<th class="tl" colspan="1" rowspan="1"><div style="width: 200px;"><strong>CONSOLIDATED STATEMENTS OF CASH FLOWS (Parenthetical) - USD ($)<br> $ in Millions</strong></div></th>
<th class="th"><div>Dec. 31, 2021</div></th>
<th class="th"><div>Nov. 30, 2021</div></th>
<th class="th"><div>Apr. 30, 2021</div></th>
<th class="th"><div>Dec. 31, 2020</div></th>
<th class="th"><div>Dec. 31, 2019</div></th>
<th class="th"><div>Dec. 31, 2016</div></th>
<th class="th"><div>Nov. 30, 2014</div></th>
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<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DebtInstrumentAxis=ions_ConvertibleSeniorNotes0PercentMember', window );">0 Percent Convertible Senior Notes [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_CashAndCashEquivalentsPeriodIncreaseDecreaseAbstract', window );"><strong>Consolidated Statements of Cash Flows [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DebtInstrumentInterestRateStatedPercentage', window );">Interest rate on convertible senior notes</a></td>
<td class="nump">0.00%<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">0.00%<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">0.00%<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DebtInstrumentAxis=ions_ConvertibleSeniorNotes0125PercentMember', window );">0.125 Percent Convertible Senior Notes [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_CashAndCashEquivalentsPeriodIncreaseDecreaseAbstract', window );"><strong>Consolidated Statements of Cash Flows [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DebtInstrumentInterestRateStatedPercentage', window );">Interest rate on convertible senior notes</a></td>
<td class="nump">0.125%<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">0.125%<span></span>
</td>
<td class="nump">0.125%<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
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<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DebtInstrumentAxis=ions_ConvertibleSeniorNotes1PercentMember', window );">1 Percent Convertible Senior Notes [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_CashAndCashEquivalentsPeriodIncreaseDecreaseAbstract', window );"><strong>Consolidated Statements of Cash Flows [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
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<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DebtInstrumentInterestRateStatedPercentage', window );">Interest rate on convertible senior notes</a></td>
<td class="nump">1.00%<span></span>
</td>
<td class="nump">1.00%<span></span>
</td>
<td class="nump">1.00%<span></span>
</td>
<td class="nump">1.00%<span></span>
</td>
<td class="nump">1.00%<span></span>
</td>
<td class="nump">1.00%<span></span>
</td>
<td class="nump">1.00%<span></span>
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<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DebtInstrumentRepurchasedFaceAmount', window );">Principal amount repurchased</a></td>
<td class="nump">$ 247.9<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 247.9<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 375.6<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_CashAndCashEquivalentsPeriodIncreaseDecreaseAbstract</td>
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<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_DebtInstrumentInterestRateStatedPercentage">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Contractual interest rate for funds borrowed, under the debt agreement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 470<br> -SubTopic 20<br> -Section 50<br> -Paragraph 1B<br> -Subparagraph (b)<br> -URI http://asc.fasb.org/extlink&amp;oid=123466505&amp;loc=SL123495323-112611<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 210<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.5-02.22(a)(1))<br> -URI http://asc.fasb.org/extlink&amp;oid=120391452&amp;loc=d3e13212-122682<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_DebtInstrumentInterestRateStatedPercentage</td>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Face (par) amount of the original debt instrument that was repurchased.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
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<tr>
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<span style="display: none;">v3.22.0.1</span><table class="report" border="0" cellspacing="2" id="idm139691017274136">
<tr>
<th class="tl" colspan="1" rowspan="2"><div style="width: 200px;"><strong>Organization and Significant Accounting Policies<br></strong></div></th>
<th class="th" colspan="1">12 Months Ended</th>
</tr>
<tr><th class="th"><div>Dec. 31, 2021</div></th></tr>
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<td class="text">
<div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">1. Organization and Significant Accounting Policies</div>

<div><br/>
  </div>

<div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Basis of Presentation</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">In our consolidated financial statements we included the accounts of Ionis Pharmaceuticals, Inc. and the consolidated
    results of our subsidiary, Akcea Therapeutics, Inc. and its wholly owned subsidiaries (&#8220;we&#8221;, &#8220;us&#8221; or &#8220;our&#8221;). We formed Akcea in December 2014. In July 2017, Akcea completed an initial public offering, or IPO, which reduced our ownership of Akcea&#8217;s
    common stock below 100 percent. In October 2020, we completed a merger transaction with Akcea such that following the completion of the merger,
    Akcea became our wholly owned subsidiary. We will refer to this transaction as the Akcea Merger throughout the remainder of this document. We reflected changes in our ownership percentage in our financial statements as an adjustment to noncontrolling
    interest in the period the changes occurred<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">.</span></div>

<div><br/>
  </div>

<div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Organization and Business Activity</div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt;"><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We incorporated in California on January 10, 1989. In conjunction with our IPO, we reorganized as a Delaware corporation
    in April 1991. We were organized principally to develop human therapeutic medicines using antisense technology. In December 2015, we changed our name from Isis Pharmaceuticals, Inc. to Ionis Pharmaceuticals, Inc.</div>

<div><br/>
  </div>

<div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Basic and Diluted Net Income (Loss) per Share</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;">Basic net income (loss) per share</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We compute basic net income (loss) per share by dividing the total net income (loss) attributable to our common
    stockholders by our weighted-average number of common shares outstanding during the period. For the year ended December 31, 2021, we did not have to consider Akcea results separately in our calculation because we owned 100 percent of Akcea for the entire period. Our basic net loss per share for the year ended December 31, 2021 was $0.20.</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">For the years ended December 31, 2020 and 2019, we calculated total net income (loss) attributable to our common
    stockholders for each year using our net income (loss) for Ionis on a stand-alone basis plus our share of Akcea&#8217;s net income (loss) for the period. To calculate the portion of Akcea&#8217;s net income (loss) attributable to our ownership for each year, we
    multiplied Akcea&#8217;s income (loss) per share by the weighted average shares we owned in Akcea during the period. As a result of this calculation, our total net income (loss) available to Ionis common stockholders for the calculation of net income (loss)
    per share is different than net income (loss) attributable to Ionis Pharmaceuticals, Inc. common stockholders in our consolidated statements of operations for each year.</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We calculated our basic net loss per share for the year ended December 31, 2020 as follows (in thousands, except
    per share amounts):</div>

<div><br/>
  </div>

<table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;">


  <tr>

    <td style="vertical-align: bottom; border-bottom: #000000 2px solid; white-space: nowrap;" valign="bottom">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Year Ended December 31, 2020</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Weighted</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Average Shares</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Owned in Akcea</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Akcea</span>&#8217;<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">s</span></div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Net Loss</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Per Share</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Basic Net Loss</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Per Share</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Calculation</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: top; width: 64%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Akcea&#8217;s net loss in the pre-merger period attributable to our ownership</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">77,095</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(1.45</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(111,775</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

  </tr>

  <tr>

    <td style="vertical-align: top; width: 64%; white-space: nowrap;" valign="bottom">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Akcea&#8217;s net loss in the post-merger period attributable to our ownership</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(85,987</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

  </tr>

  <tr>

    <td style="vertical-align: top; width: 64%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Akcea&#8217;s total net loss attributable to our ownership</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(197,762</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

  </tr>

  <tr>

    <td style="vertical-align: top; width: 64%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">
          <div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Ionis&#8217; stand-alone net loss</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(246,702</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

  </tr>

  <tr>

    <td style="vertical-align: top; width: 64%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Net loss available to Ionis common stockholders</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(444,464</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

  </tr>

  <tr>

    <td style="vertical-align: top; width: 64%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">
          <div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Weighted average shares outstanding</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">139,612</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: top; width: 64%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Basic net loss per share</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(3.18</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

  </tr>


</table>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We calculated our basic net income per share for the year ended December 31, 2019 as follows (in thousands, except per share amounts):</div>

<div><br/>
  </div>

<table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;">


  <tr>

    <td style="vertical-align: bottom; border-bottom: #000000 2px solid; white-space: nowrap;" valign="bottom">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Year Ended December 31, 2019</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Weighted</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Average Shares</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Owned in Akcea</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Akcea</span>&#8217;<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">s</span></div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Net Income</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Per Share</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Basic Net Income</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Per Share</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Calculation</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: top; width: 64%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Common shares</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">70,100</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">0.49</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">34,073</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: top; width: 64%; white-space: nowrap;" valign="bottom">
          <div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Akcea&#8217;s net income attributable to our ownership</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">34,073</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: top; width: 64%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Ionis&#8217; stand-alone net income</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">246,487</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: top; width: 64%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">
          <div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Net income available to Ionis common stockholders</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">280,560</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: top; width: 64%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Weighted average shares outstanding</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">139,998</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: top; width: 64%; padding-bottom: 4px; white-space: nowrap;" valign="bottom">
          <div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Basic net income per share</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">2.00</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>


</table>

<div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 12pt;"><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;">Diluted net income (loss) per share</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">For the years ended December 31, 2021 and 2020, we incurred a net loss; therefore, we did not include dilutive common
    equivalent shares in the computation of diluted net loss per share because the effect would have been anti-dilutive. Common stock underlying the following would have had an anti-dilutive effect on net loss per share:</div>

<div><br/>
  </div>

<table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">


  <tr>

    <td style="width: 36pt;"/>

    <td style="width: 18pt; vertical-align: top; align: right; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;">0.125 percent<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> convertible senior notes, or </span>0.125%<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> Notes;</span></div>
        </td>

  </tr>


</table>

<table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">


  <tr>

    <td style="width: 36pt;"/>

    <td style="width: 18pt; vertical-align: top; align: right; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">Note hedges related to the </span>0.125%<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> Notes;</span></div>
        </td>

  </tr>


</table>

<table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">


  <tr>

    <td style="width: 36pt;"/>

    <td style="width: 18pt; vertical-align: top; align: right; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;">1 percent<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> convertible senior notes, or </span>1%<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> Notes;</span></div>
        </td>

  </tr>


</table>

<table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">


  <tr>

    <td style="width: 36pt;"/>

    <td style="width: 18pt; vertical-align: top; align: right; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Dilutive stock options;</div>
        </td>

  </tr>


</table>

<table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">


  <tr>

    <td style="width: 36pt;"/>

    <td style="width: 18pt; vertical-align: top; align: right; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Unvested restricted stock units, or RSUs;</div>
        </td>

  </tr>


</table>

<table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">


  <tr>

    <td style="width: 36pt;"/>

    <td style="width: 18pt; vertical-align: top; align: right; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Unvested performance restricted stock units, or PRSUs; and</div>
        </td>

  </tr>


</table>

<table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">


  <tr>

    <td style="width: 36pt;"/>

    <td style="width: 18pt; vertical-align: top; align: right; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Employee Stock Purchase Plan, or ESPP.</div>
        </td>

  </tr>


</table>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">For the year ended December 31, 2021, common stock underlying the following would also have had an anti-dilutive effect on
    net loss per share:</div>

<div><br/>
  </div>

<table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">


  <tr>

    <td style="width: 36pt;"/>

    <td style="width: 18pt; vertical-align: top; align: right; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;">0 percent<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> convertible senior notes, or </span>0%<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> Notes; and</span></div>
        </td>

  </tr>


</table>

<table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">


  <tr>

    <td style="width: 36pt;"/>

    <td style="width: 18pt; vertical-align: top; align: right; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">Note hedges related to the </span>0%<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> Notes.</span></div>
        </td>

  </tr>


</table>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Additionally as of December 31, 2021, we had warrants related to our 0 percent and 0.125 percent Notes outstanding. We will include the shares issuable
    under these warrants in our calculation of diluted earnings per share when the average market price per share of our common stock for the reporting period exceeds the strike price of the warrants.</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">For the
      year ended December 31, 2019, we reported net income available to Ionis common stockholders. As a result, we computed diluted net income per share using the weighted-average number of common shares and dilutive common equivalent shares outstanding
      during each period.</span> We calculated our diluted net income per share as follows <span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">(in thousands except per share amounts):</span></div>

<div><br/>
  </div>

<table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;">


  <tr>

    <td style="vertical-align: bottom; border-bottom: #000000 2px solid;" valign="bottom">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Year Ended December 31, 2019</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Net Income Available</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">to Ionis Common</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Stockholders</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">(Numerator)</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Shares</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">(Denominator)</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Per-Share</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Amount</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: top; width: 64%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Net income available to Ionis common stockholders</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">280,560</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">139,998</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">2.00</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: top; width: 64%;" valign="bottom">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Effect of dilutive securities:</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: top; width: 64%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: left; text-indent: -8.9pt; margin-left: 18pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Shares issuable upon exercise of stock options</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#8212;</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">2,090</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: top; width: 64%;" valign="bottom">
          <div style="text-align: left; text-indent: 0.1pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Shares issuable upon restricted stock award issuance</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#8212;</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">766</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: top; width: 64%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: left; text-indent: 9.1pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Shares issuable related to our ESPP</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#8212;</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">18</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: top; width: 64%;" valign="bottom">
          <div style="text-align: left; text-indent: 9.1pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">Shares issuable related to our </span>0.125<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> percent convertible notes</span></div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">860</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">217</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: top; width: 64%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: left; text-indent: 9.1pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Shares issuable related to our 1 percent convertible notes</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">9,527</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">10,075</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: top; width: 64%; padding-bottom: 4px;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">290,947</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">153,164</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">1.90</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>


</table>

<div style="text-align: left;"><br/>
  </div>

<div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Revenue Recognition</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="text-decoration: underline;">Our Revenue Sources</span></div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We generally recognize revenue when we have satisfied all contractual obligations and are reasonably assured of collecting
    the resulting receivable. We are often entitled to bill our customers and receive payment from our customers in advance of recognizing the revenue. In the instances in which we have received payment from our customers in advance of recognizing revenue,
    we include the amounts in deferred revenue on our consolidated balance sheet.</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">At contract inception, we analyze our collaboration arrangements to assess whether such arrangements involve joint
    operating activities performed by parties that are both active participants in the activities and exposed to significant risks and rewards dependent on the commercial success of such activities and therefore within the scope of ASC Topic 808,
    Collaborative Arrangements (ASC 808).&#160; For collaboration arrangements within the scope of ASC 808 that contain multiple elements, we first determine which elements of the collaboration reflect a vendor-customer relationship and therefore within the
    scope of ASC 606. When we determine elements of a collaboration do not reflect a vendor-customer relationship, we consistently apply the reasonable and rational policy election we made by analogizing to authoritative accounting literature.</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We evaluate the income statement classification for presentation of amounts due from or owed to other participants
    associated with multiple activities in a collaboration arrangement based on the nature of each separate activity. For example, in our eplontersen collaboration with AstraZeneca, we recognize funding received from AstraZeneca for co-development
    activities as revenue. While, we recognize cost sharing payments to and from AstraZeneca associated with co-commercialization activities and co-medical affairs activities as SG&amp;A expense and research and development expense, respectively.</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;">Commercial Revenue: SPINRAZA royalties and Licensing and other royalty revenue</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We earn commercial revenue primarily in the form of royalty payments on net sales of SPINRAZA. We will also recognize as
    commercial revenue sales milestone payments and royalties we earn under our other partnerships.</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;">Commercial Revenue: TEGSEDI and WAYLIVRA revenue, net</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We began commercializing TEGSEDI and WAYLIVRA in Europe in January 2021 and TEGSEDI in North America in April 2021 through distribution
    agreements with Swedish Orphan Biovitrum AB, or Sobi. Under our agreements, we are responsible for supplying finished goods inventory to Sobi and Sobi is responsible for selling each medicine to the end customer. As a result of these agreements, we
    earn a distribution fee on net sales from Sobi for each medicine.</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Prior to the second quarter of 2021 in North America, we sold TEGSEDI through exclusive distribution agreements with third-party logistics
    companies, or 3PLs, that took title to TEGSEDI. The 3PLs then distributed TEGSEDI to a specialty pharmacy and a specialty distributor, which we collectively refer to as wholesalers, who then distributed TEGSEDI to health care providers and patients. In
    the United States, or U.S., we had a single 3PL as our sole customer and in Canada we also had a single 3PL as our sole customer. Prior to 2021 in Europe, we sold TEGSEDI and WAYLIVRA to hospitals and pharmacies, which were our customers, using 3PLs as
    distributors.</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">Under our collaboration agreement with PTC
      Therapeutics International Limited, or PTC, PTC is responsible for commercializing TEGSEDI and WAYLIVRA in Latin America and Caribbean countries. In the third quarter of 2021, we earned a </span>$4 million milestone payment from PTC when WAYLIVRA was approved in Brazil, which we included in TEGSEDI and WAYLIVRA revenue in our consolidated statement of operations. Under our agreement, we
    started receiving royalties from PTC for TEGSEDI sales beginning in December 2021.</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: left; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;">Research and development revenue under collaborative agreements</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We often enter into collaboration agreements to license and sell our technology on an exclusive or non-exclusive basis.
    Our collaboration agreements typically contain multiple elements, or performance obligations, including technology licenses or options to obtain technology licenses, research and development, or R&amp;D, services, and manufacturing services.</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We provide details about our collaboration agreements in Note 6, <span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Collaborative Arrangements and Licensing Agreements.</span><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">&#160;</span>For each collaboration, we discuss our specific revenue
    recognition conclusions, including our significant performance obligations under each collaboration.</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: left; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="text-decoration: underline;">Steps to Recognize Revenue</span></div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We use a five-step process to determine the amount of revenue we should recognize and when we should recognize it. The
    five step process is as follows:</div>

<div><br/>
  </div>

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  <tr>

    <td style="width: 36pt;"/>

    <td style="width: 18pt; vertical-align: top; align: right; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic; font-weight: bold;">1.</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic; font-weight: bold;">Identify the contract</div>
        </td>

  </tr>


</table>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Accounting rules require us to first determine if we have a contract with our partner, including confirming that we have met each of the
    following criteria:</div>

<div><br/>
  </div>

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  <tr>

    <td style="width: 36pt;"/>

    <td style="width: 18pt; vertical-align: top; align: right; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We and our partner approved the contract and we are both committed to perform our obligations;</div>
        </td>

  </tr>


</table>

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  <tr>

    <td style="width: 36pt;"/>

    <td style="width: 18pt; vertical-align: top; align: right; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We have identified our rights, our partner&#8217;s rights and the payment terms;</div>
        </td>

  </tr>


</table>

<table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">


  <tr>

    <td style="width: 36pt;"/>

    <td style="width: 18pt; vertical-align: top; align: right; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We have concluded that the contract has commercial substance, meaning that the risk, timing, or amount of our future cash flows is expected to change as a result of the
            contract; and</div>
        </td>

  </tr>


</table>

<table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">


  <tr>

    <td style="width: 36pt;"/>

    <td style="width: 18pt; vertical-align: top; align: right; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We believe collectability of the consideration is probable.</div>
        </td>

  </tr>


</table>

<div><br/>
  </div>

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  <tr>

    <td style="width: 36pt;"/>

    <td style="width: 18pt; vertical-align: top; align: right;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold; font-style: italic;">2.</span></td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic; font-weight: bold;">Identify the performance obligations</div>
        </td>

  </tr>


</table>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We next identify our performance obligations, which represent the distinct goods and services we are required to provide under the
    contract.</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">Often we enter into a collaboration agreement
      in which we provide our partner with an option to license a medicine in the future. We may also provide our partner with an option to request that we provide additional goods or services in the future, such as active pharmaceutical ingredient, or
      API. We evaluate whether these options are material rights at the inception of the agreement. If we determine an option is a material right, we will consider the option a separate performance obligation. Historically, we have concluded that the
      options we grant to license a medicine in the future or to provide additional goods and services as requested by our partner are not material rights because these items are contingent upon future events that may not occur and are not priced at a
      significant discount. When a partner exercises its option to license a medicine or requests additional goods or services, then we identify a new performance obligation for that item</span>.</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">In some cases, we deliver a license at the start of an agreement. If we determine that our partner has full use of the license and we do
    not have any additional material performance obligations related to the license after delivery, then we consider the license to be a separate performance obligation. For example, in the fourth quarter of 2021, we received a $200 million upfront payment when we entered into an agreement with AstraZeneca to jointly develop and commercialize eplontersen. We recognized the upfront
    payment in full in the fourth quarter of 2021 because we did not have any remaining performance obligations after we delivered the license to AstraZeneca.</div>

<div><br/>
  </div>

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  <tr>

    <td style="width: 36pt;"/>

    <td style="width: 18pt; vertical-align: top; align: right; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic; font-weight: bold;">3.</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic; font-weight: bold;">Determine the transaction price</div>
        </td>

  </tr>


</table>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We then determine the transaction price by reviewing the amount of consideration we are eligible to earn under the
        collaboration agreement, including any variable consideration. Under our collaboration agreements, consideration typically includes fixed consideration in the form of an upfront payment and variable consideration in the form of potential milestone
        payments, license fees and royalties. At the start of an agreement, our transaction price usually consists of only the upfront payment. We do not typically include any payments we may receive in the future in our initial transaction price because
        the payments are not probable and are contingent on certain future events. We reassess the total transaction price at each reporting period to determine if we should include additional payments in the transaction price.</div>

<div><br/>
    </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">Milestone payments are our most common type
      of variable consideration. We recognize milestone payments using the most likely amount method because we will either receive the milestone payment or we will not, which makes the potential milestone payment a binary event. The most likely amount
      method requires us to determine the likelihood of earning the milestone payment. We include a milestone payment in the transaction price once it is probable we will achieve the milestone event. Most often, we do not consider our milestone payments
      probable until we or our partner achieve the milestone event because the majority of our milestone payments are contingent upon events that are not within our control and/ or are usually based on scientific progress which is inherently uncertain. For
      example, in the fourth quarter of 2021, we earned</span> a $10 million <span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">milestone payment from AstraZeneca when AstraZeneca advanced a target for a metabolic disease. We did not consider the milestone payment probable until AstraZeneca achieved the milestone event because advancing the target was
      contingent on AstraZeneca initiating a Phase 1 study and was not within our control. We recognized the milestone payment in full in the period the milestone event was achieved because we did not have any remaining performance obligations related to
      the milestone payment</span>.</div>

<div><br/>
  </div>

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  <tr>

    <td style="width: 36pt;"/>

    <td style="width: 18pt; vertical-align: top; align: right; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic; font-weight: bold;">4.</td>

    <td style="width: auto; vertical-align: top; text-align: left;">
          <div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic; font-weight: bold;">Allocate the transaction price</div>
        </td>

  </tr>


</table>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Next, we allocate the transaction price to
        each of our performance obligations. When we have to allocate the transaction price to more than </span>one<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> performance obligation, we make estimates of the relative
        stand-alone selling price of each performance obligation because we do not typically sell our goods or services on a stand-alone basis. We then allocate the transaction price to each performance obligation based on the relative stand-alone selling
        price. We do not reallocate the transaction price after the start of an agreement to reflect subsequent changes in stand-alone selling prices.</span></div>

<div><br/>
    </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We may engage a </span>third<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> party, independent valuation specialist to assist us with determining a stand-alone selling price for collaborations in which we deliver a license at the start of an agreement.
      We estimate the stand-alone selling price of these licenses using valuation methodologies, such as the relief from royalty method. Under this method, we estimate the amount of income, net of taxes, for the license. We then discount the projected
      income to present value. The significant inputs we use to determine the projected income of a license could include</span>:</div>

<div><br/>
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    <td style="width: 36pt;"/>

    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Estimated future product sales;</div>
        </td>

  </tr>


</table>

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    <td style="width: 36pt;"/>

    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Estimated royalties we may receive from future product sales;</div>
        </td>

  </tr>


</table>

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    <td style="width: 36pt;"/>

    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Estimated contractual milestone payments we may receive;</div>
        </td>

  </tr>


</table>

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  <tr>

    <td style="width: 36pt;"/>

    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Expenses we expect to incur;</div>
        </td>

  </tr>


</table>

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  <tr>

    <td style="width: 36pt;"/>

    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Estimated income taxes; and</div>
        </td>

  </tr>


</table>

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  <tr>

    <td style="width: 36pt;"/>

    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">A discount rate.</div>
        </td>

  </tr>


</table>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We typically estimate the selling price of R&amp;D services by using our internal estimates of the cost to perform the
    specific services. The significant inputs we use to determine the selling price of our R&amp;D services include:</div>

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    <td style="width: 36pt;"/>

    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">The number of internal hours we estimate we will spend performing these services;</div>
        </td>

  </tr>


</table>

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  <tr>

    <td style="width: 36pt;"/>

    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">The estimated cost of work we will perform;</div>
        </td>

  </tr>


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  <tr>

    <td style="width: 36pt;"/>

    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">The estimated cost of work that we will contract with third parties to perform; and</div>
        </td>

  </tr>


</table>

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  <tr>

    <td style="width: 36pt;"/>

    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">The estimated cost of API we will use.</div>
        </td>

  </tr>


</table>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">For purposes of determining the stand-alone selling price of the R&amp;D services we perform and the API we will deliver,
    accounting guidance requires us to include a markup for a reasonable profit margin.</div>

<div><br/>
  </div>

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  <tr>

    <td style="width: 36pt;"/>

    <td style="width: 18pt; vertical-align: top; align: right; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic; font-weight: bold;">5.</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic; font-weight: bold;">Recognize revenue</div>
        </td>

  </tr>


</table>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We recognize revenue in </span>one<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> of </span>two<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> ways, over time or at a point in time. We recognize revenue over time when we are
        executing on our performance obligation over time and our partner receives benefit over time. For example, we recognize revenue over time when we provide R&amp;D services. We recognize revenue at a point in time when our partner receives full use
        of an item at a specific point in time. For example, we recognize revenue at a point in time when we deliver a license or API to a partner.</span></div>

<div><br/>
    </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">For R&amp;D services that we recognize over
      time, we measure our progress using an input method. The input methods we use are based on the effort we expend or costs we incur toward the satisfaction of our performance obligation. We estimate the amount of effort we expend, including the time we
      estimate it will take us to complete the activities, or costs we incur in a given period, relative to the estimated total effort or costs to satisfy the performance obligation. This results in a percentage that we multiply by the transaction price to
      determine the amount of revenue we recognize each period. This approach requires us to make numerous estimates and use significant judgement. If our estimates or judgements change over the course of the collaboration, they may affect the timing and
      amount of revenue that we recognize in the current and future periods.</span> Refer to Note 6, <span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Collaborative Arrangements and Licensing Agreements</span>,
    for further discussion of the cumulative catch up adjustment we made.</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: left; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">The following are examples of when we typically recognize revenue based on the types of payments we receive.</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: left; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;"><span style="text-decoration: underline;">Commercial Revenue: SPINRAZA royalties and Licensing and other royalty revenue</span></div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We recognize royalty revenue, including
      royalties from SPINRAZA sales, in the period in which the counterparty sells the related product and recognizes the related revenue, which in certain cases may require us to estimate our royalty revenue</span>.</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: left; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;"><span style="text-decoration: underline;">Commercial Revenue: TEGSEDI and WAYLIVRA revenue, net</span></div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Under our distribution agreements with Sobi we concluded that our performance obligation is to provide services to
      Sobi over the term of the agreement, which includes supplying finished goods inventory to Sobi and because we retained the marketing authorization for TEGSEDI and WAYLIVRA we are responsible for leading the global commercial strategy for each
      medicine. We view this performance obligation as a series of distinct activities that are substantially the same. Therefore, we recognize as revenue the price Sobi pays us for the inventory when we deliver the finished goods inventory to Sobi. We
      also recognize distribution fee revenue based on Sobi&#8217;s net sales of TEGSEDI and WAYLIVRA in the period in which the sales occurred. Under our agreements with Sobi, Sobi does not generally have a right of return.</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">Prior to our distribution agreements with
      Sobi, we recognized TEGSEDI and WAYLIVRA commercial revenue in the period when our customer obtained control of our products, which occurred at a point in time upon transfer of title to the customer. We classified payments to customers or other
      parties in the distribution channel for services that were distinct and priced at fair value as selling, general and administrative, or SG&amp;A, expenses in our consolidated statements of operations. We classified payments to customers or other
      parties in the distribution channel that did not meet those criteria as a reduction of revenue, as discussed further below. We excluded from revenues taxes collected from customers relating to TEGSEDI and WAYLIVRA commercial revenue and remitted
      these amounts to governmental authorities</span>.</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;">Reserves for TEGSEDI and WAYLIVRA commercial revenue</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Prior to our distribution agreements with Sobi, we recorded TEGSEDI and WAYLIVRA commercial revenue at our net sales
      price, or transaction price. We included in our transaction price estimated reserves for discounts, returns, chargebacks, rebates and other allowances that we offered within contracts between us and our customers, wholesalers, distributors, health
      care providers and other indirect customers. We estimated our reserves using the amounts we have earned or we could claim on the associated sales. We classified our reserves as a reduction of accounts receivable when we were not required to make a
      payment or as a current liability when we were required to make a payment. In certain cases, our estimates included a range of possible outcomes that were probability weighted for relevant factors such as our historical experience, current
      contractual and statutory requirements, specific known market events and trends, industry data and forecasted customer buying and payment patterns. Overall, our reserves reflected our best estimates under the terms of our respective contracts. When
      calculating our reserves and related TEGSEDI and WAYLIVRA commercial revenue, we only recognized amounts to the extent that we considered it probable that we would not have to reverse a significant amount of the cumulative sales we previously
      recognized in a future period. Under our agreements with Sobi, we transferred all reserves to Sobi.</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: left; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">The following were the components of variable consideration related to TEGSEDI and WAYLIVRA product sales prior to our agreements with Sobi:</div>

<div><br/>
  </div>

<div style="text-align: justify; margin-left: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Chargebacks: </span><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">In the U.S., we estimated obligations resulting from contractual commitments with the government and other entities to sell products to qualified healthcare
      providers at prices lower than the list prices charged to our U.S. customer. Our U.S. customer charged us for the difference between what it paid for the product and the selling price to the qualified healthcare providers. We also estimated the
      amount of chargebacks related to our estimated product remaining in the distribution channel at the end of the reporting period that we expected our customer to sell to healthcare providers in future periods. We recorded these reserves as a reduction
      to contracts receivable on our consolidated balance sheet</span>.</div>

<div><br/>
  </div>

<div style="text-align: justify; margin-left: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic; color: #000000;">Government rebates</span><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">: We were subject to discount obligations under government programs, including Medicaid and Medicare programs in the U.S. and we recorded reserves for government
      rebates based on statutory discount rates and estimated utilization. We estimated Medicaid and Medicare rebates based on a range of possible outcomes that were probability weighted for the estimated payer mix. We recorded these reserves as an accrued
      liability on our consolidated balance sheet with a corresponding offset reducing our product sales in the same period we recognized the related sale. For Medicare, we also estimated the number of patients in the prescription drug coverage gap for
      whom we would owe an additional liability under the Medicare Part D program. On a quarterly basis, we updated our estimates and recorded any adjustments in the period that we identified the adjustments</span>.</div>

<div><br/>
  </div>

<div style="text-align: justify; margin-left: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Managed care rebates: </span><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">We were subject to rebates in connection with agreements with certain contracted commercial payers. We recorded these rebates as a liability on our consolidated
      balance sheet in the same period we recognized the related revenue. We estimated our managed care rebates based on our estimated payer mix and the applicable contractual rebate rate</span>.</div>

<div><br/>
  </div>

<div style="text-align: justify; margin-left: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Trade discounts: </span><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">We provided customary invoice discounts on product sales to our U.S. customer for prompt payment. We recorded this discount as a reduction of product sales in the
      period in which we recognized the related product revenue</span>.</div>

<div><br/>
  </div>

<div style="text-align: justify; margin-left: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Distribution services</span>: <span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">We received and paid for various distribution services from our U.S. and European customers (prior to our agreement with Sobi) and wholesalers in the U.S. We
      classified the costs for services we received that are either not distinct from the sale of the product or for which we could not reasonably estimate the fair value as a reduction of product sales. To the extent that the services we received are
      distinct from the sale of the product, we classified the costs for such services as SG&amp;A expenses.</span></div>

<div><br/>
  </div>

<div style="text-align: justify; margin-left: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Product returns: </span><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">Our U.S. customer had return rights and the wholesalers had limited return rights primarily related to the product&#8217;s expiration date. We estimated the amount of
      product sales that our customer may return. We recorded our return estimate as an accrued refund liability on our consolidated balance sheet with a corresponding offset reducing our product sales in the same period we recognized the related sale.
      Based on our distribution model for product sales, contractual inventory limits with our customer and wholesalers and the price of the product, we had minimal returns. Our European customers generally only took title to the product after they
      received an order and therefore they did not maintain excess inventory levels of our products. Accordingly, we had limited return risk in Europe and we did not estimate returns in Europe</span>.</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: left; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;"><span style="text-decoration: underline;">Research and development revenue under collaboration agreements:</span></div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: left; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;"><span style="text-decoration: underline;">Upfront payments</span></div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">When we enter into a collaboration agreement
      with an upfront payment, we typically record the entire upfront payment as deferred revenue if our only performance obligation is for R&amp;D services we will provide in the future. We amortize the upfront payment into revenue as we perform the
      R&amp;D services. For example, under our collaboration agreement with Roche to</span><span style="background-color: #FBFBFB; font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> develop IONIS-FB-L</span><sub style="color: #000000;">Rx</sub><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> for the treatment of complement-mediated diseases, we received a $</span>75<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> million upfront payment in the fourth quarter of 2018. We allocated the upfront payment to our
      single performance obligation, R&amp;D services. We are amortizing the $</span>75<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> million upfront payment using an input method over the estimated period of time we are providing R&amp;D services</span>.</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;"><span style="text-decoration: underline;">Milestone payments</span></div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We are required to include additional consideration in the transaction price when it is probable. We typically
        include milestone payments for R&amp;D services in the transaction price when they are achieved. We include these milestone payments when they are achieved because typically there is considerable uncertainty in the research and development
        processes that trigger these payments. Similarly, we include approval milestone payments in the transaction price once the medicine is approved by the applicable regulatory agency. We will recognize sales-based milestone payments in the period in
        which we achieve the milestone under the sales-based royalty exception allowed under accounting rules.</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">We recognize milestone payments that relate
      to an ongoing performance obligation over our period of performance. For example, in the fourth quarter of 2021, we achieved a</span> $7.5&#160;<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">million milestone payment from Biogen when we advanced</span>&#160;<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">a </span>target
    under our 2018 strategic collaboration.<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> We added this payment to the transaction price and allocated it to our R&amp;D services performance obligation. We are
      recognizing revenue related to this milestone payment over our estimated period of performance</span>.</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Conversely, we recognize in full those milestone payments that we earn based on our partners&#8217; activities when our partner achieves the
    milestone event and we do not have a performance obligation. For example, in the fourth quarter of 2021, we recognized $15 million in milestone
    payments when Biogen advanced two targets under our 2018 strategic collaboration. <span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">We concluded that the milestone payments were not related to our R&amp;D services performance obligation. Therefore, we recognized the milestone payments in full in the fourth quarter of 2021.</span></div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;"><span style="text-decoration: underline;">License fees</span></div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">We generally recognize as revenue the total
      amount we determine to be the relative stand-alone selling price of a license when we deliver the license to our partner. This is because our partner has full use of the license and we do not have any additional performance obligations related to the
      license after delivery. For example, in the fourth quarter of 2021, we earned a</span> $60&#160;<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">million license fee from Biogen when Biogen licensed ION306, an investigational medicine in development to treat SMA.</span></div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;"><span style="text-decoration: underline;">Sublicense fees</span></div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">We recognize sublicense fee revenue in the
      period in which a party, who has already licensed our technology, further licenses the technology to another party because we do not have any performance obligations related to the sublicense. </span>For example, in the fourth quarter of 2020, we
    earned a $41.2 million sublicense fee from Alnylam Pharmaceuticals for its sublicense of our technology to Sanofi Genzyme.</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic; font-weight: bold;">Amendments to Agreements</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">From time to time we amend our collaboration agreements. When this occurs, we are required to assess the following items
    to determine the accounting for the amendment:</div>

<div><br/>
  </div>

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  <tr>

    <td style="width: 36pt;"/>

    <td style="width: 18pt; vertical-align: top; align: right; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">1)</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;">If the additional goods and/or services are distinct from the other performance obligations in the original agreement; and</div>
        </td>

  </tr>


</table>

<table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">


  <tr>

    <td style="width: 36pt;"/>

    <td style="width: 18pt; vertical-align: top; align: right; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">2)</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;">If the goods and/or services are at a stand-alone selling price.</div>
        </td>

  </tr>


</table>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">If we conclude the goods and/or services in the amendment are distinct from the performance obligations in the
        original agreement and at a stand-alone selling price, we account for the amendment as a separate agreement. If we conclude the goods and/or services are not distinct and are sold at a stand-alone selling price, we then assess whether the remaining
        goods or services are distinct from those already provided. If the goods and/or services are distinct from what we have already provided, then we allocate the remaining transaction price from the original agreement and the additional transaction
        price from the amendment to the remaining goods and/or services. If the goods and/or services are not distinct from what we have already provided, we update the transaction price for our single performance obligation and recognize any change in our
        estimated revenue as a cumulative adjustment.</div>

<div><br/>
    </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">For example, in May 2015, we entered into an exclusive license agreement with Bayer to develop and commercialize IONIS-FXI<sub>Rx</sub>
    for the prevention of thrombosis. As part of the agreement, Bayer paid us a $100 million upfront payment. At the onset of the agreement, we were
    responsible for completing a Phase 2 study of IONIS-FXI<sub>Rx</sub> in people with end-stage renal disease on hemodialysis and for providing an initial supply of API. In February 2017, we amended our agreement with Bayer to advance IONIS-FXI<sub>Rx</sub>
    and to initiate development of fesomersen, which Bayer licensed. As part of the 2017 amendment, Bayer paid us $75 million. We are also eligible
    to receive milestone payments and tiered royalties on gross margins of IONIS-FXI<sub>Rx</sub> and fesomersen. Under the 2017 amendment, we concluded we had a new agreement with three performance obligations. These performance obligations were to deliver the license of fesomersen, to provide R&amp;D services and to deliver API. We allocated the $75 million transaction price to these performance obligations. Refer to Note 6, <span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Collaborative Arrangements and Licensing Agreements</span>, for further discussion of the Bayer collaboration.</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic; font-weight: bold;">Multiple agreements</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">From time to time, we may enter into separate agreements at or near the same time with the same partner. We evaluate such
    agreements to determine whether we should account for them individually as distinct arrangements or whether the separate agreements should be combined and accounted for together. We evaluate the following to determine the accounting for the agreements:</div>

<div><br/>
  </div>

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  <tr>

    <td style="width: 36pt;"/>

    <td style="width: 18pt; vertical-align: top; align: right; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Whether the agreements were negotiated together with a single objective;</div>
        </td>

  </tr>


</table>

<table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">


  <tr>

    <td style="width: 36pt;"/>

    <td style="width: 18pt; vertical-align: top; align: right; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Whether the amount of consideration in one contract depends on the price or performance of the other agreement; or</div>
        </td>

  </tr>


</table>

<table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">


  <tr>

    <td style="width: 36pt;"/>

    <td style="width: 18pt; vertical-align: top; align: right; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Whether the goods and/or services promised under the agreements are a single performance obligation.</div>
        </td>

  </tr>


</table>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Our evaluation involves significant judgment to determine whether a group of agreements might be so closely related that accounting
    guidance requires us to account for them as a combined arrangement.</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">For example, in the second quarter of 2018, we entered into two separate agreements with Biogen at the same time: <span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">a new strategic neurology collaboration
      agreement and a stock purchase agreement, or SPA. We evaluated the Biogen agreements to determine whether we should treat the agreements separately or combine them. We considered that the agreements were negotiated concurrently and in contemplation
      of one another. Based on these facts and circumstances, we concluded that we should evaluate the provisions of the agreements on a combined basis.</span></div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: left; text-indent: -54pt; margin-left: 54pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Contracts Receivable</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">Our contracts receivable balance represents
      the amounts we have billed our partners or customers and that are due to us unconditionally for goods we have delivered or services we have performed. When we bill our partners or customers with payment terms based on the passage of time, we consider
      the contracts receivable to be unconditional. We typically receive payment within one </span><span style="-sec-ix-hidden:Fact_e2c2673a057f412ebd5831ca8712546a">quarter</span><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> of billing our partner or customer</span>.</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">As of December 31, 2021, approximately 93.8 percent of our contracts receivables were from two significant customers. As of December 31, 2020, approximately 99.5 percent of our contracts receivables were from two
    significant customers.</div>

<div><br/>
  </div>

<div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Unbilled SPINRAZA Royalties</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Our unbilled SPINRAZA royalties represent our right to receive consideration from Biogen in advance of when we are
    eligible to bill Biogen for SPINRAZA royalties. We include these unbilled amounts in other current assets on our consolidated balance sheet.</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: left; text-indent: -54pt; margin-left: 54pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Deferred Revenue</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">We are often entitled to bill our customers
      and receive payment from our customers in advance of our obligation to provide services or transfer goods to our partners. In these instances, we include the amounts in deferred revenue on our consolidated balance sheet.</span> During the years ended
    December 31, 2021 and 2020, we recognized $98.1 million and $100.4 million of revenue from amounts that were in our beginning deferred revenue balance for each respective period. For further discussion, refer to our revenue recognition policy above.</div>

<div><br/>
  </div>

<div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Cost of Sales</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Our cost of sales includes manufacturing costs, transportation and freight costs and indirect overhead costs associated with the
    manufacturing and distribution of our products. We also may include certain period costs related to manufacturing services and inventory adjustments in cost of sales. We also may include certain period costs related to manufacturing services and
    inventory adjustments in cost of sales.</div>

<div><br/>
  </div>

<div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Research, Development and Patent Expenses</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Our research and development expenses include wages, benefits, facilities, supplies, external
    services, clinical trial and manufacturing costs and other expenses that are directly related to our research and development operations. We expense research and development costs as we incur them. When we make payments for research and development
    services prior to the services being rendered, we record those amounts as prepaid assets on our consolidated balance sheet and we expense them as the services are provided. For the years ended December 31, 2021, 2020 and 2019, research and development expenses were $638.2 million, $531.0 million and $461.5 million, respectively. A
    portion of the costs included in research and development expenses are costs associated with our partner agreements.</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We capitalize costs consisting principally of outside legal costs and filing fees related to obtaining
    patents. We amortize patent costs over the useful life of the patent, beginning with the date the U.S. Patent and Trademark Office, or foreign equivalent, issues the patent. The weighted average remaining amortizable life of our issued patents was 10.2 years at December 31, 2021.</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">The cost of our patents capitalized on our consolidated balance sheet at December 31, 2021 and 2020 was $38.4 million and $37.0 million, respectively.
    Accumulated amortization related to patents was $9.4 million and $9.1 million at December 31, 2021 and 2020, respectively.</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Based on our existing patents, we estimate amortization expense related to patents in each of
    the next five years to be the following:</div>

<div><br/>
  </div>

<table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;">


  <tr>

    <td style="vertical-align: bottom; border-bottom: #000000 2px solid;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Year Ending December 31,</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Amortization</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">(in millions)</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 88%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="text-indent: 0pt;">2022</span></div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">2.2</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 88%;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="text-indent: 0pt;">2023</span></div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">2.1</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 88%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="text-indent: 0pt;">2024</span></div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">1.9</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 88%;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="text-indent: 0pt;">2025</span></div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">1.8</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 88%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="text-indent: 0pt;">2026</span></div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">1.8</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>


</table>

<div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 12pt;"><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We review our capitalized patent costs regularly to ensure that they include costs for patents and patent applications
    that have future value. When we identify patents and patent applications that we are not actively pursuing, we write off any associated costs. In 2021,
    2020 and 2019, patent expenses
    were $5.3 million, $4.1 million and $4.2 million, respectively, and included non-cash charges related to the write-down of our patent costs to their estimated net realizable values of $2.7 million, $1.9 million and $2.2 million, respectively.</div>

<div><br/>
  </div>

<div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Accrued Liabilities</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Our accrued liabilities consisted of the following (in thousands):</div>

<div><br/>
  </div>

<table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;">


  <tr>

    <td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">

        </td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="6" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">December 31,</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2021</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2020</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 76%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Clinical expenses</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">65,730</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">39,477</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 76%;" valign="bottom">
          <div style="text-align: left; text-indent: -18pt; margin-left: 18pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">In-licensing expenses</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">8,044</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">8,264</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 76%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: left; text-indent: -18pt; margin-left: 18pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Commercial expenses</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">2,471</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">11,559</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 76%; padding-bottom: 2px;" valign="bottom">
          <div style="text-align: left; text-indent: -18pt; margin-left: 18pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Other miscellaneous expenses</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">12,315</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">30,861</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 76%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Total accrued liabilities</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">88,560</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">90,161</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>


</table>

<div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 12pt;"><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: left; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;">Estimated Liability for Clinical Development Costs</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We have numerous medicines in preclinical studies and/or clinical trials at clinical sites throughout the world. On at least a quarterly
    basis, we estimate our liability for preclinical and clinical development costs we have incurred and services that we have received but for which we have not yet been billed and maintain an accrual to cover these costs. These costs primarily relate to
    third-party clinical management costs, laboratory and analysis costs, toxicology studies and investigator grants. We estimate our liability using assumptions about study and patient activities and the related expected expenses for those activities
    determined based on the contracted fees with our service providers. The assumptions we use represent our best estimates of the activity and expenses at the time of our accrual and involve inherent uncertainties and the application of our judgment. Upon
    settlement, these costs may differ materially from the amounts accrued in our consolidated financial statements. Our historical accrual estimates have not been materially different from our actual amounts.</div>

<div><br/>
  </div>

<div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Noncontrolling Interest in Akcea Therapeutics, Inc.</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">Since Akcea&#8217;s IPO in July 2017 and prior to
      the Akcea Merger in October 2020, the shares of Akcea&#8217;s common stock third parties owned represented an interest in Akcea&#8217;s equity that we did not control. During this period our ownership ranged from </span>68 percent<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> to </span>77 percent<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">. However, as we maintained overall control of Akcea through our voting interest, we
      reflected the assets, liabilities and results of operations of Akcea in our consolidated financial statements. Since Akcea&#8217;s IPO in July 2017 and through the closing of the Akcea Merger, we reflected the noncontrolling interest attributable to other
      owners of Akcea&#8217;s common stock on a separate line on our statement of operations and a separate line within stockholders&#8217; equity in our consolidated balance sheet. In addition, through the closing of the Akcea Merger, we recorded a noncontrolling
      interest adjustment to account for the stock options Akcea granted, which if exercised, would have diluted our ownership in Akcea. This adjustment was a reclassification within stockholders&#8217; equity from additional paid-in capital to noncontrolling
      interest in Akcea equal to the amount of stock-based compensation expense Akcea had recognized. Additionally, w</span>e reflected changes in our ownership percentage in our financial statements as an adjustment to noncontrolling interest in the
    period the change occurred.</div>

<div><br/>
  </div>

<div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Concentration of Credit Risk</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Financial instruments that potentially subject us to concentrations of credit risk consist primarily of cash equivalents,
    short-term investments and receivables. We place our cash equivalents and short-term investments with reputable financial institutions. We primarily invest our excess cash in commercial paper and debt instruments of the U.S. Treasury, financial
    institutions, corporations, and U.S. government agencies with strong credit ratings and an investment grade rating at or above A-1, P-1 or F-1 by Moody&#8217;s, Standard &amp; Poor&#8217;s, or S&amp;P, or Fitch, respectively. We have established guidelines
    relative to diversification and maturities that maintain safety and liquidity. We periodically review and modify these guidelines to maximize trends in yields and interest rates without compromising safety and liquidity.</div>

<div><br/>
  </div>

<div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Cash, Cash Equivalents and Investments</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We consider all liquid investments with maturities of three months or less when we purchase them to be cash equivalents.
    Our short-term investments have initial maturities of greater than three months from date of purchase. We classify our short-term debt investments as &#8220;available-for-sale&#8221; and carry them at fair market value based upon prices on the last day of the
    fiscal period for identical or similar items. We record unrealized gains and losses on debt securities as a separate component of comprehensive income (loss) and include net realized gains and losses in gain (loss) on investments in our consolidated
    statement of operations. We use the specific identification method to determine the cost of securities sold.</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We also have equity investments of less than 20 percent ownership in publicly and privately held biotechnology companies
      that we received as part of a technology license or partner agreement. At December 31, 2021, we held equity investments in three publicly held companies, Antisense Therapeutics Limited, or ATL, Bicycle Therapeutics plc, or Bicycle, and ProQR Therapeutics N.V., or ProQR. We
      also held equity investments in seven privately-held companies, Aro Biotherapeutics, Atlantic Pharmaceuticals Limited, Dynacure SAS, Empirico,
      Inc., Flamingo Therapeutics BV, YourBio Health, Inc. (formerly Seventh Sense Biosystems) and Suzhou-Ribo Life Science Co, Ltd.</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We are required to measure and record our equity investments at fair value and to recognize the changes in fair value in our consolidated
    statement of operations. We account for our equity investments in privately held companies at their cost minus impairments, plus or minus changes resulting from observable price changes in orderly transactions for the identical or similar investment of
    the same issuer. For example, d<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">uring 2020, we revalued our investments in </span>three<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> privately held companies, Dynacure, Suzhou-Ribo and Aro Biotherapeutics because the companies
      sold additional equity securities that were similar to the equity we own. As a result of these observable price changes, we recognized a $</span>6.3<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> million gain on our investment in Dynacure, a $</span>3.0<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> million gain on our investment in Suzhou-Ribo and a $</span>5.5<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> million gain on our investment in Aro Biotherapeutics in our consolidated statement of operations during 2020 because the sales were at higher prices compared to
      our recorded value.</span></div>

<div><br/>
  </div>

<div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Inventory Valuation</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We reflect our inventory on our consolidated balance sheet at the lower of cost or net realizable value under the first-in, first-out
    method, or FIFO. We capitalize the costs of raw materials that we purchase for use in producing our medicines because until we use these raw materials, they have alternative future uses, which we refer to as clinical raw materials. We include in
    inventory raw material costs for medicines that we manufacture for our partners under contractual terms and that we use primarily in our clinical development activities and drug products. We can use each of our raw materials in multiple products and,
    as a result, each raw material has future economic value independent of the development status of any single medicine. For example, if one of our medicines failed, we could use the raw materials for that medicine to manufacture our other medicines. We
    expense these costs as R&amp;D expenses when we begin to manufacture API for a particular medicine if the medicine has not been approved for marketing by a regulatory agency. Our raw materials- commercial inventory includes API for our commercial
    medicines. We capitalize material, labor and overhead costs as part of our raw materials- commercial inventory.</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We review our inventory periodically and reduce the carrying value of items we consider to be slow moving or obsolete to
    their estimated net realizable value based on forecasted demand compared to quantities on hand. We consider several factors in estimating the net realizable value, including shelf life of our inventory, alternative uses for our medicines in development
    and historical write-offs. We recorded an <span style="-sec-ix-hidden:Fact_df7c1770e27a4789b9f7ad5345f29256"><span style="-sec-ix-hidden:Fact_7ba6995a24424942b581829d4ed245cc">insignificant</span></span> amount of inventory write-offs during the years ended December 31, 2021 and 2020.</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Our inventory consisted of the following (in thousands):</div>

<div><br/>
  </div>

<table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;">


  <tr>

    <td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">

        </td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="6" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">December 31,</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2021</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2020</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom;" valign="bottom">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Raw materials:</div>
        </td>

    <td colspan="1" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 76%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 19.4pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Raw materials- clinical</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">14,507</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">9,206</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 76%; padding-bottom: 2px;" valign="bottom">
          <div style="text-align: justify; text-indent: -18pt; margin-left: 28.4pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Raw materials- commercial</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">4,139</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">7,502</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 76%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 28.45pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Total raw materials</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">18,646</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">16,708</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 76%;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Work in process</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">5,770</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">2,252</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 76%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Finished goods</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">390</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">3,005</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 76%; padding-bottom: 4px;" valign="bottom">
          <div style="text-align: justify; margin-left: 28.45pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Total inventory</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">24,806</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">21,965</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>


</table>

<div style="text-align: left;"><br/>
  </div>

<div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Property, Plant and Equipment</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We carry our property, plant and equipment at cost and depreciate it on the straight-line method
    over its estimated useful life, which consists of the following (in thousands):</div>

<div><br/>
  </div>

<table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;">


  <tr>

    <td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">

        </td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; white-space: nowrap;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Estimated Useful</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="6" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">December 31,</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Lives (in years)</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2021</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2020</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Computer software, laboratory, manufacturing and other equipment</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">3 to 10</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">72,802</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">68,990</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Building, building improvements and building systems</div>
        </td>

    <td colspan="1" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">15 to 40</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">144,046</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">137,879</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Land improvements</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="2" rowspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: rgb(0, 0, 0); font-family: 'Times New Roman',Times,serif; font-size: 10pt; text-align: center;">20</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">10,077</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">8,391</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Leasehold improvements</div>
        </td>

    <td colspan="1" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">5 to 15</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">20,144</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">17,263</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Furniture and fixtures</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">5 to 10</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">10,591</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">12,871</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 64%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">257,660</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">245,394</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Less accumulated depreciation</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(102,653</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(87,379</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 64%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">155,007</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">158,015</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Land</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">23,062</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">23,062</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 64%; padding-bottom: 4px;" valign="bottom">
          <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#160;Total</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">178,069</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">181,077</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>


</table>

<div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 12pt;"><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We depreciate our leasehold improvements using the shorter of the estimated useful life or remaining lease term.</div>

<div><br/>
  </div>

<div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Fair Value of Financial Instruments</div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt;"><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We have estimated the fair value of our financial instruments. The amounts reported for cash, accounts receivable,
    accounts payable and accrued expenses approximate the fair value because of their short maturities. We report our investment securities at their estimated fair value based on quoted market prices for identical or similar instruments.</div>

<div><br/>
  </div>

<div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Leases</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We determine if an arrangement contains a lease at inception. We currently only have operating leases. We recognize a
    right-of-use operating lease asset and associated short- and long-term operating lease liability on our consolidated balance sheet for operating leases greater than one year. Our right-of-use assets represent our right to use an underlying asset for
    the lease term and our lease liabilities represent our obligation to make lease payments arising from the lease arrangement. We recognize our right-of-use operating lease assets and lease liabilities based on the present value of the future minimum
    lease payments we will pay over the lease term.<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">&#160;</span>We determine the lease term at the inception of each lease, and in certain cases our lease term could
    include renewal options if we concluded we were reasonably certain that we will exercise the renewal option. When we exercise a lease option that was not previously included in the initial lease term, we reassess our right-of-use asset and lease
    liabilities for the new lease term.</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">As our leases do not provide an interest rate implicit in the lease, we used our incremental borrowing rate, based on the
    information available on the date we adopted Topic 842 (January 2019), as of the lease inception date or at the lease option extension date in determining the present value of future payments. We recognize rent expense for our minimum lease payments on
    a straight-line basis over the expected term of our lease. We recognize period expenses, such as common area maintenance expenses, in the period we incur the expense.</div>

<div><br/>
  </div>

<div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Long-Lived Assets</div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt;"><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We evaluate long-lived assets, which include property, plant and equipment and patent costs, for impairment on at least a
    quarterly basis and whenever events or changes in circumstances indicate that we may not be able to recover the carrying amount of such assets. We recorded charges of $2.7 million, $1.9 million and $2.2 million for the years ended December 31, 2021, 2020 and 2019, respectively, related to the
    write-down of patents.</div>

<div><br/>
  </div>

<div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Use of Estimates</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We prepare our consolidated financial statements in conformity with accounting principles generally accepted in the U.S.
    that require us to make estimates and assumptions that affect the amounts reported in our consolidated financial statements and accompanying notes. Actual results could differ from our estimates.</div>

<div><br/>
  </div>

<div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Stock-Based Compensation Expense</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We measure stock-based compensation expense for equity-classified awards, principally related to stock options, RSUs,
    PRSUs and stock purchase rights under our ESPP based on the estimated fair value of the award on the date of grant. We recognize the value of the portion of the award that we ultimately expect to vest as stock-based compensation expense over the
    requisite service period in our consolidated statements of operations. We reduce stock-based compensation expense for estimated forfeitures at the time of grant and revise in subsequent periods if actual forfeitures differ from those estimates. We use
    the Black-Scholes model to estimate the fair value of stock options granted and stock purchase rights under our ESPP.</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">On the grant date, we use our stock price and assumptions regarding a number of variables to determine the estimated fair
    value of stock-based payment awards. These variables include, but are not limited to, our expected stock price volatility over the term of the awards, and actual and projected employee stock option exercise behaviors. The expected term of stock options
    granted represents the period of time that we expect them to be outstanding. We estimate the expected term of options granted based on historical exercise patterns.</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We recognize compensation expense for stock options granted, RSUs, PRSUs and stock purchase rights under the ESPP using
    the accelerated multiple-option approach. Under the accelerated multiple-option approach (also known as the graded-vesting method), we recognize compensation expense over the requisite service period for each separately vesting tranche of the award as
    though the award were in substance multiple awards, which results in the expense being front-loaded over the vesting period.</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">In December 2020, we amended and restated the
      Akcea 2015 equity plan, including renaming the plan as the Ionis Pharmaceuticals, Inc. 2020 Equity Incentive Plan, or 2020 Plan. As a result, all employees are now under an Ionis stock plan and subject to the same Black-Scholes assumptions</span>.</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;">RSU&#8217;s:</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">The fair value of RSUs is based on the market price of our common stock on the date of grant. The RSUs we have granted to
    employees vest annually over a four-year period. The RSUs we granted to our board of directors prior to June 2020 vest annually over a four-year period. RSUs granted to our board of directors after June 2020 fully vest after one year.</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;">PRSU&#8217;s:</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Beginning in 2020, we added PRSU awards to the compensation for our Chief Executive Officer, Dr. Brett Monia. Under the
    terms of the grants, <span style="-sec-ix-hidden:Fact_65d15117ab79462e81dfb8bbb86a0107"><span style="-sec-ix-hidden:Fact_e9934b85c6af480197be8d0d8b5ea434"><span style="-sec-ix-hidden:Fact_5599af32346c4fce91fa6d27caf4b474">one third</span></span></span> of the PRSUs may vest at the end of three separate performance periods spread over the three years following the date of
    grant (i.e., the one-year period commencing on the date of grant and ending on the first anniversary of the date of grant; the two-year period commencing on the date of grant and ending on the second anniversary of the date of grant; and the three-year period commencing on the date of grant and ending on the third anniversary of the date of grant) based on our relative total shareholder return, or TSR, as compared to a
    peer group of companies, and as measured, in each case, at the end of the applicable performance period. Under the terms of the grants no number
    of PRSUs is guaranteed to vest and the actual number of PRSUs that will vest at the end of each performance period may be anywhere from zero to
    150 percent of the target number depending on our relative TSR.</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We determined the fair value of Dr. Monia&#8217;s PRSUs using a Monte Carlo model because the performance target is based on our
    relative TSR, which represents a market condition. We are recognizing the grant date fair value of these awards as stock-based compensation expense using the accelerated multiple-option approach over the vesting period. The weighted-average grant date
    fair value of PRSUs granted to Dr. Monia for the years ended December 31, 2021 and 2020 were $77.17 and $93.09 per share, respectively.</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">See Note 4, <span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Stockholders&#8217;
      Equity,</span> for additional information regarding our stock-based compensation plans.</div>

<div><br/>
  </div>

<div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Accumulated Other Comprehensive Loss</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 12pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Accumulated
      other comprehensive loss is comprised of unrealized gains and losses on investments, net of taxes and currency translation adjustments. The following table summarizes changes in accumulated other comprehensive loss for the years ended December 31, 2021, 2020 and 2019 (in thousands):</span></div>

<div style="text-align: justify;"><br/>
  </div>

<table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;">


  <tr>

    <td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">

        </td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="10" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Year Ended December 31,</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2021</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2020</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2019</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Beginning balance accumulated other comprehensive loss</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(21,071</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(25,290</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(32,016</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 64%;" valign="bottom">
          <div style="text-align: left; text-indent: -9pt; margin-left: 18pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Unrealized gains (losses) on securities, net of tax (1)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(11,486</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">3,729</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">6,633</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: left; text-indent: -9pt; margin-left: 18pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Currency translation adjustment</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(111</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">617</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">93</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 64%; padding-bottom: 2px;" valign="bottom">
          <div style="text-align: left; text-indent: -9pt; margin-left: 18pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Adjustments to other comprehensive loss from purchase of noncontrolling interest of Akcea
            Therapeutics, Inc.</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#8212;</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(127</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#8212;</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Net other comprehensive loss for the period</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(11,597</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">4,219</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">6,726</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 64%; padding-bottom: 4px;" valign="bottom">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Ending balance accumulated other comprehensive loss</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(32,668</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(21,071</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(25,290</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

  </tr>


</table>

<div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">________________</div>

<div>
    <table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">


  <tr>

    <td style="width: 18pt; vertical-align: top; align: right;">
            <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(1)</div>
          </td>

    <td style="width: auto; vertical-align: top;">
            <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We did not have tax expense included in our other comprehensive loss for the years ended December 31, 2021 and 2020. For the year ended December 31,
              2019, we had a tax benefit of $1.4
              million included in other comprehensive loss.&#160;</div>
          </td>

  </tr>


</table>
    </div>

<div><br/>
  </div>

<div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Convertible Debt</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;">Adoption of ASU 2020-06</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">In August 2020, the FASB issued ASU 2020-06, which simplifies the accounting for convertible debt instruments, amends the
    guidance on derivative scope exceptions for contracts in an entity&#8217;s own equity, and modifies the guidance on diluted earnings per share calculations. We adopted ASU 2020-06 on January 1, 2021 under the full retrospective approach, which required us to
    revise our prior period financial statements. This guidance impacted our accounting for outstanding convertible debt. At January 1, 2021, we had two
    outstanding convertible notes, our 0.125% Notes, which mature in December 2024, and our 1% Notes, which matured in November 2021. In April 2021, we completed a $632.5 million
    offering of 0% Notes primarily to repurchase a majority of our 1% Notes. We accounted for our 0% Notes under ASU 2020-06 at issuance. Refer to Note
    3, <span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Long-Term Obligations and Commitments</span>, for further information.</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">The updated guidance eliminates the cash conversion accounting model we previously followed in Accounting Standard
    Codification, or ASC, 470-20, which required us to separate each of our convertible debt instruments at issuance into two units of accounting, a liability component, based on our nonconvertible debt borrowing rate at issuance, and an equity component.
    Under ASU 2020-06, we now account for each of our convertible debt instruments as a single unit of accounting, a liability, because we concluded that the conversion features do not require bifurcation as a derivative under ASC 815-15 and we did not
    issue our convertible debt instruments at a substantial premium. Since we adopted ASU 2020-06 using the full retrospective approach, we were required to apply the guidance to all convertible debt instruments we had outstanding as of January 1, 2019. We
    recomputed the basis of each convertible debt instrument as if we accounted for each as a single unit of accounting at issuance. This update included recalculating the amortization of debt issuance costs using an updated effective interest rate. As a
    result of adopting ASU 2020-06, we recorded a cumulative adjustment to decrease our additional paid in capital and our accumulated deficit at January 1, 2019. We have updated these financial statements to reflect the cumulative adjustment for the
    periods presented. We have labeled our prior period financial statements &#8220;as revised&#8221; to indicate the change required under the new accounting guidance. Below is a summary of the change in our balance sheet at December 31, 2020 and statement of
    operations from the years ended December 31, 2020 and 2019 under the ASC 470-20 legacy guidance compared to the new ASU 2020-06 guidance we adopted:</div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt;"><br/>
  </div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">The following table summarizes the adjustments we made to the consolidated balance sheet we
    originally reported at December 31, 2020 to adopt ASU 2020-06 (in thousands):</div>

<div><br/>
  </div>

<table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;">


  <tr>

    <td style="vertical-align: top; padding-bottom: 2px;" valign="bottom">

        </td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="10" style="vertical-align: top; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">December 31, 2020</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: top; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">As Previously</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Reported</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">ASU 2020-06</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Adjustment</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">As Revised</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: top; width: 64%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">1 percent convertible
            senior notes</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">293,161</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">15,648</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">308,809</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: top; width: 64%;" valign="bottom">
          <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">0.125 percent convertible
            senior notes</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">455,719</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">84,417</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">540,136</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: top; width: 64%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Additional paid-in-capital</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">2,113,646</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(218,127</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">1,895,519</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: top; width: 64%;" valign="bottom">
          <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Accumulated deficit</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(1,249,368</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">118,062</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(1,131,306</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

  </tr>


</table>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#160;<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">Under ASU 2020-06, our revised
      ending balances for our </span>1%<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> Notes and </span>0.125%<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> Notes as of December 31, 2020 represent the principal
      balance of each convertible debt instrument less debt issuance costs. Additionally, because we have deferred tax assets related to our convertible debt instruments, we also adjusted these amounts as part of our adoption of ASU 2020-06. However,
      because we have a full valuation allowance on our deferred tax assets, there was </span>no<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> impact to our consolidated balance sheet related to our deferred tax assets.</span></div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#160;<span style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; color: #000000;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">The following
      tables summarize the adjustments we made to the consolidated statement of operations we originally reported for the years ended December 31, 2020 and 2019 to adopt ASU 2020-06 (in thousands):</span></span></div>

<div><br/>
  </div>

<table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;">


  <tr>

    <td style="vertical-align: top; padding-bottom: 2px;" valign="bottom">

        </td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="10" style="vertical-align: top; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Year Ended December 31, 2020</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: top; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">As Previously</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Reported</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">ASU 2020-06</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Adjustment</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">As Revised</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: top; width: 64%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Interest expense</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(44,990</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">35,480</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(9,510</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

  </tr>

  <tr>

    <td style="vertical-align: top; width: 64%;" valign="bottom">
          <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Loss before income tax expense</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(170,032</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">35,480</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(134,552</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

  </tr>

  <tr>

    <td style="vertical-align: top; width: 64%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Income tax expense</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(316,734</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(28,457</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(345,191</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

  </tr>

  <tr>

    <td style="vertical-align: top; width: 64%;" valign="bottom">
          <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Net loss</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(486,766</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">7,023</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(479,743</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

  </tr>

  <tr>

    <td style="vertical-align: top; width: 64%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Net loss attributable to Ionis Pharmaceuticals, Inc. common stockholders</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(451,286</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">7,023</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(444,263</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

  </tr>

  <tr>

    <td style="vertical-align: top; width: 64%;" valign="bottom">
          <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Basic and diluted net loss per share</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(3.23</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">0.05</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(3.18</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

  </tr>


</table>

<div><br/>
  </div>

<table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;">


  <tr>

    <td style="vertical-align: top; padding-bottom: 2px;" valign="bottom">

        </td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="10" style="vertical-align: top; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Year Ended December 31, 2019</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: top; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">As Previously</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Reported</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">ASU 2020-06</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Adjustment</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">As Revised</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: top; width: 64%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Interest expense</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(48,768</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">36,328</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(12,440</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

  </tr>

  <tr>

    <td style="vertical-align: top; width: 64%;" valign="bottom">
          <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Loss on early retirement of debt</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(21,865</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(44,331</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(66,196</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

  </tr>

  <tr>

    <td style="vertical-align: top; width: 64%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Income before income tax benefit (expense)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">346,769</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(8,003</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">338,766</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: top; width: 64%;" valign="bottom">
          <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Income tax expense</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(43,507</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(8,000</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(51,507</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

  </tr>

  <tr>

    <td style="vertical-align: top; width: 64%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Net income</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">303,262</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(16,003</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">287,259</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: top; width: 64%;" valign="bottom">
          <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Net income attributable to Ionis Pharmaceuticals, Inc. common stockholders</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">294,146</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(16,003</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">278,143</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: top; width: 64%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Basic net income per share</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">2.12</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(0.12</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">2.00</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: top; width: 64%;" valign="bottom">
          <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Diluted net income per share</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">2.08</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(0.18</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">1.90</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>


</table>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Under ASU 2020-06, our revised interest expense is lower because we are no longer recording non-cash
    interest expense related to a debt discount. This decrease was partially offset by the increase in interest expense related to the amortization of debt issuance costs because we no longer allocate a portion of our debt issuance costs to stockholders&#8217;
    equity at issuance. Instead, the entire debt issuance costs were recorded as a contra-liability on our consolidated balance sheet at issuance and we are amortizing them over the contractual term using an updated effective interest rate. Our updated
    effective interest rates for our 1% Notes and 0.125%
    Notes were 1.4 percent and 0.5 percent,
    respectively.</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">The following tables summarize the adjustments we made to our consolidated statements of
    stockholders&#8217; equity we originally reported at December 31, 2020 and 2019 to adopt ASU 2020-06 (in thousands):</div>

<div><br/>
  </div>

<table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;">


  <tr>

    <td style="vertical-align: top; padding-bottom: 2px;" valign="bottom">

        </td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="10" style="vertical-align: top; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">December 31, 2020</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: top; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">As Previously</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Reported</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">ASU 2020-06</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Adjustment</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">As Revised</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: top; width: 64%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Additional paid-in-capital</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">2,113,646</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(218,127</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">1,895,519</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: top; width: 64%;" valign="bottom">
          <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Accumulated deficit</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(1,249,368</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">118,062</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(1,131,306</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

  </tr>

  <tr>

    <td style="vertical-align: top; width: 64%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Total stockholders&#8217; equity</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">843,347</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(100,065</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">743,282</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>


</table>

<div><br/>
  </div>

<table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;">


  <tr>

    <td style="vertical-align: top; padding-bottom: 2px;" valign="bottom">

        </td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="10" style="vertical-align: top; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">December 31, 2019</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: top; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">As Previously</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Reported</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">ASU 2020-06</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Adjustment</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">As Revised</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: top; width: 64%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Additional paid-in-capital</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">2,203,778</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(218,128</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">1,985,650</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: top; width: 64%;" valign="bottom">
          <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Accumulated deficit</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(707,534</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">111,039</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(596,495</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

  </tr>

  <tr>

    <td style="vertical-align: top; width: 64%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Total stockholders&#8217; equity</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">1,684,547</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(107,088</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">1,577,459</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>


</table>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt;"><br/>
  </div>

<div><br/>
  </div>

<div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Call Spread</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">In conjunction with the issuance of our 0% Notes and 0.125% Notes in April 2021 and December 2019, respectively, we entered
    into call spread transactions, which were comprised of purchasing note hedges and selling warrants. We account for the note hedges and warrants as separate freestanding financial instruments and treat each instrument as a separate unit of accounting.
    We determined that the note hedges and warrants do not meet the definition of a liability using the guidance contained in ASC Topic 480; therefore, we account for the note hedges and warrants using the Derivatives and Hedging &#8211; Contracts in Entity&#8217;s
    Own Equity accounting guidance contained in ASC Topic 815. We determined that the note hedges and warrants meet the definition of a derivative, are indexed to our stock and meet the criteria to be classified in shareholders&#8217; equity. We recorded the
    aggregate amount paid for the note hedges and the aggregate amount received for the warrants as additional paid-in capital in our consolidated balance sheet. We reassess our ability to continue to classify the note hedges and warrants in shareholders&#8217;
    equity at each reporting period.</div>

<div><br/>
  </div>

<div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Segment Information</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">In 2021, we began operating as a single segment, Ionis operations, because our chief decision maker reviews operating
    results on an aggregate basis and manages our operations as a <span style="-sec-ix-hidden:Fact_33bc30118e9548358994c912eadf2161">single</span> operating segment. Previously, we had operated as two operating segments, Ionis Core and Akcea Therapeutics. We completed the Akcea Merger in October 2020 and fully integrated Akcea&#8217;s operations into ours
    as of January 1, 2021<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">.</span></div>

<div><br/>
  </div>

<div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Fair Value Measurements</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We use a three-tier fair value hierarchy to prioritize the inputs used in our fair value measurements. These tiers
    include: Level 1, defined as observable inputs such as quoted prices in active markets for identical assets, which includes our money market funds and treasury securities classified as available-for-sale securities and our investment in equity
    securities in publicly held biotechnology companies; Level 2, defined as inputs other than quoted prices in active markets that are either directly or indirectly observable, which includes our fixed income securities and commercial paper classified as
    available-for-sale securities; and Level 3, defined as unobservable inputs in which little or no market data exists, therefore requiring us to develop our own assumptions. We classify most of our securities as Level 2. We obtain the fair value of our
    Level 2 investments from our custodian bank or from a professional pricing service. We validate the fair value of our Level 2 investments by understanding the pricing model used by the custodian banks or professional pricing service provider and
    comparing that fair value to the fair value based on observable market prices.</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">The following tables present the major security types we held at December 31, 2021 and 2020&#160;<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">that we regularly measure and carry at fair value</span>. As of December 31, 2021, our Bicycle investment was subject to trading restrictions that extend to the third quarter of 2022; as
    a result, we included a lack of marketability discount in valuing this investment, which is a Level 3 input. As of December 31, 2020, we did not
    have any investments that we valued using Level 3 inputs. The following tables segregate each security type by the level within the fair value hierarchy of the valuation techniques we utilized to determine the respective securities&#8217; fair value (in
    thousands):</div>

<div><br/>
  </div>

<table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;">


  <tr>

    <td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">At</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">December 31, 2021</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Quoted Prices in</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Active Markets</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">(Level 1)</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Significant Other</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Observable Inputs</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">(Level 2)</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Significant</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Unobservable Inputs</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">(Level 3)</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 52%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Cash equivalents (1)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">541,199</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">541,199</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#8212;</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#8212;</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 52%;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Corporate debt securities (2)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">764,059</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#8212;</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">764,059</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#8212;</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 52%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Debt securities issued by U.S. government agencies (2)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">120,868</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#8212;</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">120,868</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#8212;</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 52%;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Debt securities issued by the U.S. Treasury (2)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">182,634</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">182,634</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#8212;</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#8212;</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 52%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Debt securities issued by states of the U.S. and political subdivisions of the states (3)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">174,464</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#8212;</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">174,464</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#8212;</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 52%;" valign="bottom">
          <div>
            <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Other municipal debt securities (2)</div>
          </div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">6,099</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#8212;</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">6,099</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#8212;</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 52%; background-color: #CCEEFF;" valign="bottom">
          <div>
            <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Investment in Bicycle Therapeutics plc (4)</div>
          </div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">14,330</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#8212;</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#8212;</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">14,330</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 52%; padding-bottom: 2px;" valign="bottom">
          <div>
            <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Investment in ProQR Therapeutics N.V. (4)</div>
          </div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">3,875</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">3,875</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#8212;</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#8212;</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 52%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; text-indent: -8.9pt; margin-left: 22.55pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Total</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">1,807,528</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">727,708</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">1,065,490</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">14,330</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>


</table>

<div><br/>
  </div>

<table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;">


  <tr>

    <td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">

        </td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">At</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">December 31, 2020</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Quoted Prices in</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Active Markets</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">(Level 1)</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Significant Other</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Observable Inputs</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">(Level 2)</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Cash equivalents (1)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">221,125</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">221,125</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#8212;</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 64%;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Corporate debt securities (5)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">846,315</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#8212;</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">846,315</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Debt securities issued by U.S. government agencies (2)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">174,861</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#8212;</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">174,861</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 64%;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Debt securities issued by the U.S. Treasury (6)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">358,497</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">358,497</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#8212;</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Debt securities issued by states of the U.S. and political subdivisions of the states (2)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">136,309</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#8212;</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">136,309</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 64%;" valign="bottom">
          <div>
            <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Other municipal debt securities (2)</div>
          </div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">6,225</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#8212;</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">6,225</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">
          <div>
            <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Investment in ProQR Therapeutics N.V. (4)</div>
          </div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">2,031</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">2,031</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#8212;</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 64%; padding-bottom: 4px;" valign="bottom">
          <div style="text-align: justify; text-indent: -8.9pt; margin-left: 22.55pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Total</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">1,745,363</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">581,653</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">1,163,710</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>


</table>

<div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">________________</div>

<table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">


  <tr>

    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(1)</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Included in cash and cash
            equivalents on our consolidated balance sheet.</div>
        </td>

  </tr>


</table>

<div><br/>
  </div>

<table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">


  <tr>

    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(2)</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Included in short-term
            investments.</div>
        </td>

  </tr>


</table>

<div><br/>
  </div>

<table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">


  <tr>

    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(3)</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$2.3 million included in cash and cash equivalents on our consolidated balance sheet, with the difference included in short-term investments on our
            consolidated balance sheet.</div>
        </td>

  </tr>


</table>

<div><br/>
  </div>

<table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">


  <tr>

    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(4)</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Included in other current assets
            on our consolidated balance sheet.</div>
        </td>

  </tr>


</table>

<div><br/>
  </div>

<table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">


  <tr>

    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(5)</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$10.0 million included in cash and cash equivalents on our consolidated balance sheet, with the difference included in short-term investments on our
            consolidated balance sheet.</div>
        </td>

  </tr>


</table>

<div><br/>
  </div>

<table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">


  <tr>

    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(6)</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$17.5 million included in cash and cash equivalents on our consolidated balance sheet, with the difference included in short-term investments on our
            consolidated balance sheet.</div>
        </td>

  </tr>


</table>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;">Convertible Notes</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Our 0.125% Notes and 0% Notes had a fair value of $495.4 million and $559.2 million at December 31, 2021, respectively. We determine the fair value of our notes based on quoted market prices for these notes, which are Level 2
    measurements because the notes do not trade regularly.</div>

<div><br/>
  </div>

<div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Income Taxes</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We account for income taxes using the asset and liability method, which requires the recognition of deferred tax assets and liabilities
    for the expected future tax consequences of events that have been recognized in our financial statements or tax returns. In addition, deferred tax assets are recorded for the future benefit of utilizing net operating losses and research and development
    credit carryforwards. We record a valuation allowance when necessary to reduce our net deferred tax assets to the amount expected to be realized.</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We apply the authoritative accounting guidance prescribing a threshold and measurement attribute for the financial recognition and
    measurement of a tax position taken or expected to be taken in a tax return. We recognize liabilities for uncertain tax positions based on a two-step process. The first step is to evaluate the tax position for recognition by determining if the weight
    of available evidence indicates that it is more likely than not that the position will be sustained on audit, including resolution of related appeals or litigation processes, if any. The second step requires us to estimate and measure the tax benefit
    as the largest amount that is more than 50 percent likely to be realized upon ultimate settlement.</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We are required to use significant judgment in evaluating our uncertain tax positions and determining our provision for income taxes.
    Although we believe our reserves are reasonable, no assurance can be given that the final tax outcome of these matters will not be different from that which is reflected in our historical income tax provisions and accruals. We adjust these reserves for
    changing facts and circumstances, such as the closing of a tax audit or the refinement of an estimate. To the extent that the final tax outcome of these matters is different than the amounts recorded, such differences may impact the provision for
    income taxes in the period in which such determination is made.</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We are also required to use significant judgment in determining any valuation allowance recorded against our deferred tax assets. In
    assessing the need for a valuation allowance, we consider all available evidence, including scheduled reversal of deferred tax liabilities, past operating results, the feasibility of tax planning strategies and estimates of future taxable income. We
    base our estimates of future taxable income on assumptions that are consistent with our plans. The assumptions we use represent our best estimates and involve inherent uncertainties and the application of our judgment. Should actual amounts differ from
    our estimates, the amount of our tax expense and liabilities we recognize could be materially impacted. We record a valuation allowance to reduce the balance of our net deferred tax assets to the amount we believe is more-likely-than-not to be
    realized.</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We do not provide for a U.S. income tax liability and foreign withholding taxes on undistributed foreign earnings of our foreign
    subsidiaries.</div>

<div><br/>
  </div>

<div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Impact of Recently Issued Accounting Standards</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">As disclosed in the &#8220;Convertible Debt&#8221; policy above within this footnote, we adopted the simplified accounting for
    convertible debt instrument guidance (ASU 2020-06) on January 1, 2021. Refer to the section above for the impact of adoption. We do not expect any other recently issued accounting standards to have a material impact to our financial results.</div>
<span></span>
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<span style="display: none;">v3.22.0.1</span><table class="report" border="0" cellspacing="2" id="idm139691008461080">
<tr>
<th class="tl" colspan="1" rowspan="2"><div style="width: 200px;"><strong>Investments<br></strong></div></th>
<th class="th" colspan="1">12 Months Ended</th>
</tr>
<tr><th class="th"><div>Dec. 31, 2021</div></th></tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_InvestmentsAbstract', window );"><strong>Investments [Abstract]</strong></a></td>
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<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_InvestmentTextBlock', window );">Investments</a></td>
<td class="text">
<div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2. Investments</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">The following table summarizes the contract maturity of the available-for-sale securities we held as of
    December 31, 2021:</div>

<div><br/>
  </div>

<table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;">


  <tr>

    <td style="vertical-align: bottom; width: 88%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="text-indent: 0pt;">One year</span> or less</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">51</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">%</div>
        </td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 88%; background-color: #FFFFFF;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">After <span style="text-indent: 0pt;">one year</span> but within <span style="text-indent: 0pt;">two years</span></div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">34</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">%</div>
        </td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 88%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">After <span style="text-indent: 0pt;">two years</span> but within <span style="text-indent: 0pt;"><span style="-sec-ix-hidden:Fact_5b50da2d62974df399b2ebfcfccf0c30">three and a half years</span></span></div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">15</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">%</div>
        </td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 88%; padding-bottom: 4px; background-color: #FFFFFF;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Total</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">100</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">%</div>
        </td>

  </tr>


</table>

<div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 12pt;"><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">As illustrated above, at December 31, 2021, 85 percent of our available-for-sale securities had a maturity of less than two years.</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">All of our available-for-sale securities are available to us for use in our current operations. As a result, we categorize
    all of these securities as current assets even though the stated maturity of some individual securities may be one year or more beyond the balance sheet date.</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">At December 31, 2021,
    we had an ownership interest of less than 20 percent <span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">in seven
      private companies and three public companies with which we conduct business. The privately-held companies are </span>Aro Biotherapeutics,
    Atlantic Pharmaceuticals Limited, Dynacure SAS, Empirico, Inc., Flamingo Therapeutics BV, YourBio Health, Inc. and Suzhou-Ribo Life Science Co, Ltd. The publicly traded companies are Antisense Therapeutics Ltd., Bicycle and ProQR.</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">The following is a summary of our investments (in thousands):</div>

<div><br/>
  </div>

<table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;">


  <tr>

    <td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">

        </td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Amortized</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="6" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Gross Unrealized</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Estimated</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">December 31, 2021</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"> Cost</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Gains</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Losses</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Fair Value</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom;" valign="bottom">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Available-for-sale securities:</div>
        </td>

    <td colspan="1" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 52%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Corporate debt securities (1)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">383,870</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">728</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(226</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">384,372</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 52%; background-color: #FFFFFF;" valign="bottom">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Debt securities issued by U.S. government agencies</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">48,493</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">19</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(18</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">48,494</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 52%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Debt securities issued by the U.S. Treasury (1)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">45,424</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#8212;</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(64</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">45,360</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 52%; padding-bottom: 2px; background-color: #FFFFFF;" valign="bottom">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Debt securities issued by states of the U.S. and political subdivisions of the states</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">134,770</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">45</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(37</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">134,778</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 52%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Total securities with a maturity of one year or less</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">612,557</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">792</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">
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    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">613,004</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 52%; background-color: #FFFFFF;" valign="bottom">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Corporate debt securities</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">382,000</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">331</div>
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    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(2,644</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">379,687</div>
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    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 52%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Debt securities issued by U.S. government agencies</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">72,935</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#8212;</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(561</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">72,374</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 52%; background-color: #FFFFFF;" valign="bottom">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Debt securities issued by the U.S. Treasury</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">137,635</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">139</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(500</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">137,274</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 52%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Debt securities issued by states of the U.S. and political subdivisions of the states</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">39,909</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">1</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(224</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">39,686</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 52%; padding-bottom: 2px; background-color: #FFFFFF;" valign="bottom">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Other municipal debt securities</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">6,136</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#8212;</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(37</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">6,099</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 52%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Total securities with a maturity of more than one year</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">638,615</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">471</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(3,966</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">635,120</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 52%; padding-bottom: 2px; background-color: #FFFFFF;" valign="bottom">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Total available-for-sale securities</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">1,251,172</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">1,263</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(4,311</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">1,248,124</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 52%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Equity securities:</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 52%; background-color: #FFFFFF;" valign="bottom">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Total equity securities included in other current assets (2)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">11,897</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">7,145</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(837</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">18,205</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 52%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Total equity securities included in deposits and other assets (3)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">15,615</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">16,707</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#8212;</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">32,322</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 52%; padding-bottom: 2px; background-color: #FFFFFF;" valign="bottom">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Total equity securities</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">27,512</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">23,852</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(837</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">50,527</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 52%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Total available-for-sale and equity securities</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">1,278,684</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">25,115</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(5,148</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">1,298,651</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>


</table>

<div><br/>
  </div>

<table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;">


  <tr>

    <td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">

        </td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Amortized</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="6" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Gross Unrealized</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Estimated</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">December 31, 2020</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"> Cost</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Gains</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Losses</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Fair Value</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom;" valign="bottom">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Available-for-sale securities:</div>
        </td>

    <td colspan="1" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 52%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Corporate debt securities (1)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">514,182</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">2,194</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(41</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">516,335</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 52%; background-color: #FFFFFF;" valign="bottom">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Debt securities issued by U.S. government agencies</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">94,234</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">354</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(2</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">94,586</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 52%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Debt securities issued by the U.S. Treasury (1)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">307,576</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">233</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(9</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">307,800</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 52%; background-color: #FFFFFF;" valign="bottom">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Debt securities issued by states of the U.S. and political subdivisions of the states</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">104,271</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">196</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(12</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">104,455</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 52%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Other municipal debt securities</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">5,191</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#8212;</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(7</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">5,184</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 52%; padding-bottom: 2px; background-color: #FFFFFF;" valign="bottom">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Total securities with a maturity of one year or less</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">1,025,454</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">2,977</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(71</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">1,028,360</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 52%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Corporate debt securities</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">325,079</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">4,941</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(40</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">329,980</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 52%; background-color: #FFFFFF;" valign="bottom">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Debt securities issued by U.S. government agencies</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">80,099</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">185</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(9</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
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    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">80,275</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 52%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Debt securities issued by the U.S. Treasury</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">50,318</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">383</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(4</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">50,697</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 52%; background-color: #FFFFFF;" valign="bottom">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Debt securities issued by states of the U.S. and political subdivisions of the states</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">31,779</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">91</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(16</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">31,854</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 52%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Other municipal debt securities</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">1,041</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#8212;</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#8212;</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">1,041</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 52%; padding-bottom: 2px; background-color: #FFFFFF;" valign="bottom">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Total securities with a maturity of more than one year</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">488,316</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">5,600</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(69</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">493,847</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 52%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Total available-for-sale securities</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">1,513,770</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">8,577</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(140</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">1,522,207</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 52%; background-color: #FFFFFF;" valign="bottom">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Equity securities:</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 52%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Total equity securities included in other current assets (2)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">4,712</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#8212;</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(2,681</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">2,031</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 52%; padding-bottom: 2px; background-color: #FFFFFF;" valign="bottom">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Total equity securities included in deposits and other assets (3)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">15,062</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">15,938</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#8212;</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">31,000</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 52%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Total equity securities</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">19,774</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">15,938</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(2,681</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">33,031</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 52%; padding-bottom: 4px; background-color: #FFFFFF;" valign="bottom">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Total available-for-sale and equity securities</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">1,533,544</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">24,515</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(2,821</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">1,555,238</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>


</table>

<div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">________________</div>

<table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">


  <tr>

    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(1)</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Includes investments classified
            as cash equivalents on our consolidated balance sheet.</div>
        </td>

  </tr>


</table>

<div><br/>
  </div>

<table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">


  <tr>

    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(2)</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Our equity securities included in other current
            assets consisted of our investments in publicly traded companies. We recognize publicly traded equity securities at fair value.</div>
        </td>

  </tr>


</table>

<div><br/>
  </div>

<table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">


  <tr>

    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(3)</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">Our equity securities included in deposits and other assets consisted of our investments in privately held companies. We recognize our private company equity securities at</span> cost minus
            impairments, plus or minus changes resulting from observable price changes in orderly transactions for the identical or similar investment of the same issuer<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> on our consolidated balance sheet.</span></div>
        </td>

  </tr>


</table>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">The following is a summary of our investments we
      considered to be temporarily impaired at&#160;</span>December 31, 2021<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">&#160;(in thousands). All of these investments have less than 12 months of temporary impairment. We believe that the decline in value of these securities is temporary and is primarily related to the change in market interest rates since
      purchase. We believe it is more likely than not that we will be able to hold our debt securities to maturity. Therefore, we anticipate full recovery of our debt securities&#8217; amortized cost basis at maturity.</span></div>

<div><br/>
  </div>

<table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;">


  <tr>

    <td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">

        </td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Number of</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Investments</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Estimated</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Fair Value</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Unrealized</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Losses</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Corporate debt securities</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">272</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">552,966</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(2,870</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 64%;" valign="bottom">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Debt securities issued by U.S. government agencies</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">15</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">114,338</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(579</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Debt securities issued by the U.S. Treasury</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">13</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">134,987</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(564</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 64%;" valign="bottom">
          <div style="text-align: left; text-indent: -11.2pt; margin-left: 11.2pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Debt securities issued by states of the U.S. and political subdivisions of the states</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">425</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

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    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">126,401</div>
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    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(261</div>
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    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">2</div>
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    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">6,099</div>
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    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(37</div>
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    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
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    <td style="vertical-align: bottom; width: 64%; padding-bottom: 4px;" valign="bottom">
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    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" valign="bottom">&#160;</td>

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          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">727</div>
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    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" valign="bottom">
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          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">934,791</div>
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    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" valign="bottom">&#160;</td>

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          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(4,311</div>
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    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
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<th class="tl" colspan="1" rowspan="2"><div style="width: 200px;"><strong>Long-Term Obligations and Commitments<br></strong></div></th>
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<div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">3. Long-Term Obligations and Commitments</div>

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<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">The carrying value of our long-term obligations was as follows (in thousands):</div>

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  <tr>

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    <td colspan="1" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom;" valign="bottom">&#160;</td>

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          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">542,314</div>
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    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
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    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">540,136</div>
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    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

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          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="text-indent: 0pt;">1 percent</span> convertible senior notes (1)</div>
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    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

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    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">308,809</div>
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    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 76%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="text-indent: 0pt;">0 percent</span> convertible senior notes</div>
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    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">619,119</div>
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    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#8212;</div>
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    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 76%;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Long-term mortgage debt</div>
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    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">59,713</div>
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    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">59,984</div>
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    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 76%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Leases and other obligations</div>
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    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">29,904</div>
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    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">30,710</div>
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    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 76%;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Total</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">1,251,050</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">939,639</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 76%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Less: current portion (1)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(3,526</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(316,110</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 76%; padding-bottom: 4px;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 18pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Total Long-Term Obligations</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">1,247,524</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">623,529</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>


</table>

<div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">________________</div>

<table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">


  <tr>

    <td style="width: 18pt; vertical-align: top; align: right; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(1)</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We classified the carrying value of
            our 1% Notes as a current liability on our consolidated balance sheet at December 31, 2020 because it matured in November 2021.</div>
        </td>

  </tr>


</table>

<div><br/>
  </div>

<table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">


  <tr>

    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">*</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We revised our 2020 amounts to reflect the simplified convertible instruments accounting guidance, which we adopted retrospectively. Refer to Note 1, <span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Organization and Significant Accounting Policies</span>, for further information.</div>
        </td>

  </tr>


</table>

<div><br/>
  </div>

<div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Convertible Debt and Call Spread</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;">0 Percent
    Convertible Senior Notes and Call Spread</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">In April 2021, we completed a $632.5
    million offering of convertible senior notes. We used a portion of the net proceeds from the issuance of the 0% Notes to repurchase $247.9 million in principal of our 1% Notes for $257.0 million.</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">At December 31, 2021,
    we had the following <span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">0%</span> Notes outstanding (amounts in
    millions except interest rate and price per share data):</div>

<div><br/>
  </div>

<table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;">


  <tr>

    <td style="vertical-align: top; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: top; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">0%</span> Notes</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: top; width: 88%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Outstanding principal balance</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">632.5</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: top; width: 88%;" valign="bottom">
          <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Unamortized debt issuance costs</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">13.4</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: top; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Maturity date</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: top; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="-sec-ix-hidden:Fact_7dc5959ba24b47e092541cc149b2023c">April 2026</span></div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: top;" valign="bottom">
          <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Interest rate</div>
        </td>

    <td colspan="1" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: top;" valign="bottom">
          <div style="text-align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">0 percent</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: top; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Effective interest rate</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: top; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">0.5 percent</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: top; width: 88%;" valign="bottom">
          <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Conversion price per share</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">57.84</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: top; width: 88%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Effective conversion price per share with call spread</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">76.39</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: top; width: 88%;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Total shares of common stock subject to conversion</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">10.9</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>


</table>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 12pt;"><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">In conjunction with the April 2021 offering, we entered into a call spread transaction, which was comprised of purchasing
    note hedges and selling warrants, to minimize the impact of potential economic dilution upon conversion of our <span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">0%</span> Notes by increasing the effective conversion price on our <span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">0%</span> Notes. We increased our effective conversion price to $76.39
    with the same number of underlying shares as our <span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">0%</span> Notes.
    The call spread cost us $46.9 million, of which $136.7
    million was for the note hedge purchase, offset by $89.8 million we received for selling the warrants. Similar to our <span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">0%</span> Notes, our note hedges are subject to adjustment. Additionally, our note hedges
    are exercisable upon conversion of the <span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">0%</span> Notes. The note
    hedges will expire upon maturity of the <span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">0%</span> Notes, or April
    2026. The note hedges and warrants are separate transactions and are not part of the terms of our <span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">0%</span> Notes. The holders of the <span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">0%</span> Notes do not have any rights with respect to the note hedges and warrants.</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We recorded the amount we paid for the note hedges and the amount we received for the warrants in additional paid-in
    capital in our consolidated balance sheet. See our Call Spread accounting policy in Note 1, <span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Organization and</span>&#160;<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Significant Accounting Policies</span>, in the Notes to the Consolidated Financial Statements. We reassess our ability to continue to classify the note hedges and warrants in
    shareholders&#8217; equity at each reporting period.</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: left; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;">0.125 Percent
    Convertible Senior Notes and Call Spread</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">In December 2019, we entered into privately negotiated exchange and/or subscription agreements with certain new investors
    and certain holders of our existing 1% Notes to exchange $375.6 million of our 1% Notes for $439.3 million of our 0.125% Notes, and to issue $109.5 million of our 0.125% Notes.</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">At December 31, 2021,
    we had the following 0.125% Notes outstanding with interest payable semi-annually (amounts in millions except interest rate and price per share
    data):</div>

<div><br/>
  </div>

<table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;">


  <tr>

    <td style="vertical-align: top; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: top; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">0.125%
            Notes</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: top; width: 88%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Outstanding principal balance</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">548.8</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: top; width: 88%;" valign="bottom">
          <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Unamortized debt issuance costs</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">6.5</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: top; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Maturity date</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: top; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="-sec-ix-hidden:Fact_ef7fbbee87c14676a78b2a22d99ec0ae">December 2024</span></div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: top;" valign="bottom">
          <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Interest rate</div>
        </td>

    <td colspan="1" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: top;" valign="bottom">
          <div style="text-align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">0.125 percent</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: top; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Effective interest rate</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: top; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">0.5 percent</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: top; width: 88%;" valign="bottom">
          <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Conversion price per share</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">83.28</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: top; width: 88%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Effective conversion price per share with call spread</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">123.38</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: top; width: 88%;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Total shares of common stock subject to conversion</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">6.6</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>


</table>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 12pt;"><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">In conjunction with the issuance of our </span>0.125%<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> Notes in December 2019, we entered into a call spread
      transaction, which was comprised of purchasing note hedges and selling warrants, to minimize the impact of potential economic dilution upon conversion of our </span>0.125% Notes by increasing the effective conversion price on our 0.125% Notes<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">. We increased our effective conversion price to $</span>123.38<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> with the same number of underlying shares as our </span>0.125%<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> Notes. The call spread cost us $</span>52.6<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> million, of which $</span>108.7<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> million was for the note hedge purchase, offset by $</span>56.1<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> million we received for selling the warrants. Similar to our </span>0.125%
    Notes<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">, our note hedges are subject to adjustment. Additionally, our note hedges are exercisable upon conversion of the </span>0.125% Notes<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">. The note hedges will expire upon maturity of the
    </span>0.125% Notes<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">, or December 2024. The note
      hedges and warrants are separate transactions and are not part of the terms of our </span>0.125% Notes<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">. The holders of the </span>0.125% Notes<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> do not have any rights with respect to the note hedges and warrants.</span></div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We recorded the amount we paid for the note hedges and the amount we received for the warrants in additional paid-in
    capital in our consolidated balance sheet. See our Call Spread accounting policy in Note 1, <span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Organization and</span>&#160;<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Significant Accounting Policies</span>, in the Notes to the Consolidated Financial Statements. We reassess our ability to continue to classify the note hedges and warrants in
    shareholders&#8217; equity at each reporting period.</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;">1 Percent
    Convertible Senior Notes</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">In November 2014, we completed a $500 million offering of convertible senior notes, which matured in 2021 and beared interest at 1 percent with interest payable semi-annually. In December 2016, we issued an additional $185.5 million of 1% Notes in exchange for the redemption of a portion of our previously outstanding 2.75% convertible senior notes, or 2.75% Notes. In December 2019, we exchanged a
    portion of our 1% Notes for new 0.125%
    Notes. As a result, the principal balance of 1% Notes was $309.9 million. Additionally, we recorded a $66.2 million non-cash loss on the early
    retirement of debt, reflecting the early retirement of a significant portion of our 1% Notes in December 2019. The non-cash loss on the early
    retirement of our debt is the difference between the amount paid to exchange our 1% Notes and the net carrying balance of the liability at the
    time that we completed the debt exchange.</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">In April 2021, we repurchased $247.9 million in aggregate principal amount of our 1% Notes in privately negotiated
    transactions. As a result of the repurchase, we recognized an $8.6 million loss on early retirement of debt, reflecting the early retirement of a
    significant portion of our 1% Notes. The loss on the early retirement of our debt is the difference between the amount paid to retire our 1% Notes and the net carrying balance of the liability at the time that we retired the debt. We paid the remaining principal balance of our 1% Notes with $62.0 million of cash at maturity
    in November 2021.</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: left; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;">Other Terms of Convertible Senior Notes</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">The 0% and 0.125% Notes are convertible under certain conditions, at the option of the note holders. We can settle conversions of the notes, at our election, in cash,
    shares of our common stock or a combination of both. We may not redeem the notes prior to maturity, and we do not have to provide a sinking fund for them. Holders of the notes may require us to purchase some or all of their notes upon the occurrence of
    certain fundamental changes, as set forth in the indentures governing the notes, at a purchase price equal to 100 percent of the principal
    amount of the notes to be purchased, plus any accrued and unpaid interest. The 1% Notes were subject to similar terms.</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Our total interest expense for our outstanding senior convertible notes for the years ended December 31, 2021, 2020 and 2019 included $4.9 million, $3.2 million and $2.9 million, respectively, of
    non-cash interest expense related to the amortization of debt issuance costs for our convertible notes.</div>

<div><br/>
  </div>

<div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Financing Arrangements</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic; font-weight: bold;">Research and Development and Manufacturing Facilities</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">In July 2017, we purchased the building that houses our primary R&amp;D facility for $79.4 million and our manufacturing facility for $14.0 million. We financed the purchase
    of these two facilities with mortgage debt of $60.4
    million in total. Our primary R&amp;D facility mortgage has an interest rate of 3.88 percent. Our manufacturing facility mortgage has an
    interest rate of 4.20 percent. During the first five years of both mortgages, we are only required to make interest payments. We will begin making principal payments in 2022. Both mortgages mature in August 2027.</div>

<div><br/>
  </div>

<div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Maturity Schedules</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Annual debt and other obligation
    maturities, including fixed and determinable interest, at December 31, 2021 are as follows (in thousands):</div>

<div><br/>
  </div>

<table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;">


  <tr>

    <td style="vertical-align: bottom; width: 88%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="text-indent: 0pt;">2022</span></div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">3,498</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 88%;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="text-indent: 0pt;">2023</span></div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">4,180</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 88%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="text-indent: 0pt;">2024</span></div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">4,180</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 88%;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="text-indent: 0pt;">2025</span></div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">1,184,820</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 88%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="text-indent: 0pt;">2026</span></div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">3,494</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 88%; padding-bottom: 2px;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Thereafter</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">57,439</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 88%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Subtotal</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">1,257,611</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 88%;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Less: current portion</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(3,526</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 88%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Less: fixed and determinable interest</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(15,498</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 88%;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Less: debt issuance costs</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(20,302</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 88%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Plus: lease liabilities</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">22,058</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 88%; padding-bottom: 2px;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Plus: other liabilities</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">7,181</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 88%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Total long-term debt</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">1,247,524</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>


</table>
<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_LesseeOperatingLeasesTextBlock', window );">Long-Term Obligations and Commitments</a></td>
<td class="text">
<div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Operating Leases</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;">Carlsbad Leases</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We lease a facility adjacent to our manufacturing facility that has laboratory and office space that we use to support our
    manufacturing facility. We lease this space under a non-cancelable operating lease. In May 2020, we exercised our option to extend our lease, extending our lease term from June 2021 to August 2026. We have one remaining option to extend the lease for an additional five-year
    period.</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We also lease additional office spaces in Carlsbad. We lease these spaces under non-cancelable operating leases with
    initial terms ending in 2023 with options to extend each of the leases for one&#160;five-year period.</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;">Boston Leases</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We entered into an operating lease agreement for office space located in Boston, Massachusetts in the second quarter of
    2018. The lease commencement date was in August 2018 and we took occupancy in September 2018. We are leasing this space under a non-cancelable operating lease with an initial term ending after 123 months and an option to extend the lease for an additional five-year term. Under
    the lease agreement, we received a three-month free rent period, which commenced on August 15, 2018, and a tenant improvement allowance up to $3.8 million.</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">In January 2022, we entered into a sublease agreement for our office space located in Boston, Massachusetts. The sublease commencement
    date was in January 2022 when the office space was ready for our tenant&#8217;s occupancy. We are subleasing this space under a non-cancelable operating sublease with a sublease term ending 83 months following the sublease commencement date with no option to extend the sublease. Under the sublease agreement we provided a seven-month free rent period, which commenced on January 6, 2022. We will receive lease payments over the sublease term totaling $9.6 million.</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">In September 2021, we entered into an operating lease agreement for another office space located in Boston, Massachusetts. The lease
    commencement date was in November 2021 when the office space was ready for our occupancy. We are leasing this space under a non-cancelable operating lease with an initial term ending 91 months following the lease commencement date and an option to extend the lease for <span style="-sec-ix-hidden:Fact_75e2ca0ba9ea409188caefc97441d96a">an</span>
    additional five-year term. Under the lease agreement, we will receive a seven-month free rent period, which commenced on November 1, 2021. Our lease payments over the initial term total $6.8 million. We recognized a right-of-use lease asset and lease liability in the fourth quarter of 2021 upon the lease commencement date.</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">When we determined our lease term for our operating lease right-of-use assets and lease liabilities for these leases, we
    did not include the extension options for these leases in the original lease term.</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Amounts related to our operating leases were as follows (dollar amounts in millions):</div>

<div><br/>
  </div>

<table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;">


  <tr>

    <td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">

        </td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">At December 31, 2021</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 88%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Right-of-use operating lease assets (1)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">18.0</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 88%;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Operating lease liabilities (2)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">22.1</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Weighted average remaining lease term</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">6.6 years</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 88%;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Weighted average discount rate</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">6.0</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">%</div>
        </td>

  </tr>


</table>

<div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">________________</div>

<table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">


  <tr>

    <td style="width: 18pt; vertical-align: top; align: right; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(1)</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Included in <span style="-sec-ix-hidden:Fact_f81ca57385a04657b8ecd0f06d505159">deposits and other assets</span> on our consolidated balance sheet.</div>
        </td>

  </tr>


</table>

<div><br/>
  </div>

<table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">


  <tr>

    <td style="width: 18pt; vertical-align: top; align: right; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(2)</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Current portion of $2.6 million was included in <span style="-sec-ix-hidden:Fact_b2b58e46aca04158b3b03811dd0a9c0f">current portion of long-term obligations</span> on our consolidated balance sheet, with the difference included in <span style="-sec-ix-hidden:Fact_9c37cb3853f74a4f821bbe4ed37a06ba">long-term obligations</span>.</div>
        </td>

  </tr>


</table>

<div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 12pt;"><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">During the years ended December 31, 2021, 2020, and 2019 we paid $3.3 million, $3.8 million and $3.9 million of lease payments, which were included in
    operating activities in our consolidated statements of cash flows.</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">As of December 31, 2021, the future payments for our operating lease liabilities are as follows (in thousands):</div>

<div><br/>
  </div>

<table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;">


  <tr>

    <td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">

        </td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Operating</span> <span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Leases</span></div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 88%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Year ending December 31,</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">$</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 88%;" valign="bottom">
          <div style="text-align: justify; margin-left: 18.7pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">2022</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">4,075</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 88%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; text-indent: -0.2pt; margin-left: 18.7pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="text-indent: 0pt;">2023</span></div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">4,314</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 88%;" valign="bottom">
          <div style="text-align: justify; text-indent: -0.2pt; margin-left: 18.7pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="text-indent: 0pt;">2024</span></div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">4,223</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 88%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; margin-left: 18.7pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">2025</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">4,062</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 88%;" valign="bottom">
          <div style="text-align: justify; margin-left: 18.7pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">2026</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">3,778</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 88%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Thereafter</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">7,035</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 88%;" valign="bottom">
          <div style="text-align: left; margin-left: 18.7pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Total minimum lease payments</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">27,487</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 88%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Less:</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 88%; padding-bottom: 2px;" valign="bottom">
          <div style="text-align: left; margin-left: 18.7pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Imputed interest</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(5,429</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 88%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: left; margin-left: 36.7pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Total operating lease liabilities</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">22,058</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>


</table>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 12pt;"><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Rent expense was $3.4
    million, $3.7 million and $3.6 million
    for the years ended December 31, 2021, 2020
    and 2019, respectively. </div>
<span></span>
</td>
</tr>
</table>
<div style="display: none;">
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The entire disclosure for information about short-term and long-term debt arrangements, which includes amounts of borrowings under each line of credit, note payable, commercial paper issue, bonds indenture, debenture issue, own-share lending arrangements and any other contractual agreement to repay funds, and about the underlying arrangements, rationale for a classification as long-term, including repayment terms, interest rates, collateral provided, restrictions on use of assets and activities, whether or not in compliance with debt covenants, and other matters important to users of the financial statements, such as the effects of refinancing and noncompliance with debt covenants.</p></div>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The entire disclosure for operating leases of lessee. Includes, but is not limited to, description of operating lease and maturity analysis of operating lease liability.</p></div>
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<span style="display: none;">v3.22.0.1</span><table class="report" border="0" cellspacing="2" id="idm139691015027560">
<tr>
<th class="tl" colspan="1" rowspan="2"><div style="width: 200px;"><strong>Stockholders' Equity<br></strong></div></th>
<th class="th" colspan="1">12 Months Ended</th>
</tr>
<tr><th class="th"><div>Dec. 31, 2021</div></th></tr>
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<div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">4. Stockholders</span>&#8217;<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"> Equity</span></div>

<div><br/>
  </div>

<div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Preferred Stock</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We are authorized to issue up to 15 million shares of &#8220;blank check&#8221; Preferred Stock. As of December 31, 2021, there
    were no shares of Preferred Stock outstanding. We have designated Series C Junior Participating Preferred Stock but have no issued or outstanding shares as of December 31, 2021.</div>

<div><br/>
  </div>

<div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Common Stock</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">At December 31, 2021
    and 2020, we had 300 million
    shares of common stock authorized, of which 141.2 million and 140.4 million were issued and outstanding, respectively. As of December 31, 2021,
    total common shares reserved for future issuance were 46.2 million.</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">During the years ended December 31, 2021, 2020 and 2019, we issued 1.1 million, 1.7 million and 3.1 million shares of common stock, respectively, for stock option
    exercises, vesting of restricted stock units, and ESPP purchases. We received net proceeds from these transactions of $11.6 million, $52.0 million and $119.7 million in 2021, 2020 and 2019, respectively.</div>

<div><br/>
  </div>

<div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Share Repurchase Program</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">In September 2019, our board of directors approved a share repurchase program of up to $125 million of our common stock. In 2019, we repurchased 535,000
    shares for $34.4 million. In the first quarter of 2020, we repurchased an additional 1.5 million shares for $90.5 million.</div>

<div><br/>
  </div>

<div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Stock Plans</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;">1989 Stock Option Plan</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">In June 1989, our Board of Directors adopted, and the stockholders subsequently approved, a stock option plan that, as
    amended, provides for the issuance of non-qualified and incentive stock options for the purchase of up to 20.0 million shares of common stock to
    our employees, directors, and consultants. The plan expires in January 2024. The 1989 Plan does not allow us to grant stock bonuses or restricted stock awards and prohibits us from repricing any options outstanding under the plan unless our
    stockholders approve the repricing. Options vest over a four-year period, with 25percent exercisable at the end of one year from the date of the grant and the
    balance vesting ratably, on a monthly basis, thereafter and have a term of seven years. At December 31, 2021, a total of 28 thousand options were outstanding, of which
    options to purchase 28 thousand shares were exercisable, and 49 thousand shares were available for future grant under the 1989 Plan.</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: -18pt; margin-left: 54pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;">2011 Equity Incentive Plan</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">In March 2011, our Board of Directors adopted, and the stockholders subsequently approved, a stock option plan that
    provides for the issuance of stock options, stock appreciation rights, restricted stock awards, restricted stock unit awards, and performance cash awards to our employees, directors, and consultants. In June 2015, May 2017 and June 2019, after
    receiving approval from our stockholders, we amended our 2011 Equity Incentive Plan, or<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> 2011 Plan,</span> to increase the total number of shares reserved for issuance. We
    increased the shares available under our 2011 Equity Incentive Plan from 5.5 million to 11.0 million in June 2015, from 11.0 million to 16.0 million in May 2017 and from 16.0 million to 23.0 million in June 2019. In the second quarter of 2021, after receiving approval from our stockholders, we amended our <span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">2011 Plan. The amendment increased the total number of shares of common stock authorized for issuance under the 2011 Plan from </span>23.0<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> million to </span>29.7<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> million and added a fungible share counting ratio whereby the share reserve will be reduced by </span>1.7<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> shares for each share of common stock issued pursuant to a full value award (i.e., RSU or PRSU) and increased by
    </span>1.7<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> shares for each share of common stock returning from a
      full value award. </span>The plan expires in June 2031. The 2011 Plan does not allow us to reduce the exercise price of any outstanding stock options or stock appreciation rights or cancel any outstanding stock options or stock appreciation rights
    that have an exercise price or strike price greater than the current fair market value of the common stock in exchange for cash or other stock awards unless our stockholders approve such action. Currently we anticipate awarding only stock options, RSU
    and PRSU awards to our employees, directors and consultants. Options vest over a four-year period, with 25 percent exercisable at the end of one year from the date of the grant
    and the balance vesting ratably, on a monthly basis, thereafter and have a term of seven years. Options granted after December 31, 2021 have a
    term of ten years. We have granted restricted stock unit awards to our employees under the 2011 Plan which vest annually over a four-year period. At December 31, 2021, a
    total of 12.8 million options were outstanding, of which 8.3 million were exercisable, 2.5 million restricted stock unit awards were
    outstanding, and 8.5 million shares were available for future grant under the 2011 Plan.</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Under the 2011 Plan, we may issue a stock award with additional acceleration of vesting and exercisability upon or after a
    change in control. In the absence of such provisions, no such acceleration will occur. The stock options and restricted stock unit awards we issued to Dr. Stanley T. Crooke in his former role as chief executive officer and certain stock options and
    restricted stock unit awards we issued to B. Lynne Parshall in her former role as chief operating officer have accelerated vesting upon a change of control, as defined in the 2011 Plan. In addition, we implemented a change of control and severance
    benefit plan that provides for change of control and severance benefits to our executive officers, including our chief executive officer and chief financial officer. If we terminate one of our executive officers or if an executive officer resigns for good reason during the period that begins three months before and ends twelve months following a change in control of the
    company, the impacted executive officers&#8217; stock options and RSUs vesting will accelerate for options and RSUs outstanding as of the termination date.</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: -18pt; margin-left: 54pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;">2020 Equity Incentive Plan</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">In connection with the Akcea Merger in October 2020, we
      assumed the unallocated portion of the available share reserve under the Akcea 2015 Equity Incentive Plan. In December 2020, we amended and restated the Akcea 2015 equity plan, including renaming the plan as the Ionis Pharmaceuticals, Inc. 2020
      Equity Incentive Plan, or 2020 Plan. The 2020 Plan provided for the issuance of up to </span>2.6<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> million shares of our Common Stock to our employees, directors and consultants who were employees of Akcea prior to the Akcea Merger. </span><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">In the second quarter of 2021, our Compensation Committee approved an amendment to the 2020 Plan. The amendment decreased the total number of shares of common stock authorized for issuance under the 2020 Plan from
      approximately </span>2.6<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> million to </span>1.6<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> million. We assumed the 2020 Plan in connection with Ionis&#8217;
      reacquisition of all of the outstanding shares of Akcea Therapeutics, Inc. as part of the Akcea Merger.</span></div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">The plan expires in December 2025. The 2020 Plan does not allow us to reduce the exercise price of any outstanding stock
    options or stock appreciation rights or cancel any outstanding stock options or stock appreciation rights that have an exercise price or strike price greater than the current fair market value of the common stock in exchange for cash or other stock
    awards unless our stockholders approve such action. Currently we anticipate awarding only stock options and RSU awards to our eligible employees, directors and consultants. Options vest over a four-year period, with 25 percent exercisable at the end of one year from the date of the grant and the balance vesting ratably, on a monthly basis, thereafter and have a term of seven years. Options granted after December 31, 2021 have a term of ten years.
    We have granted restricted stock unit awards to our employees under the 2020 Plan which vest annually over a four-year period. At December 31, 2021, a total of 0.2 million
    options were outstanding, of which none were exercisable, 0.1 million restricted stock unit awards were outstanding, and 1.3 million shares were
    available for future grant under the 2020 Plan.</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Under the 2020 Plan, we may issue a stock award with additional acceleration of vesting and exercisability upon or after a
    change in control. In the absence of such provisions, no such acceleration will occur.</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: left; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;">Corporate Transactions and Change in Control under 2011 and 2020 Plans</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">In the event of certain significant corporate transactions, our Board of Directors has the discretion to take one or more
    of the following actions with respect to outstanding stock awards under the 2011 and 2020 Plans:</div>

<div><br/>
  </div>

<table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">


  <tr>

    <td style="width: 36pt;"/>

    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">arrange for assumption, continuation, or substitution of a stock award by a surviving or acquiring entity (or its parent company);</div>
        </td>

  </tr>


</table>

<table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">


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    <td style="width: 36pt;"/>

    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">arrange for the assignment of any reacquisition or repurchase rights applicable to any shares of our common stock issued pursuant to a stock award to the
            surviving or acquiring corporation (or its parent company);</div>
        </td>

  </tr>


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    <td style="width: 36pt;"/>

    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">accelerate the vesting and exercisability of a stock award followed by the termination of the stock award;</div>
        </td>

  </tr>


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  <tr>

    <td style="width: 36pt;"/>

    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">arrange for the lapse of any reacquisition or repurchase rights applicable to any shares of our common stock issued pursuant to a stock award;</div>
        </td>

  </tr>


</table>

<table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">


  <tr>

    <td style="width: 36pt;"/>

    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">cancel or arrange for the cancellation of a stock award, to the extent not vested or not exercised prior to the effective date of the corporate
            transaction, in exchange for cash consideration, if any, as the Board, in its sole discretion, may consider appropriate; and</div>
        </td>

  </tr>


</table>

<table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">


  <tr>

    <td style="width: 36pt;"/>

    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">arrange for the surrender of a stock award in exchange for a payment equal to the excess of (a) the value of the property the holder of the stock award
            would have received upon the exercise of the stock award, over (b) any exercise price payable by such holder in connection with such exercise.</div>
        </td>

  </tr>


</table>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;">2002 Non-Employee Directors&#8217; Stock Option Plan</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">In September 2001, our Board of Directors adopted, and the stockholders subsequently approved, an amendment and
    restatement of the 1992 Non-Employee Directors&#8217; Stock Option Plan, which provides for the issuance of non-qualified stock options and restricted stock units to our non-employee directors. The name of the resulting plan is the 2002 Non-Employee
    Directors&#8217; Stock Option Plan, or the 2002 Plan. In June 2015, after receiving approval from our stockholders, we amended our 2002 Plan to increase the total number of shares reserved for issuance from 1.2 million to 2.0 million. In June 2020, after receiving approval from our
    stockholders, we further amended our 2002 Plan. <span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">The amendments included:</span></div>

<div><br/>
  </div>

<table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">


  <tr>

    <td style="width: 36pt;"/>

    <td style="width: 18pt; vertical-align: top; align: right; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">An increase to the total number of shares reserved for issuance under the
              plan from </span>2.0<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> million to </span>2.8<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> million shares;</span></div>
        </td>

  </tr>


</table>

<table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">


  <tr>

    <td style="width: 36pt;"/>

    <td style="width: 18pt; vertical-align: top; align: right; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">A reduction to the amount of the automatic awards under the plan;</div>
        </td>

  </tr>


</table>

<table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">


  <tr>

    <td style="width: 36pt;"/>

    <td style="width: 18pt; vertical-align: top; align: right; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">A revision to the vesting schedule of new awards granted; and</div>
        </td>

  </tr>


</table>

<table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">


  <tr>

    <td style="width: 36pt;"/>

    <td style="width: 18pt; vertical-align: top; align: right; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;">An extension of the term of the plan.</div>
        </td>

  </tr>


</table>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Options under this plan expire 10 years from the date of grant. At December 31, 2021, a total of 1.0 million options were outstanding, of which 0.8
    million were exercisable, 0.1 million restricted stock unit awards were outstanding, and 0.7 million shares were available for future grant under the 2002 Plan.</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: -18pt; margin-left: 54pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;">Employee Stock Purchase Plan</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">In June 2009, our Board of Directors adopted, and the stockholders subsequently approved, the amendment and restatement of
    the ESPP and we reserved an additional 150,000 shares of common stock for issuance thereunder. In each of the subsequent years until 2019, we
    reserved an additional 150,000 shares of common stock for the ESPP resulting in a total of 3.2 million shares authorized under the plan as of December 31, 2021. The ESPP
    permits full-time employees to purchase common stock through payroll deductions (which cannot exceed 10percent of each employee&#8217;s compensation)
    at the lower of 85percent of fair market value at the beginning of the purchase period or the end of each purchase period. Under the amended
    and restated ESPP, employees must hold the stock they purchase for a minimum of six months from the date of purchase. During 2021, employees purchased and we issued to employees 0.07
    million shares under the ESPP at a weighted average price of $39.26 per share. At December 31, 2021, there were 0.6 million shares available for purchase under the
    ESPP.</div>

<div><br/>
  </div>

<div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Stock Option Activity</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">The following table summarizes the stock option activity under our stock plans for the year ended December 31, 2021 (in thousands, except per share and contractual life data):</div>

<div><br/>
  </div>

<table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;">


  <tr>

    <td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">

        </td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Number</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">of Shares</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Weighted</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Average Exercise</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Price Per Share</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Average</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Remaining</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Contractual Term</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">(Years)</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Aggregate</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Intrinsic</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Value</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="text-indent: 0pt;">Outstanding at December 31, 2020</span></div>
        </td>

    <td colspan="1" style="vertical-align: bottom; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">12,439</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">54.11</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 18pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Granted</div>
        </td>

    <td colspan="1" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">3,382</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">53.07</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 18pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Exercised</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(219</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">38.69</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 18pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Cancelled/forfeited/expired</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(1,513</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; padding-bottom: 2px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">54.65</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 52%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="text-indent: 0pt;">Outstanding at December 31, 2021</span></div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">14,089</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">54.04</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">3.89</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">1,131</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 52%; padding-bottom: 4px;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="text-indent: 0pt;">Exercisable at December 31, 2021</span></div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">9,175</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">53.65</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">2.94</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">1,067</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>


</table>

<div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 12pt;"><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">The weighted-average estimated fair values of options granted were $24.35, $29.43 and $28.76 for the years ended December 31, 2021, 2020 and 2019, respectively. The total intrinsic value of options
    exercised during the years ended December 31, 2021, 2020 and 2019 were $2.5 million, $15.5 million and $83.8 million, respectively, which we determined as of the date of exercise. The amount of cash received from the exercise of stock options was $8.5 million, $43.7 million and $105.9 million for the years ended December 31, 2021, 2020 and 2019, respectively. For the year
    ended December 31, 2021, the weighted-average fair value of options exercised was $50.13. As of December 31, 2021, total unrecognized compensation cost related to
    non-vested stock options was $49.6 million. We expect to recognize this cost over a weighted average period of 1.1 years. We will adjust the total unrecognized compensation cost for future changes in estimated forfeitures.</div>

<div><br/>
  </div>

<div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Restricted Stock Unit Activity</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">The following table summarizes the RSU activity for the year ended December 31, 2021 (in thousands, except per share data):</div>

<div><br/>
  </div>

<table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;">


  <tr>

    <td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">

        </td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Number</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">of Shares</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Weighted Average</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Grant Date Fair</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Value Per Share</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 76%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="text-indent: 0pt;">Non-vested at December 31, 2020</span></div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">2,374</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">58.81</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 76%;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 18pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Granted</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">1,548</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">57.69</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 76%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 18pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Vested</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(834</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">57.47</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 76%; padding-bottom: 2px;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 18pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Cancelled/forfeited</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(411</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">59.24</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 76%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="text-indent: 0pt;">Non-vested at December 31, 2021</span></div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">2,677</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">58.51</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>


</table>

<div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 12pt;"><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">For the years ended December 31, 2021, 2020 and 2019, the weighted-average grant date fair value of RSUs granted was $57.69, $60.86 and $60.23 per RSU, respectively. As of
    December 31, 2021, total unrecognized compensation cost related to RSUs was $57.0 million. We expect to recognize this cost over a weighted average period of 1.2
    years. We will adjust the total unrecognized compensation cost for future changes in estimated forfeitures.</div>

<div><br/>
  </div>

<div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Stock-based Compensation Expense and Valuation Information</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">The following table summarizes stock-based compensation expense for the years ended December 31, 2021, 2020 and 2019 (in thousands):</div>

<div><br/>
  </div>

<table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;">


  <tr>

    <td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">

        </td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="10" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Year Ended December 31,</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2021</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2020</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2019</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Cost of sales</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">456</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">1,991</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">438</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 64%;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Research, development and patent</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">87,522</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">115,584</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">95,348</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Selling, general and administrative</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">32,700</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">112,542</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">50,788</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 64%; padding-bottom: 4px;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Total</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">120,678</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">230,117</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">146,574</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>


</table>

<div style="text-align: justify; font-family: 'Times New Roman', Times, serif; font-size: 12pt;"><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">In October 2020, as part of the Akcea Merger, Akcea&#8217;s outstanding equity awards vested under Akcea&#8217;s Plan. As a result, in
    the fourth quarter of 2020, we recognized all unrecognized stock-based compensation ($59.3 million) under Akcea&#8217;s Plan. See Note 7, <span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Akcea Merger</span>, in the Notes to the Consolidated Financial Statements for further details.</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">In the third quarter of 2019, </span>three<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> Akcea executive officers terminated their employment and entered into
      separation agreements with Akcea. As a result, in the third quarter of 2019, Akcea reversed $</span>19.1<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> million of stock-based compensation expense it had previously recognized related to the executive officers&#8217; stock options and RSUs that were no longer going to vest.</span></div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: -18pt; margin-left: 54pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;">Determining Fair Value</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Valuation.</span> We
    measure stock-based compensation expense for equity-classified awards, principally related to stock options, RSUs, PRSUs and stock purchase rights under the ESPP at the grant date, based on the estimated fair value of the award and we recognize the
    expense over the employee&#8217;s requisite service period. We value RSUs based on the market price of our common stock on the date of grant. See Note 1, <span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Organization
      and Significant Accounting Policies</span>, in the Notes to the Consolidated Financial Statements for further details on how we determine the fair value of PRSUs.</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We use the Black-Scholes model to estimate the fair value of stock options granted and stock purchase rights under our
    ESPP. The expected term of stock options granted represents the period of time that we expect them to be outstanding. We estimate the expected term of stock options granted based on actual and projected exercise patterns. We recognize compensation
    expense for stock options granted, RSUs, PRSUs and stock purchase rights under the ESPP using the accelerated multiple-option approach. Under the accelerated multiple-option approach (also known as the graded-vesting method), we recognize compensation
    expense over the requisite service period for each separately vesting tranche of the award as though the award were in substance multiple awards, which results in the expense being front-loaded over the vesting period.</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">For the years ended December 31, 2021, 2020 and 2019, we used the following weighted-average assumptions in our Black-Scholes calculations:</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;">Ionis Employee Stock Options:</div>

<div><br/>
  </div>

<table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;">


  <tr>

    <td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">

        </td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="10" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Year Ended December 31,</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2021</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2020</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2019</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Risk-free interest rate</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">0.6</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">%</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">1.5</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">%</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">2.3</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">%</div>
        </td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 64%;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Dividend yield</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">0.0</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">%</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">0.0</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">%</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">0.0</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">%</div>
        </td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Volatility</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">54.0</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">%</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">58.6</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">%</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">60.3</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">%</div>
        </td>

  </tr>

  <tr>

    <td style="vertical-align: bottom;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Expected life</div>
        </td>

    <td colspan="1" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom;" valign="bottom">
          <div style="text-align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">4.9 years</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom;" valign="bottom">
          <div style="text-align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">4.7 years</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom;" valign="bottom">
          <div style="text-align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">4.8 years</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>


</table>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;">Ionis Board of Director Stock Options:</div>

<div><br/>
  </div>

<table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;">


  <tr>

    <td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">

        </td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="10" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Year Ended December 31,</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2021</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2020</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2019</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Risk-free interest rate</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">1.2</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">%</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">0.5</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">%</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">1.9</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">%</div>
        </td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 64%;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Dividend yield</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">0.0</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">%</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">0.0</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">%</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">0.0</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">%</div>
        </td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Volatility</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">55.9</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">%</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">57.6</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">%</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">60.7</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">%</div>
        </td>

  </tr>

  <tr>

    <td style="vertical-align: bottom;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Expected life</div>
        </td>

    <td colspan="1" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom;" valign="bottom">
          <div style="text-align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">7.3 years</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom;" valign="bottom">
          <div style="text-align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">6.7 years</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom;" valign="bottom">
          <div style="text-align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">6.6 years</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>


</table>

<div style="display:none;"><br/></div>
<div style="text-align: left; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 12pt;"><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: left; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;">Ionis ESPP:</div>

<div><br/>
  </div>

<table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;">


  <tr>

    <td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">

        </td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="10" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Year Ended December 31,</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2021</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2020</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2019</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Risk-free interest rate</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">0.1</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">%</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">0.8</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">%</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">2.4</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">%</div>
        </td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 64%;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Dividend yield</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">0.0</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">%</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">0.0</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">%</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">0.0</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">%</div>
        </td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Volatility</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">42.4</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">%</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">47.9</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">%</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">45.6</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">%</div>
        </td>

  </tr>

  <tr>

    <td style="vertical-align: bottom;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Expected life</div>
        </td>

    <td colspan="1" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom;" valign="bottom">
          <div style="text-align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">6 months</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom;" valign="bottom">
          <div style="text-align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">6 months</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom;" valign="bottom">
          <div style="text-align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">6 months</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>


</table>

<div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 12pt;"><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Risk-Free Interest Rate.</span>
    We base the risk-free interest rate assumption on observed interest rates appropriate for the term of our stock option plans or ESPP.</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Dividend Yield.</span> We
    base the dividend yield assumption on our history and expectation of dividend payouts. We have not paid dividends in the past and do not expect to in the future.</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Volatility.</span> We use
    an average of the historical stock price volatility of our stock for the Black-Scholes model. We computed the historical stock volatility based on the expected term of the awards.</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Expected Life. </span>The
    expected term of stock options we have granted represents the period of time that we expect them to be outstanding. We estimated the expected term of options we have granted based on actual and projected exercise patterns.</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Forfeitures.</span> We
    reduce stock-based compensation expense for estimated forfeitures. We estimate forfeitures at the time of grant and revise, if necessary, in subsequent periods if actual forfeitures differ from those estimates. We estimate forfeitures based on
    historical experience. </div>
<span></span>
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<span style="display: none;">v3.22.0.1</span><table class="report" border="0" cellspacing="2" id="idm139691017275304">
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<th class="tl" colspan="1" rowspan="2"><div style="width: 200px;"><strong>Income Taxes<br></strong></div></th>
<th class="th" colspan="1">12 Months Ended</th>
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<tr><th class="th"><div>Dec. 31, 2021</div></th></tr>
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<div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">5. Income Taxes</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Income (loss) before income taxes is comprised of (in thousands):</div>

<div><br/>
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          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Year Ended December 31,</div>
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    <td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

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          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2021</div>
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    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2020</div>
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    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2019</div>
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    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

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  <tr>

    <td style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">(as revised*)</div>
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    <td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">(as revised*)</div>
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    <td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">United States</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(29,966</div>
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    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
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    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(137,222</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">336,277</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 64%; padding-bottom: 2px;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Foreign</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">818</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">2,670</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">2,489</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 64%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Income (loss) before income taxes</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(29,148</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(134,552</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">338,766</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>


</table>

<div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 12pt;"><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Our income tax expense (benefit) was as follows (in thousands):</div>

<div><br/>
  </div>

<table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;">


  <tr>

    <td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">

        </td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="10" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Year Ended December 31,</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2021</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2020</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2019</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

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    <td colspan="1" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">(as revised*)</div>
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    <td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">(as revised*)</div>
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    <td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom">&#160;</td>

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  <tr>

    <td style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Current:</div>
        </td>

    <td colspan="1" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Federal</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(200</div>
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    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(837</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">35,861</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 64%;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">State</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(690</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">3,782</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">14,329</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Foreign</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">339</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">518</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">413</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 64%;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Total current income tax expense (benefit)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(551</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">3,463</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">50,603</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 64%;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Deferred:</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Federal</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#8212;</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">341,728</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">904</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 64%; padding-bottom: 2px;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">State</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#8212;</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#8212;</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#8212;</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Total deferred income tax benefit</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#8212;</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">341,728</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">904</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 64%; padding-bottom: 4px;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Total income tax expense (benefit)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(551</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom">
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    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">345,191</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
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    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">51,507</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>


</table>

<div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 12pt;"><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Our expense (benefit) for income taxes differs from the amount computed by applying the U.S. federal
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<div><br/>
  </div>

<table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;">


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    <td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">

        </td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="22" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
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    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="6" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2021</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="6" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2020</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="6" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
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        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="6" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="6" style="vertical-align: bottom;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">(as revised*)</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="6" style="vertical-align: bottom;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">(as revised*)</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="6" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="6" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="6" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; background-color: #CCEEFF;" valign="bottom">
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        </td>

    <td colspan="1" style="vertical-align: bottom; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(29,148</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(134,552</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">338,766</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 28%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Statutory rate</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(6,121</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">21.0</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">%</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(28,256</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">21.0</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">%</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">71,141</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">21.0</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">%</div>
        </td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 28%;" valign="bottom">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">State income tax net of federal benefit</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">4,278</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(14.7</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)%</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(37,705</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">28.0</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">%</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">49,000</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">14.5</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">%</div>
        </td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 28%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Foreign</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">143</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(0.5</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)%</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">49</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

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    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
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    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">%</div>
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    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
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    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
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    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">%</div>
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  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 28%;" valign="bottom">
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    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
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    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
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    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)%</div>
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    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">460,898</div>
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    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(342.5</div>
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    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)%</div>
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    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(37,314</div>
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    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
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    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(11.0</div>
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    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)%</div>
        </td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 28%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Loss on debt transactions</div>
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    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">262</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(0.9</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)%</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#8212;</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#8212;</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">9,911</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">2.9</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">%</div>
        </td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 28%;" valign="bottom">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Impact from outside basis differences</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#8212;</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#8212;</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#8212;</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#8212;</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(16,344</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(4.8</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)%</div>
        </td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 28%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Tax credits</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(23,198</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">79.6</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">%</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(18,774</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">14.0</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">%</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(22,296</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(6.6</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)%</div>
        </td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 28%;" valign="bottom">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Deferred tax true-up</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(24</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">0.1</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">%</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(206</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">0.2</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">%</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">646</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">0.2</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">%</div>
        </td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 28%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Tax rate change</div>
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    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">12,838</div>
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    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
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    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)%</div>
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    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(32,951</div>
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    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
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    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">24.5</div>
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    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
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    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">1,248</div>
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    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">0.4</div>
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    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
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  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 28%;" valign="bottom">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Non-deductible compensation</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">5,085</div>
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    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
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    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)%</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">7,931</div>
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    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(5.9</div>
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    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)%</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">3,361</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">1.0</div>
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    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">%</div>
        </td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 28%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Other non-deductible items</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">84</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(0.3</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)%</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">193</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(0.1</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)%</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">329</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">0.1</div>
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    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">%</div>
        </td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 28%;" valign="bottom">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Stock-based compensation</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">4,720</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(16.2</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)%</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">17,435</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(13.0</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)%</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(4,837</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(1.4</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)%</div>
        </td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 28%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Foreign-derived intangible income benefit</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#8212;</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#8212;</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#8212;</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#8212;</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(2,071</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(0.6</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)%</div>
        </td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 28%;" valign="bottom">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Impacts from Akcea Merger</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#8212;</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#8212;</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(22,032</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">16.4</div>
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    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">%</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#8212;</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#8212;</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 28%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Other</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(1,503</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">5.1</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">%</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(1,391</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">0.9</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">%</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(1,607</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(0.6</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)%</div>
        </td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 28%; padding-bottom: 4px;" valign="bottom">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Effective rate</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(551</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">1.9</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">%</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">345,191</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(256.5</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)%</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">51,507</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">15.2</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">%</div>
        </td>

  </tr>


</table>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 12pt;"><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Deferred income taxes reflect the net tax effects of temporary differences between the carrying amounts of assets and
    liabilities for financial reporting purposes and the amounts used for income tax purposes.</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Significant components of our deferred tax assets and liabilities as of December 31, 2021 and 2020 are as follows (in thousands):</div>

<div><br/>
  </div>

<table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;">


  <tr>

    <td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">

        </td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="6" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Year Ended December 31,</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2021</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2020</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">(as revised*)</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Deferred Tax Assets:</div>
        </td>

    <td colspan="1" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 76%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Net operating loss carryovers</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">85,600</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">83,681</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 76%;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Tax credits</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">269,538</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">245,746</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 76%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Deferred revenue</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">104,330</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">124,452</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 76%;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Stock-based compensation</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">86,611</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">80,055</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 76%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Intangible and capital assets</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">92,542</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">98,443</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 76%;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Convertible debt</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">45,681</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">22,395</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 76%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Interest expense limitation</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">6,996</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#8212;</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 76%; padding-bottom: 2px;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Other</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">15,048</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">13,402</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 76%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Total deferred tax assets</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">706,346</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">668,174</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 76%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 76%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Deferred Tax Liabilities:</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 76%;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Fixed assets</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(3,303</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(3,611</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 76%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Other</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(5,270</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(5,808</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 76%;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Net deferred tax asset</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">697,773</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">658,755</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 76%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Valuation allowance</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(697,773</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(658,755</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 76%; padding-bottom: 4px;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Total net deferred tax assets and liabilities</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#8212;</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#8212;</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>


</table>

<div><br/>
  </div>

<table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">


  <tr>

    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">*</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We revised our 2020 and 2019 amounts to reflect the simplified convertible instruments accounting guidance, which we adopted retrospectively. Refer to
            Note 1, <span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Organization and Significant Accounting Policies</span>, for further information.</div>
        </td>

  </tr>


</table>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We evaluate our deferred tax assets regularly to determine whether adjustments to the valuation allowance are appropriate
    due to changes in facts or circumstances, such as changes in expected future pre-tax earnings, tax law, interactions with taxing authorities and developments in case law. In making this evaluation, we rely on our recent history of pre-tax earnings. Our
    material assumptions are our forecasts of future pre-tax earnings and the nature and timing of future deductions and income represented by the deferred tax assets and liabilities, all of which involve the exercise of significant judgment. Although we
    believe our estimates are reasonable, we are required to use significant judgment in determining the appropriate amount of valuation allowance recorded against our deferred tax assets.</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Ionis and Akcea filed separate U.S. federal income tax returns from the date of Akcea&#8217;s IPO in 2017 through October 12,
    2020, the date on which we completed the Akcea Merger. As a result of the Akcea Merger, Ionis and Akcea now file a consolidated U.S. federal income tax return, and we now assess our U.S. federal and state valuation allowance requirements on a
    consolidated basis.</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We assessed our valuation allowance requirements and recorded a valuation allowance of $341 million against all of Ionis&#8217; U.S. federal net deferred tax assets in the fourth quarter of 2020, due to uncertainties related to our ability to realize
    the tax benefits associated with these assets. We based this determination largely on Akcea rejoining the Ionis consolidated U.S. federal tax group in the fourth quarter of 2020. Due to Akcea&#8217;s historical and projected financial statement losses, and
    the expected negative impact this will have on Ionis&#8217; consolidated taxable income, we are uncertain if we will generate sufficient consolidated pre-tax income in future periods to realize the Ionis deferred tax benefits. We also expect that Ionis&#8217;
    pre-tax income in future periods will be lower due to significant investments in research and development associated with our pipeline of wholly owned medicines. We now maintain a valuation allowance against all our consolidated U.S. federal and state
    net deferred tax assets.</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Our valuation allowance increased by $39 million from December 31, 2020 to December 31, 2021. The increase was primarily related to increases in our deferred tax assets for tax credits and convertible debt offset against a decrease in our
    deferred tax asset for deferred revenue.</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">At December 31, 2021,
    we had federal and state, primarily California, tax net operating loss carryforwards of $271.5 million and $333.8 million, respectively. Our federal tax loss carryforwards are available indefinitely. Our California tax loss carryforwards will begin to expire in 2031. At December 31, 2021, we also had federal and California research and development tax credit carryforwards of $225.5 million and $99.7 million, respectively. Our federal research and development tax
    credit carryforwards will begin to expire in 2034. Our California research and development tax credit carryforwards are available indefinitely.</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Utilization of the net operating loss and tax credit carryforwards may be subject to an annual limitation due to the ownership change
    limitations provided by the Internal Revenue Code of 1986, as amended, and similar state provisions. The annual limitation may result in the expiration of net operating losses and credits before utilization.</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We analyze filing positions in all U.S. federal, state and foreign jurisdictions where we file income tax returns, and all open tax years
    in these jurisdictions to determine if we have any uncertain tax positions on any of our income tax returns. We recognize the impact of an uncertain tax position on an income tax return at the largest amount that the relevant taxing authority is
    more-likely-than not to sustain upon audit. We do not recognize uncertain income tax positions if they have less than 50 percent likelihood of the applicable tax authority sustaining our position.</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">The following table summarizes our gross unrecognized tax benefits <span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">(in thousands):</span></div>

<div><br/>
  </div>

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          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">54,163</div>
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    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

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          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">69,784</div>
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    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

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          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">68,301</div>
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        </td>

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    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

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          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(24,154</div>
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          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
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    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

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          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(867</div>
        </td>

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    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

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          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">263</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

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          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">7,023</div>
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    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

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          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">1,354</div>
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    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">1,510</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">1,614</div>
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    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

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          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">55,085</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

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          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">54,163</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

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          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
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          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">69,784</div>
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<div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 12pt;"><br/>
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<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Included in the balance of unrecognized tax benefits at December 31, 2021, 2020 and 2019 was $6.2 million, $6.4 million and $0.4 million respectively, that if we recognized, could impact our effective tax rate, subject to our remaining valuation allowance.</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We do not foresee any material changes to our gross unrecognized tax benefits within the next twelve months.</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We recognize interest and/or penalties related to income tax matters in income tax expense. During the year ended December
    31, 2021 and 2020, we recognized $0.5
    million and $0.3 million, respectively, of accrued interest and penalties related to gross unrecognized tax benefits. We did not record any accrued interest and penalties for the years ended December 31, 2019.</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We are subject to taxation in the U.S. and various state and foreign jurisdictions. Our tax years for 1999 through 2020
    are subject to examination by the U.S. federal, state and foreign tax authorities.</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">We do not provide for a U.S. income tax
      liability and foreign withholding taxes on undistributed foreign earnings of our foreign subsidiaries as we consider those earnings to be permanently reinvested. It is not practicable for us to calculate the amount of unrecognized deferred tax
      liabilities associated with these earnings</span>.</div>
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<span style="display: none;">v3.22.0.1</span><table class="report" border="0" cellspacing="2" id="idm139691015155480">
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<th class="tl" colspan="1" rowspan="2"><div style="width: 200px;"><strong>Collaborative Arrangements and Licensing Agreements<br></strong></div></th>
<th class="th" colspan="1">12 Months Ended</th>
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<tr><th class="th"><div>Dec. 31, 2021</div></th></tr>
<tr class="re">
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<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_CollaborativeArrangementDisclosureTextBlock', window );">Collaborative Arrangements and Licensing Agreements</a></td>
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<div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">6. Collaborative Arrangements and Licensing Agreements</div>

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<div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Strategic Partnership</div>

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<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;">Biogen</div>

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<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We have several strategic collaborations with Biogen focused on using antisense technology to advance the treatment of
    neurological disorders. These collaborations combine our expertise in creating antisense medicines with Biogen&#8217;s expertise in developing therapies for neurological disorders. We developed and licensed to Biogen SPINRAZA, our approved medicine to treat
    people with spinal muscular atrophy, or SMA. We and Biogen are currently developing nine investigational medicines to treat neurodegenerative
    diseases under these collaborations, including medicines in development to treat people with ALS, SMA, AS, Alzheimer&#8217;s disease<sub>&#160;</sub>and Parkinson&#8217;s disease. In addition to these medicines, our collaborations with Biogen include a substantial
    research pipeline that addresses a broad range of neurological diseases. From inception through December 2021, we have received more than $3.1 billion from our Biogen collaborations.</div>

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<div style="text-align: left; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic; font-weight: bold;">Spinal Muscular Atrophy Collaborations</div>

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<div style="text-align: left; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;">SPINRAZA</div>

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<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">In January 2012, we entered into a
      collaboration agreement with Biogen to develop and commercialize SPINRAZA, an RNA-targeted therapy for the treatment of SMA.</span>&#160;<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">From inception through
      December 2021, we earned more than $</span>1.6<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">
      billion in total revenue under our SPINRAZA collaboration, including nearly $</span>1.2<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> billion in revenue from SPINRAZA royalties and more than $</span>435<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> million in R&amp;D revenue. We are receiving tiered royalties ranging from </span>11 percent<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> to </span>15 percent<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> on net sales of SPINRAZA. We have exclusively in-licensed patents related to SPINRAZA from Cold Spring Harbor Laboratory and the University of Massachusetts. We pay Cold Spring Harbor
      Laboratory and the University of Massachusetts a low single digit royalty on net sales of SPINRAZA. Biogen is responsible for all global development, regulatory and commercialization activities and costs for SPINRAZA. We completed our performance
      obligations under our collaboration in 2016</span>.</div>

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<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;">New antisense medicines for the treatment of SMA</div>

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<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">In December 2017, we entered into a
      collaboration agreement with Biogen to </span>identify <span style="background-color: #FBFBFB; font-size: 10pt; font-family: 'Times New Roman', Times, serif;">new antisense medicines for the treatment of SMA</span><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">. </span><span style="background-color: #FBFBFB; font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">Biogen has the option to license therapies arising out of
      this collaboration following the completion of preclinical studies. Upon licensing, Biogen </span><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">will be responsible for global development, regulatory and
      commercialization activities and costs for such therapies</span><span style="background-color: #FBFBFB; font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">. Under the collaboration agreement, we received a </span>$25 million<span style="background-color: #FBFBFB; font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> upfront payment in the </span><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">fourth</span><span style="background-color: #FBFBFB; font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> quarter of </span><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">2017</span><span style="background-color: #FBFBFB; font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">. </span><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">In December 2021, we earned a $</span>60<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> million license fee payment when Biogen exercised its option to license ION306. </span><span style="background-color: #FBFBFB; font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">We will receive development and regulatory milestone payments from Biogen if new medicines advance towards marketing approval. </span><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">In total over the term of our collaboration, we are eligible to receive up to $</span>1.2<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> billion in license fees, milestone payments and other payments, including up to $</span>555<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> million in payments if Biogen advances ION306, which includes up to $</span>45<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> million for the achievement of development milestones, up to $</span>110<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> million for the achievement of regulatory milestones and up
      to $</span>400<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> million for the achievement of
      sales milestones. In addition, we are eligible to receive tiered royalties </span><span style="background-color: #FBFBFB; font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">from the mid-teens to </span><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">mid-</span>20 percent<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> range </span><span style="background-color: #FBFBFB; font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">on net sales.</span><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> We will achieve the next payment of up to $</span>45<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> millionfor the initiation of a Phase 3 trial under this collaboration. </span></div>

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<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">At the commencement of this collaboration, we identified one performance obligation, which was to perform R&amp;D services for Biogen. We determined the transaction price to be the $25 million upfront payment we received when we entered into the collaboration. We allocated the transaction price to our single performance obligation. In the fourth quarter of 2019, we
    completed our R&amp;D services performance obligation under this collaboration. We recognized revenue as we performed services based on our effort to satisfy our performance obligation relative to the total effort expected to satisfy our performance
    obligation. We completed our performance obligation earlier than we previously estimated, as a result, we recognized $8.3 million of additional
    revenue in the fourth quarter of 2019.</div>

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<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">In the fourth quarter of 2021, we identified another performance obligation upon Biogen&#8217;s license of ION306 because the license we granted
    to Biogen is distinct from our other performance obligations. We recognized the $60 million license fee for ION306 as revenue at that time
    because Biogen had full use of the license without any continuing involvement from us. Additionally, we did not have any further performance obligations related to the license after we delivered it to Biogen. Biogen is solely responsible for the costs
    and expenses related to the development, manufacturing and potential future commercialization of ION306 following the option exercise. We do not have any remaining performance obligations under this collaboration.</div>

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<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic; font-weight: bold;">Neurology Collaborations</div>

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<div style="text-align: left; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;">2018 Strategic Neurology</div>

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<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">In April 2018, we and Biogen entered into a
      strategic collaboration to develop novel antisense medicines for a broad range of neurological diseases and entered into a SPA. As part of the collaboration, Biogen gained exclusive rights to the use of our antisense technology to develop therapies
      for these diseases for </span>10<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> years. We are
      responsible for the identification of antisense drug candidates based on selected medicines</span>. Biogen is responsible for conducting IND-enabling toxicology studies for the selected medicine. <span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">Biogen will have the option to license the selected medicine </span>after it completes the IND-enabling toxicology study. <span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">If Biogen exercises its option to license a medicine, it will assume global development, regulatory and commercialization responsibilities and costs for that medicine.</span></div>

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<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="background-color: #FBFBFB; font-size: 10pt; font-family: 'Times New Roman', Times, serif;">In the </span>second<span style="background-color: #FBFBFB; font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> quarter of </span>2018<span style="background-color: #FBFBFB; font-size: 10pt; font-family: 'Times New Roman', Times, serif;">, we received </span>$1 billion from Biogen, comprised of $625 million
    to purchase our stock at an approximately 25 percent cash premium and $375 million in an upfront payment. <span style="background-color: #FBFBFB; font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We are eligible to receive up to $</span>270<span style="background-color: #FBFBFB; font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> million in milestone payments for each medicine
      that achieves marketing approval. </span>In addition, we are eligible to receive tiered royalties <span style="background-color: #FBFBFB; font-size: 10pt; font-family: 'Times New Roman', Times, serif;">up to the </span>20 percent range <span style="background-color: #FBFBFB; font-size: 10pt; font-family: 'Times New Roman', Times, serif;">on net sales.</span>&#160;<span style="background-color: #FBFBFB; font-size: 10pt; font-family: 'Times New Roman', Times, serif;">W</span>e are currently advancing nine
    programs under this collaboration and from inception through December 2021, we have received nearly $1.1 billion in payments under this
    collaboration. We will achieve the next payment of $7.5 million if Biogen designates or advances another program<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">under this collaboration. </span></div>

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<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">At the commencement of this collaboration, </span>we
    identified one performance obligation, which was to perform R&amp;D services for Biogen.<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> We determined our transaction price to be $</span>552<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> million, comprised of $</span>375<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> million from the upfront payment and $</span>177<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> million for the premium paid by Biogen for its purchase of our common stock.</span> We determined the fair value of the premium we received by using the stated premium in the SPA and applying a lack of marketability
    discount. We included a lack of marketability discount in our valuation of the premium because Biogen received restricted shares of our common stock. We allocated the transaction price to our single performance obligation.</div>

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<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">From inception through December 2021, we have included $616 million <span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">in payments in the transaction price for our R&amp;D services performance obligation
      under this collaboration, including $</span>23<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">
      million of milestone payments we achieved in 2021 and $</span>11<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> million of milestone payments we achieved in 2020. These milestone payments did not create new performance obligations because they are part of our original R&amp;D services performance obligation. Therefore, we included these
      amounts in our transaction price for our R&amp;D services performance obligation in the period we achieved the milestone payment. We are recognizing revenue for our R&amp;D services performance obligation as we perform services based on our effort to
      satisfy our performance obligation relative to our total effort expected to satisfy our performance obligation. We currently estimate we will satisfy our performance obligation at the end of the contractual term in June 2028.</span></div>

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<div style="text-align: left; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;">2013 Strategic Neurology</div>

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<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">In September 2013, we and Biogen entered into a long-term strategic relationship focused on applying antisense technology
    to advance the treatment of neurodegenerative diseases. As part of the collaboration, Biogen gained exclusive rights to the use of our antisense technology to develop therapies for neurological diseases and has the option to license medicines resulting
    from this collaboration. We will usually be responsible for drug discovery and early development of antisense medicines and Biogen has the option to license antisense medicines after Phase 2 proof-of-concept. In October 2016, we expanded our
    collaboration to include additional research activities we will perform. If Biogen exercises its option to license a medicine, it will assume global development, regulatory and commercialization responsibilities and costs for that medicine. We are
    currently advancing six investigational medicines in development under this collaboration, including <span style="-sec-ix-hidden:Fact_864d03b225ca4f548971b12e6b3ad3d0">a</span> medicine for Parkinson&#8217;s disease (ION859), three medicines for ALS
    (tofersen, IONIS-C9<sub>Rx</sub> and ION541), <span style="-sec-ix-hidden:Fact_7b05dc571fcb46f8bbbe0db51a44d460">a</span> medicine for multiple system atrophy (ION464) and <span style="-sec-ix-hidden:Fact_33617a5e2de04e8688f1a06dd038ea29">a</span> medicine for an undisclosed target. In the fourth quarter of 2018, Biogen exercised its option to license our most advanced ALS medicine, tofersen, our medicine in Phase 3
    development for SOD1 ALS. As a result, Biogen is now responsible for global development, regulatory and commercialization activities and costs for tofersen.</div>

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<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Under the terms of the agreement, we received an upfront payment of $100 million and are eligible to receive milestone payments, license fees and royalty payments for all medicines developed under this collaboration, with the specific amounts dependent upon the
    modality of the molecule advanced by Biogen. For each antisense molecule that is chosen for drug discovery and development under this collaboration, we are eligible to receive up to approximately $260 million in a license fee and milestone payments per program. The $260 million per
    program consists of approximately $60 million in development milestones, including amounts related to the cost of clinical trials, and up to $130 million in milestone payments if Biogen achieves pre-specified regulatory milestones. In addition, we are eligible to receive tiered royalties up to the
    mid-teens on net sales from any antisense medicines developed under this collaboration. From inception through December 2021, we have received over $280
    million in upfront fees, milestone payments and other payments under this collaboration. We will achieve the next payment of up to $70 million if
    Biogen licenses a medicine under this collaboration.</div>

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<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">At the commencement of our 2013 strategic neurology collaboration, we identified one performance obligation, which was to perform R&amp;D services for Biogen. At inception, we determined the transaction price to be the $100 million upfront payment we received and allocated it to our single performance obligation. As we achieve milestone payments for our R&amp;D services, we
    include these amounts in our transaction price for our R&amp;D services performance obligation. We recognized revenue for our R&amp;D services performance obligation based on our effort to satisfy our performance obligation relative to our total effort
    expected to satisfy our performance obligation<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">. </span>In the third quarter of 2019, we updated our estimate of the total effort we expect to expend to
    satisfy our performance obligation. As a result, we recorded a cumulative catch up adjustment of $16.5 million to decrease revenue in the third
    quarter of 2019. During 2020, we completed our remaining<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> research and development services and recognized the remaining revenue related to this performance
      obligation. </span>From inception through the completion of our R&amp;D services performance obligation in 2020, we included $145 million in
    total payments in the transaction price for our R&amp;D services performance obligation.</div>

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<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">Under this collaboration, we have also
      generated additional payments that we concluded were not part of our R&amp;D services performance obligation. We recognized each of these payments in full in the respective quarter we generated the payment because we did not have any performance
      obligations for the respective payment. For example, in the second quarter of 2021, we earned a </span>$10&#160;<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">million milestone payment when Biogen advanced ION541, which we recognized in full because we did not have any performance obligations related to this milestone payment.</span></div>

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<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;">2012 Neurology</div>

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<div style="text-align: justify; text-indent: 35.3pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">In December 2012, we and Biogen entered into a collaboration agreement to develop and commercialize novel antisense
    medicines to treat neurodegenerative diseases. We are responsible for the development of each of the medicines through the completion of the initial Phase 2 clinical study for such medicine. Biogen has the option to license a medicine from each of the
    programs through the completion of the first Phase 2 study for each program. Under this collaboration, we are currently advancing IONIS-MAPT<sub>Rx</sub> for Alzheimer&#8217;s disease and ION582 for AS. If Biogen exercises its option to license a medicine,
    it will assume global development, regulatory and commercialization responsibilities and costs for that medicine. In the fourth quarter of 2019, Biogen exercised its option to license IONIS-MAPT<sub>Rx</sub>. We are responsible for completing the Phase
    1/2 in study patients with mild AD and a one-year long-term extension study. Biogen will have responsibility for global development, regulatory
    and commercialization activities and costs for IONIS-MAPT<sub>Rx</sub>.</div>

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<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">Under the terms of the agreement, we received
      an upfront payment of $</span>30<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> million. Over the
      term of the collaboration, we are eligible to receive up to $</span>210<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> million in a license fee and milestone payments per program, plus a mark-up on the cost estimate of the Phase 1 and 2 studies. The $</span>210<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> million per program consists of up to $</span>10<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> million in development milestone payments, plus a mark-up on the cost estimate of the Phase 1 and
      2 studies and up to $</span>130<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> million in
      milestone payments if Biogen achieves pre-specified regulatory milestones. In addition, we are eligible to receive tiered royalties up to the mid-teens on net sales of any medicines resulting from each of the </span>three<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> programs. From inception through December 2021, we have
      received $</span>155<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> million in payments under
      this collaboration, including $</span>19.5<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> million
      we received from Biogen for achieving milestones for advancing </span>IONIS-MAPT<sub>Rx</sub><sub style="color: #000000;">&#160;</sub><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">during 2020. We will
      achieve the next payment of $</span>25<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">&#160;</span>million
    if Biogen advances a medicine under this collaboration.</div>

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<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Under our collaboration, we determined we had a performance obligation to perform R&amp;D services. We allocated $40 million in total payments to the transaction price for our R&amp;D services performance obligation. In the third quarter of 2019, we completed our
    R&amp;D services performance obligation when we designated a development candidate and Biogen accepted the development candidate. Biogen&#8217;s decision to accept the development candidate was not within our control. We were recognizing revenue as we
    performed services based on our effort to satisfy our performance obligation relative to the total effort expected to satisfy our performance obligation. Because Biogen accepted the development candidate earlier than when we were previously estimating,
    we recognized $6.3 million of accelerated revenue in the third quarter of 2019.</div>

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<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">When we commenced development for IONIS-MAPT<sub>Rx</sub> we identified our development work as a separate performance obligation. We are
    recognizing our IONIS-MAPT<sub>Rx</sub> development performance obligation based on the percentage of completion. From inception through December 2021, we have included $57 million in the transaction price for our IONIS-MAPT<sub>Rx</sub> development performance obligation, including $19.5 million milestone payments we earned from Biogen in 2020 when we advanced IONIS-MAPT<sub>Rx</sub>. We currently estimate we will satisfy our performance obligation in 2022.</div>

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  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">In the fourth quarter of 2019, we identified another performance obligation upon Biogen&#8217;s license of IONIS-MAPT<sub>Rx</sub> because the
    license we granted to Biogen is distinct from our other performance obligations. We recognized the $45 million license fee for IONIS-MAPT<sub>Rx</sub>
    as revenue at that time because Biogen had full use of the license without any continuing involvement from us. Additionally, we did not have any further performance obligations related to the license after we delivered it to Biogen.</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">In the fourth quarter of 2021, we <span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">earned a $</span>10<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> million milestone payment when Biogen advanced ION582, which
      we recognized in full because we did not have any performance obligations related to this milestone payment.</span></div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">During the years ended December 31, 2021, 2020 and 2019, we earned the following revenue from our relationship with Biogen (in millions, except percentage amounts):</div>

<div><br/>
  </div>

<table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;">


  <tr>

    <td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">

        </td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="10" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Year Ended December 31,</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2021</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2020</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2019</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: left; text-indent: -27pt; margin-left: 27pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">SPINRAZA royalties (commercial revenue)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">267.8</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">286.6</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">293.0</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 64%; padding-bottom: 2px;" valign="bottom">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">R&amp;D revenue</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">161.0</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">122.0</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">180.6</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: left; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Total revenue from our relationship with Biogen</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">428.8</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">408.6</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">473.6</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 64%;" valign="bottom">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Percentage of total revenue</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">53</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">%</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">56</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">%</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">42</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">%</div>
        </td>

  </tr>


</table>

<div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 12pt;"><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">Our </span>consolidated balance sheet at
    December 31<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">, </span>2021<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> and </span>2020<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> included deferred revenue of $</span>407.5<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> million and $</span>465.8<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> million, respectively, related to our relationship with Biogen.</span></div>

<div><br/>
  </div>

<div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Joint Development and Commercialization Arrangement</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;">AstraZeneca</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;">Eplontersen Collaboration</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">In December 2021, we entered into a joint development and commercialization agreement with AstraZeneca to develop and
    commercialize eplontersen for the treatment of ATTR. We are jointly developing and preparing to commercialize eplontersen with AstraZeneca in the U.S. We granted AstraZeneca exclusive rights to commercialize eplontersen outside the U.S., except certain
    countries in Latin America. Under the terms of the agreement, we received a $200 million upfront payment. We are eligible to receive up to $485 million in development and approval milestones, and up to $2.9
    billion in sales-related milestone payments. The agreement also includes territory-specific development, commercial and medical affairs cost-sharing provisions. In addition, we are eligible to receive up to mid-20 percent royalties for sales in the U.S. and tiered royalties up to the high teens for sales outside the U.S.</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We evaluated our eplontersen collaboration under ASC 808 and identified four material components: (i) the license we granted to AstraZeneca in 2021, (ii) the co-development activities that we and AstraZeneca will perform, (iii) the co-commercialization
    activities that we and AstraZeneca will perform and (iv) the co-medical affairs activities that we and AstraZeneca will perform.</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We determined that we had a vendor-customer relationship within the scope of ASC 606 for the license we granted to
    AstraZeneca and as a result we had one performance obligation.&#160; For our sole performance obligation, we determined the transaction price was the
    $200 million upfront payment we received. We recognized the upfront payment in full in 2021 because we did not have any remaining performance
    obligations after we delivered the license to AstraZeneca.</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We also concluded that the co-development activities, the co-commercialization activities and the co-medical affairs
    activities are within the scope of ASC 808 because we and AstraZeneca are active participants exposed to the risks and benefits of the activities under the collaboration.&#160; AstraZeneca will pay 55 percent of the costs associated with the ongoing global Phase 3 development program. As we will continue to lead the Phase 3 development program, we will recognize as revenue the 55 percent of cost-share funding AstraZeneca is responsible for in the same period we incur the related development expenses. As AstraZeneca is responsible
    for the majority of the commercial and medical affairs costs in the U.S. and all costs associated with bringing eplontersen to market outside the U.S., we will recognize cost-share funding we receive from AstraZeneca related to these activities as a
    reduction of our commercial and medical affairs expenses.</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We will achieve the next payment of up to $50 million upon the first regulatory approval under this collaboration. Through December 2021, we have generated $200 million in payments under this collaboration.</div>

<div><br/>
  </div>

<div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Research and Development Partners</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;">AstraZeneca</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">In addition to our collaboration for eplontersen, we have two other collaborations with AstraZeneca. One is focused on the treatment of
    cardiovascular, renal and metabolic diseases and the <span style="-sec-ix-hidden:Fact_e7c38e1898fc4f72b5cb9e5bb0749c53">other</span> is focused on the treatment of oncology diseases. We and AstraZeneca are currently
    developing six medicines under these collaborations, including medicines in development to treat people with ATTR amyloidosis, cardiovascular
    disease, a genetically associated form of kidney disease, <span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">NASH and cancer</span>. From inception through December 2021, we have received more than $386 million from our AstraZeneca research and
    development collaborations.</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;">Cardiovascular, Renal and Metabolic Diseases Collaboration</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">In July 2015, we and AstraZeneca formed a collaboration to discover and develop antisense therapies for treating
    cardiovascular, renal and metabolic diseases. Under our collaboration, AstraZeneca has licensed five medicines from us. AstraZeneca is
    responsible for global development, regulatory and commercialization activities and costs for each of the medicines it has licensed from us.</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Under the terms of the agreement, we received a $65 million upfront payment. We are eligible to receive license fees and milestone payments of up to more than $5.5 billion as medicines under this collaboration advance, including up to $1.1 billion
    for the achievement of development milestones, up to $2.9 billion for regulatory milestones and up to $1.5 billion for commercial milestones. In addition, we are eligible to receive tiered royalties up to the low teens on net sales from any product that AstraZeneca successfully
    commercializes under this collaboration agreement. We will achieve the next payment of $10 million under this collaboration if AstraZeneca
    advances a medicine under this collaboration<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">.</span> From inception through December 2021, we have received over $282 million in an upfront fee, license fees, milestone payments, and other payments under this collaboration, including $30 million we earned in 2021 when AstraZeneca licensed a target for a metabolic disease and $10
    million we earned in 2021 when AstraZeneca advanced a target for a metabolic disease.</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">At the commencement of this collaboration, we identified one performance obligation, which was to perform R&amp;D services for AstraZeneca. We determined the transaction price to be the $65 million upfront payment we received and we allocated it to our single performance obligation. We recognized revenue for our R&amp;D services performance obligation as we performed services
    based on our effort to satisfy this performance obligation relative to our total effort expected to satisfy our performance obligation. We<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> completed our
      performance obligation in</span> the fourth quarter of 2021. As we achieve milestone payments for our R&amp;D services, we include these amounts in our transaction price for our R&amp;D services performance obligation. From inception through December<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> 2021</span>, we have included $90 million in payments
    in the transaction price for our R&amp;D services performance obligation.</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Under this collaboration, we have also generated additional payments that we concluded were not part of our R&amp;D
    services performance obligation. We recognized each of these payments in full in the respective quarter we generated the payment because the payments were distinct and we did not have any performance obligations for the respective payment. For example,
    in the fourth quarter of 2021, we earned a $30 million license fee when AstraZeneca licensed a target for a metabolic disease. We recognized the
    license fee as revenue at that time because AstraZeneca had full use of the license without any continuing involvement from us. Additionally, we did not have any further performance obligations related to the license after we delivered it to
    AstraZeneca.</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: left; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;">Oncology Collaboration</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">In December 2012, we entered into a collaboration agreement with AstraZeneca to discover and develop antisense medicines
    to treat cancer. We and AstraZeneca also established an oncology research program. In 2020, AstraZeneca licensed ION736, an investigational medicine in development targeting FOXP3 for the treatment of cancer. AstraZeneca is responsible for global
    development, regulatory and commercialization activities and costs for ION736.</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">Under the terms of this agreement, we
      received $</span>31<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> million in upfront payments.
      We are eligible to receive milestone payments and license fees up to $</span>160<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> million under this collaboration, including up to $</span>42<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> million for the achievement of development milestones and up to $</span>105<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> million for the achievement of regulatory milestones. In addition, we are eligible to receive tiered royalties up to the low teens on net sales from any product that AstraZeneca
      successfully commercializes under this collaboration agreement. From inception through December 2021, we have received over $</span>141<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> million in upfront fees, milestone payments, and other payments under this oncology collaboration, including $</span>13<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> million we earned when AstraZeneca licensed</span> ION736 in 2020. We <span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">will achieve the next payment of $</span>12<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> million if AstraZeneca advances ION736 in development.</span></div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We completed all of the performance obligations we identified under this collaboration in the first quarter of 2018.</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">Under this collaboration, we have also
      generated additional payments that we concluded were not part of other performance obligations discussed above. We recognized each of these payments in full in the respective quarter we generated the payment because the payments were distinct and we
      did not have any performance obligations for the respective payment. In 2020, we earned a $</span>13<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> million license fee when AstraZeneca licensed ION736</span> because AstraZeneca had full use of the license without any continuing involvement from us.</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">During the years ended December 31, 2021, 2020 and 2019, we earned the following revenue from our relationship with AstraZeneca (in millions, except percentage amounts):</div>

<div><br/>
  </div>

<table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;">


  <tr>

    <td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">

        </td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="10" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Year Ended December 31,</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2021</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2020</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2019</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: left; text-indent: -27pt; margin-left: 27pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">R&amp;D revenue</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">254.6</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">88.0</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">28.1</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 64%;" valign="bottom">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Percentage of total revenue</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">31</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">%</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">12</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">%</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">3</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">%</div>
        </td>

  </tr>


</table>

<div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 12pt;"><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">We did </span>no<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">t have any deferred revenue from our relationship with
      AstraZeneca at December 31, 2021. Our </span>consolidated balance sheet at <span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">December 31, </span>2020<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> included deferred revenue of $</span>10.0<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> million from our relationship with AstraZeneca.</span></div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: left; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;">Bayer</div>

<div><br/>
    </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">In May 2015, we entered into an exclusive license agreement with Bayer to develop and commercialize IONIS-FXI<sub>Rx</sub>
      for the prevention of thrombosis. We were responsible for completing a Phase 2 study of IONIS-FXI<sub>Rx</sub> in people with end-stage renal disease on hemodialysis. Under the terms of the agreement, we received a $100 million upfront payment in the second quarter of 2015. In February 2017, we amended our agreement with Bayer to advance IONIS-FXI<sub>Rx</sub> and to
      initiate development of fesomersen, which Bayer licensed. In conjunction with the decision to advance these programs, we received a $75 million
      payment from Bayer. In October 2019, Bayer decided it would advance fesomersen following positive clinical results. Bayer is now responsible for all global development, regulatory and commercialization activities and costs for the FXI program.</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We are eligible to receive up to $385 million in license fees, milestone payments and other payments, including up to $125
    million for the achievement of development milestones and up to $110 million for the achievement of sales milestones. In addition, we are
    eligible to receive tiered royalties in the low to high 20 percent range on gross margins of both medicines combined. From inception through
    December 2021, we have received over $191 million from this collaboration. We will achieve the next payment of $20 million if Bayer initiates a Phase 3 study for the FXI program.</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">At the commencement of this collaboration, we identified three performance obligations, the license of IONIS-FXI<sub>Rx</sub>, R&amp;D services and delivery of API, all of which we completed in 2016.</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">In February 2017, when we amended our collaboration with Bayer, we identified two new performance obligations<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">, </span>one<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> for the license of fesomersen and </span>one<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> for R&amp;D services</span>. We determined the transaction price to be the $75 million payment. We allocated $64.9 million to
    <span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">the license of fesomersen based on its estimated relative stand-alone selling price and recognized the associated revenue upon our delivery of the license in
      the first quarter of 2017. We allocated $</span>10.1<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> million to our R&amp;D services performance obligation based on an estimated relative stand-alone selling price. </span>We recognized revenue for our R&amp;D services performance obligation as we performed services based on our effort to
    satisfy our performance obligation relative to our total effort expected to satisfy our performance obligation. We completed our obligation in the third quarter of 2019.</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">In the fourth quarter of 2019, we earned a $10 million milestone payment when Bayer decided it would advance fesomersen. We recognized this milestone payment in full in the fourth quarter of 2019 because we did not have any performance
    obligations related to this milestone payment.</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">During the years ended December 31, 2021, 2020 and 2019, we earned the following revenue from our relationship with Bayer (in millions, except percentage amounts):</div>

<div><br/>
  </div>

<table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;">


  <tr>

    <td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">

        </td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="10" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Year Ended December 31,</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2021</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2020</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2019</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: left; text-indent: -27pt; margin-left: 27pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">R&amp;D revenue</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">1.1</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">3.2</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">14.3</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 64%;" valign="bottom">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Percentage of total revenue</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">0</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">%</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">0</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">%</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">1</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">%</div>
        </td>

  </tr>


</table>

<div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 12pt;"><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Our consolidated balance sheet at December 31, 2021 included an <span style="-sec-ix-hidden:Fact_613e73fd93424660870569ffe2993ea8">insignificant</span> amount of deferred revenue related to our relationship with Bayer. We did not
    have any deferred revenue from our relationship with Bayer at December 31, 2020.</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;">GSK</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">In March 2010, we entered into an alliance with GSK using our antisense drug discovery platform to discover and develop
    new medicines against targets for serious and rare diseases, including infectious diseases and some conditions causing blindness. Under the terms of the agreement, we received upfront payments of $35 million. Our collaboration with GSK currently includes two medicines targeting
    hepatitis B virus, or HBV: bepirovirsen and IONIS-HBV-L<sub>Rx</sub>. We designed these medicines to reduce the production of viral proteins associated with HBV infection. In the third quarter of 2019, following positive Phase 2 results, GSK licensed
    our HBV program. GSK is responsible for all global development, regulatory and commercialization activities and costs for the HBV program.</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Under our agreement, if GSK successfully develops these medicines and achieves pre-agreed sales targets, we could receive
    license fees and milestone payments of more than $260 million, including up to $47.5 million for the achievement of development milestones, up to $120 million for the
    achievement of regulatory milestones and up to $70 million for the achievement of sales milestones. In addition, we are eligible to receive
    tiered royalties up to the mid-teens on net sales from any product that GSK successfully commercializes under this alliance. From inception through December 2021, we have received more than $190 million in payments under this alliance with GSK. We will achieve the next payment of $15
    million if GSK initiates a Phase 3 study of a medicine under this program.</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">We completed our R&amp;D services performance
      obligations under our collaboration in the first quarter of 2015. </span>We identified a new performance obligation when we granted GSK the license of the HBV program and assigned related intellectual property rights in the third quarter of 2019
    because the license was distinct from our other performance obligations. We recognized the $25 million license fee for the HBV program as revenue
    at that time because GSK had full use of the license without any continuing involvement from us. Additionally, we did not have any further performance obligations related to the license after we delivered it to GSK.</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We do not have any remaining performance obligations under our collaboration with GSK; however, we can still earn additional payments and
    royalties as GSK advances the HBV program.</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">During the years ended December 31, 2021, 2020 and 2019, we earned the following revenue from our relationship with GSK (in millions, except percentage amounts):</div>

<div><br/>
  </div>

<table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;">


  <tr>

    <td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">

        </td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="10" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Year Ended December 31,</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2021</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2020</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2019</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: left; text-indent: -27pt; margin-left: 27pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">R&amp;D revenue</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#8212;</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">0.2</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">25.4</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 64%;" valign="bottom">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Percentage of total revenue</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#8212;</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">0</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">%</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">2</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">%</div>
        </td>

  </tr>


</table>

<div style="text-align: justify; font-family: 'Times New Roman', Times, serif; font-size: 12pt;"><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We did not
    have any deferred revenue from our relationship with GSK at December 31, 2021 and 2020.</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;">Novartis</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">In January 2017, we initiated a collaboration
      with Novartis to develop and commercialize pelacarsen and olezarsen.</span><sub style="color: #000000;">&#160;</sub>We received a $75 million
    upfront payment in the first quarter of 2017. <span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">In the first quarter of 2019, Novartis licensed pelacarsen</span> and we earned a $150 million license fee. Novartis is responsible for conducting and funding future development and regulatory activities for pelacarsen, including a global
    Phase 3 cardiovascular outcomes study that Novartis initiated in the fourth quarter 2019.<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">&#160;</span>In connection with Novartis&#8217; license of pelacarsen, we and
    Novartis established a more definitive framework under which the companies would negotiate the co-commercialization of pelacarsen in selected markets. Included in this framework is an option by which Novartis could solely commercialize pelacarsen in
    exchange for Novartis paying us increased sales milestone payments based on sales of pelacarsen.<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">&#160;When Novartis decided to not exercise its option for </span>olezarsen,
    we retained rights to develop and commercialize olezarsen.</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Under the collaboration, we are eligible to receive up to $675 million in milestone payments, including $25 million for the achievement of a
    development milestone, up to $290 million for the achievement of regulatory milestones and up to $360 million for the achievement of sales milestones. <span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">From inception through December
      2021, we have received nearly $</span>425<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> million
      in upfront payments, milestone payments, license fees and other payments from this collaboration. </span>We are also eligible to receive tiered royalties in the mid-teens to low 20 percent range on net sales of pelacarsen. In August 2021, we earned a $25 million
    milestone payment from Novartis when Novartis achieved 50 percent enrollment in the Lp(a) HORIZON Phase 3 cardiovascular outcome study of
    pelacarsen. We recognized the milestone payment in full in the third quarter of 2021 because we did not have any remaining performance obligations related to the milestone payment. <span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">We</span><span style="background-color: #FBFBFB; font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> will achieve the next payment of up to $</span>75<span style="background-color: #FBFBFB; font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> million if Novartis advances regulatory activities for
      pelacarsen.</span></div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">In conjunction with this collaboration, we entered into a SPA with Novartis. As part of the SPA, Novartis purchased 1.6 million shares of our common stock for $100
    million in the first quarter of 2017.</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">At the commencement of this collaboration, we identified four separate performance obligations:</div>

<div><br/>
  </div>

<table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">


  <tr>

    <td style="width: 36pt;"/>

    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;">R&amp;D services for pelacarsen;</div>
        </td>

  </tr>


</table>

<table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">


  <tr>

    <td style="width: 36pt;"/>

    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;">R&amp;D services for olezarsen;</div>
        </td>

  </tr>


</table>

<table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">


  <tr>

    <td style="width: 36pt;"/>

    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;">API for pelacarsen; and</div>
        </td>

  </tr>


</table>

<table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">


  <tr>

    <td style="width: 36pt;"/>

    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;">API for olezarsen.</div>
        </td>

  </tr>


</table>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We determined that the R&amp;D services for each medicine and the API for each medicine were distinct performance obligations.</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We determined our transaction price to be $108.4
    million, comprised of the following:</div>

<div><br/>
  </div>

<table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">


  <tr>

    <td style="width: 36pt;"/>

    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$75 million from the upfront payment;</div>
        </td>

  </tr>


</table>

<table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">


  <tr>

    <td style="width: 36pt;"/>

    <td style="width: 18pt; vertical-align: top; align: right; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$28.4 million for the premium paid by Novartis for its purchase
            of our common stock at a premium in the first quarter of 2017; and</div>
        </td>

  </tr>


</table>

<table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">


  <tr>

    <td style="width: 36pt;"/>

    <td style="width: 18pt; vertical-align: top; align: right; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$5.0 million for the potential premium Novartis would have paid
            if they purchased our common stock in the future.</div>
        </td>

  </tr>


</table>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We allocated the transaction price based on the estimated stand-alone selling price of each performance obligation as follows:</div>

<div><br/>
  </div>

<table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">


  <tr>

    <td style="width: 36pt;"/>

    <td style="width: 18pt; vertical-align: top; align: right; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">$</span>64.0<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> million for the R&amp;D services for pelacarsen;</span></div>
        </td>

  </tr>


</table>

<table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">


  <tr>

    <td style="width: 36pt;"/>

    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$40.1 million for the R&amp;D services for <span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">olezarsen</span>; </div>
        </td>

  </tr>


</table>

<table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">


  <tr>

    <td style="width: 36pt;"/>

    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$1.5</span> million for the delivery of pelacarsen API; and</div>
        </td>

  </tr>


</table>

<table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">


  <tr>

    <td style="width: 36pt;"/>

    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$2.8</span> million for the delivery of olezarsen API.</div>
        </td>

  </tr>


</table>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We completed our R&amp;D services performance obligations for olezarsen and pelacarsen<sub>&#160;</sub>in 2019. As such, we recognized all
    revenue we allocated to the olezarsen and pelacarsen<sub>&#160;</sub>R&amp;D services as of the end of 2019.</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">We recognized revenue related to the R&amp;D
      services for pelacarsen and olezarsen performance obligations as we performed services </span>based on our effort to satisfy our performance obligations relative to our total effort expected to satisfy our performance obligations<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">.</span></div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">During the years ended December 31, 2021, 2020 and 2019, we earned the following revenue from our
    relationship with Novartis (in millions, except percentage amounts):</div>

<div><br/>
  </div>

<table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;">


  <tr>

    <td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">

        </td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="10" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Year Ended December 31,</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2021</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2020</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2019</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: left; text-indent: -27pt; margin-left: 27pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">R&amp;D revenue</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">25.5</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">1.0</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">187.4</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 64%;" valign="bottom">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Percentage of total revenue</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">3</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">%</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">0</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">%</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">17</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">%</div>
        </td>

  </tr>


</table>

<div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 12pt;"><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We did not
    have any deferred revenue from our relationship with Novartis at December 31, 2021 and 2020.</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;">Roche</div>

<div><br/>
  </div>

<div style="text-align: left; margin-left: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;">Huntington&#8217;s Disease</div>

<div><br/>
    </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">In April 2013, we formed an alliance with Hoffman-La Roche Inc. and F. Hoffmann-La Roche Ltd., collectively Roche, to
      develop treatments for HD based on our antisense technology. Under the agreement, we discovered and developed tominersen, an investigational medicine targeting HTT protein. We developed tominersen through completion of our Phase 1/2 clinical study in
      people with early stage HD. In the fourth quarter of 2017, upon completion of the Phase 1/2 study, Roche exercised its option to license tominersen. Roche is responsible for all global development, regulatory and commercialization activities and
      costs for tominersen.</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Under the terms of the agreement, we received an upfront payment of $30 million in April 2013 and an additional $3 million payment in 2017. We are eligible
    to receive up to $365 million in a license fee and milestone payments including up to $70 million for the achievement of development milestones, up to $170 million for the
    achievement of regulatory milestones and up to $80 million for the achievement of sales milestones. In addition, we are eligible to receive up to
    $136.5 million in milestone payments for each additional medicine successfully developed. We are also eligible to receive tiered royalties up to
    the mid-teens on net sales of any product resulting from this alliance. From inception through December 2021, we have received $150 million in upfront fees, milestone payments and license fees under this collaboration. We will achieve the next payment of $15 million if Roche advances tominersen into registration.</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">At the commencement of this collaboration, we identified one performance obligation, which was to perform R&amp;D services for Roche. We determined the transaction price to be the $30 million upfront payment we received and allocated it to our single performance obligation. As we achieved milestone payments for our R&amp;D services, we included these amounts in our
    transaction price for our R&amp;D services performance obligation. We recognized revenue for our R&amp;D services performance obligation over our period of performance, which ended in the third quarter of 2017.</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Under this collaboration, we have also generated additional payments that we concluded were not part of our R&amp;D
    services performance obligation. We recognized each of these payments in full in the respective quarter in which we generated the payment because the payments were distinct and we did not have any performance obligations for the respective payment. In
    2019, we earned $35 million in milestone payments when Roche dosed the first patient in the Phase 3 study of tominersen.</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">In January 2022, <span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">Roche announced it is
      actively preparing to initiate a new Phase 2 study of tominersen in patients with HD. Post-hoc analyses from the GENERATION HD1 study suggested tominersen may benefit younger adult patients with lower disease burden</span>. In March 2021, Roche
    decided to discontinue dosing in the Phase 3 GENERATION HD1 study of tominersen in patients with manifest HD based on the results of a pre-planned review of data from the Phase 3 study conducted by an unblinded iDMC. We do not have any remaining
    performance obligations related to tominersen under this collaboration with Roche; however, we can still earn additional payments and royalties as Roche advances tominersen.</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: left; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;"><span style="background-color: #FBFBFB; font-size: 10pt; font-family: 'Times New Roman', Times, serif;">IONIS-FB-L</span><sub><span style="background-color: #FBFBFB;">Rx</span></sub><span style="background-color: #FBFBFB; font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> for Complement-Mediated Diseases</span></div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">In October 2018, we entered into a
      collaboration agreement with Roche to</span><span style="background-color: #FBFBFB; font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> develop IONIS-FB-L</span><sub style="color: #000000;">Rx</sub><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> for the treatment of complement-mediated diseases. We are currently conducting Phase 2 studies in </span>two<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> disease indications for </span><span style="background-color: #FBFBFB; font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">IONIS-FB-L</span><sub style="color: #000000;">Rx</sub><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">, </span>one<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> for the treatment of patients with GA, the advanced stage
      of dry AMD, and a </span><span style="-sec-ix-hidden:Fact_04500eaf787641bfbd86183ba9891b89">second</span><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> for the treatment
      of patients with IgA nephropathy. </span>Roche<span style="background-color: #FBFBFB; font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> has the option to license IONIS-FB-L</span><sub style="color: #000000;"><span style="background-color: #FBFBFB;">Rx</span></sub><span style="background-color: #FBFBFB; font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> at the completion of these studies. Upon licensing, </span>Roche <span style="background-color: #FBFBFB; font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">will be responsible for global development, regulatory and commercialization activities and costs.</span></div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="background-color: #FBFBFB; font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">Under the terms of
      this agreement, we received a </span>$75 million<span style="background-color: #FBFBFB; font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> upfront payment in the fourth quarter of 2018. We are eligible to receive more than </span>$680 million<span style="background-color: #FBFBFB; font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> in development, regulatory and sales milestone payments and license fees. In addition, we are also eligible to receive tiered royalties
      from the high teens to </span>20 percent<span style="background-color: #FBFBFB; font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> on net sales. </span><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">From inception through December </span>2021<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">, we have received $</span>75<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> million in upfront fees, milestone payments and license fees under this collaboration. </span><span style="background-color: #FBFBFB; font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">We will achieve the next payment of $</span>20<span style="background-color: #FBFBFB; font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> million if we further advance </span>the Phase 2 study in patients with dry AMD<span style="background-color: #FBFBFB; font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">.</span></div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">At the commencement of this collaboration, we identified one performance obligation, which was to perform R&amp;D services for Roche. We determined the transaction price to be the $75 million upfront payment we received and allocated it to our single performance obligation. We are recognizing revenue for our R&amp;D services performance obligation as we perform services
    based on our effort to satisfy our performance obligation relative to our total effort expected to satisfy our performance obligation. During the fourth quarter of 2020, we <span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">updated our estimate of the total effort we expected to expend to satisfy our performance obligation under this collaboration.</span>&#160;<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">In the
      fourth quarter of 2020, we recorded a cumulative catch up adjustment of $</span>9.2<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> million to decrease revenue because we updated our total cost estimate to complete the Phase 2 study of </span><span style="background-color: #FBFBFB; font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">IONIS-FB-L</span><sub style="color: #000000;"><span style="background-color: #FBFBFB;">Rx </span></sub><span style="background-color: #FBFBFB; font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">for
      the </span><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">treatment of patients with GA. </span>We<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> currently
      estimate we will satisfy our performance obligation in </span>the fourth quarter of 2023.</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">During the years ended December 31, 2021, 2020 and 2019, we earned the following revenue from our relationship with Roche (in millions, except percentage amounts):</div>

<div><br/>
  </div>

<table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;">


  <tr>

    <td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">

        </td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="10" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Year Ended December 31,</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2021</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2020</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2019</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: left; text-indent: -27pt; margin-left: 27pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">R&amp;D revenue</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">17.2</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">5.9</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">57.0</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 64%;" valign="bottom">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Percentage of total revenue</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">2</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">%</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">1</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">%</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">5</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">%</div>
        </td>

  </tr>


</table>

<div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 12pt;"><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">Our </span>consolidated balance sheet at <span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">December 31, </span>2021<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> and </span>2020<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> included deferred revenue of $</span>31.6<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> million and $</span>47.2<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">
      million related to our relationship with Roche, respectively.</span></div>

<div><br/>
  </div>

<div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Commercialization Partnerships</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: left; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;">Swedish Orphan Biovitrum AB (Sobi)</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We began commercializing TEGSEDI and WAYLIVRA in Europe in January 2021 and TEGSEDI in North America in April 2021 through
    distribution agreements with Sobi. Under our agreements, we are responsible for supplying finished goods inventory to Sobi and Sobi is responsible for selling each medicine to the end customer. In exchange, we earn a distribution fee on net sales from
    Sobi for each medicine.</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: left; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;">PTC Therapeutics</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">In August 2018, we entered into an exclusive
      license agreement with PTC Therapeutics to commercialize TEGSEDI and WAYLIVRA in Latin America and certain Caribbean countries. Under the license agreement, we are eligible to receive royalties from PTC in the mid-</span>20 percent<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> range on net sales for each medicine. </span>In
    December 2021, we started receiving royalties from PTC for TEGSEDI sales<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">.</span></div>

<div><br/>
  </div>

<div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Technology Enhancement Collaboration</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: left; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic; font-weight: bold;">Bicycle License Agreement</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">In December 2020, we entered into a collaboration agreement with Bicycle and obtained an option to license its peptide technology to
    potentially increase the delivery capabilities of our LICA medicines. In July 2021, we paid $42 million when we exercised our option to license
    Bicycle&#8217;s technology, which included an equity investment in Bicycle. As part of our stock purchase, we entered into a lockup agreement with Bicycle that restricts our ability to trade our Bicycle shares for one year. In 2021, we recorded a $7.2 million equity investment for the
    shares we received in Bicycle. We recognized the remaining $34.8 million as R&amp;D expense in 2021. From inception through December 31, 2021, we
    have paid Bicycle $46.6 million under this collaboration agreement.</div>

<div><br/>
  </div>

<div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Other Agreements</div>

<div><br/>
    </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;">Alnylam Pharmaceuticals, Inc.</div>

<div><br/>
    </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Under the terms of our agreement with Alnylam, we co-exclusively (with ourselves) licensed to Alnylam our patent estate
      relating to antisense motifs and mechanisms and oligonucleotide chemistry for double-stranded RNAi therapeutics, with Alynylam having the exclusive right to grant platform sublicenses for double-stranded RNAi. In exchange for such rights, Alynylam
      gave us a technology access fee, participation in fees from Alnylam&#8217;s partnering programs, as well as future milestone and royalty payments from Alnylam. We retained exclusive rights to our patents for single-stranded antisense therapeutics and for a
      limited number of double-stranded RNAi therapeutic targets and all rights to single-stranded RNAi, or ssRNAi, therapeutics. In turn, Alnylam nonexclusively licensed to us its patent estate relating to antisense motifs and mechanisms and
      oligonucleotide chemistry to research, develop and commercialize single-stranded antisense therapeutics, ssRNAi therapeutics, and to research double-stranded RNAi compounds. We also received a license to develop and commercialize double-stranded RNAi
      therapeutics targeting a limited number of therapeutic targets on a nonexclusive basis. Additionally, in 2015, we and Alnylam entered into an alliance in which we cross-licensed intellectual property. Under this alliance, we and Alnylam each obtained
      exclusive license rights to four therapeutic programs. Alnylam granted us an exclusive, royalty-bearing license to its chemistry, RNA targeting mechanism and target-specific intellectual property for oligonucleotides against four targets, including
      FXI and Apo(a) and two other targets. In exchange, we granted Alnylam an exclusive, royalty-bearing license to our chemistry, RNA targeting mechanism and target-specific intellectual property for oligonucleotides against four other targets. Alnylam
      also granted us a royalty-bearing, non-exclusive license to new platform technology arising from May 2014 through April 2019 for single-stranded antisense therapeutics. In turn, we granted Alnylam a royalty-bearing, non-exclusive license to new
      platform technology arising from May 2014 through April 2019 for double-stranded RNAi therapeutics.</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">In the fourth quarter 2020, we completed an arbitration process with Alnylam. The arbitration panel awarded us $41.2 million for payments owed to us by Alnylam related to Alnylam&#8217;s agreement with Sanofi Genzyme. We recognized the $41.2 million payment from Alnylam as revenue in the fourth quarter of 2020 because we did not have any performance obligations for the respective payment.</div>

<div><br/>
    </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">During the years ended December 31, <span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">2021</span>, <span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">2020</span> and <span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">2019</span>, we
      earned the following revenue from our relationship with Alnylam (in millions, except percentage amounts):</div>

<div><br/>
    </div>

<table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;">


  <tr>

    <td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">

        </td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="10" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Year Ended December 31,</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2021</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2020</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2019</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: left; text-indent: -27pt; margin-left: 27pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">R&amp;D revenue</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#8212;</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">47.9</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">24.1</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 64%;" valign="bottom">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Percentage of total revenue</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#8212;</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">7</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">%</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">2</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">%</div>
        </td>

  </tr>


</table>

<div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 12pt;"><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We did not
    have any deferred revenue from our relationship with Alnylam at December 31, 2021 and 2020.</div>
<span></span>
</td>
</tr>
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<span style="display: none;">v3.22.0.1</span><table class="report" border="0" cellspacing="2" id="idm139691016545272">
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<th class="tl" colspan="1" rowspan="2"><div style="width: 200px;"><strong>Akcea Merger<br></strong></div></th>
<th class="th" colspan="1">12 Months Ended</th>
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<tr><th class="th"><div>Dec. 31, 2021</div></th></tr>
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<div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">7. Akcea Merger</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;">Purchase Price and Direct Transaction Costs Accounting for the Akcea Merger</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">In October 2020, we reacquired the shares of Akcea&#8217;s common stock we did not own, increasing our ownership from 76 percent to 100 percent. Under the purchase
    agreement, we purchased 24.8 million shares at $18.15
    per share, resulting in a total purchase price of $450.6 million.</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">To reflect our 100 percent
    ownership, we accounted for the increase in our ownership by eliminating the noncontrolling interest adjustment in stockholders&#8217; equity in accordance with the Consolidation accounting guidance (ASC Topic 810). We recognized the difference between the
    purchase price and the adjustment to noncontrolling interest in stockholders&#8217; equity as additional-paid-in capital. Refer to our <span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Statement of
      Stockholders&#8217; Equity</span> for detailed amounts.</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We accounted for the transaction costs related to the Akcea Merger as a direct charge to stockholders&#8217; equity. We incurred
    $40.6 million of direct transaction costs from the Akcea Merger, primarily comprised of banking and legal fees.</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;">Equity Award Payouts related to the Akcea Merger</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">In October 2020, as part of the Akcea Merger,
      Ionis cancelled all of Akcea&#8217;s equity awards. In exchange for the cancelled awards, if eligible under the terms of the Akcea Merger, we paid holder&#8217;s a cash payment. We paid $</span>18.15<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> for each outstanding RSU. For each outstanding option with an exercise price less than $</span>18.15<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">, we paid $</span>18.15<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> less the exercise price. As a result, we paid out $</span>53.4<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> million in the fourth quarter of 2020 related to Akcea&#8217;s
      cancelled equity awards. We accounted for these payments as part of the transaction costs recorded to stockholders&#8217; equity in the fourth quarter of 2020. </span>Because we did not replace the Akcea awards, we recognized all unrecognized non-cash
    stock-based compensation ($59.3 million) under Akcea&#8217;s Plan in our statement of operations in the post-merger period in the fourth quarter of
    2020.</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;">Severance and Retention Costs related to the Akcea Merger</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">As a result of the Akcea Merger, we incurred severance and retention expenses of $27.0 million. During 2021 and 2020, we recorded $11.7 million and $15.3 million of severance and retention related costs in operating expenses, respectively. As of December 31, 2021, we have recognized all severance and
    retention costs related to the Akcea Merger.</div>

<div style="text-align: justify;"><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">The following table summarizes the severance and retention expenses related to the Akcea Merger that we recognized for the periods indicated (in
    millions):</div>

<div style="text-align: justify;"><br/>
  </div>

<table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;">


  <tr>

    <td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">

        </td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Year Ended</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">December 31, 2021</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: top; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Year Ended</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">December 31, 2020</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 76%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">R&amp;D expenses</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">5.1</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">3.9</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 76%; padding-bottom: 2px;" valign="bottom">
          <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">SG&amp;A expenses</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">6.6</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">11.4</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 76%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Total</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">11.7</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">15.3</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>


</table>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">The following table summarizes the severance and retention reserve amounts related to the Akcea Merger that we included in
    accrued compensation for the period indicated (in millions):</div>

<div style="text-align: justify;"><br/>
  </div>

<table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;">


  <tr>

    <td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">

        </td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Year Ended</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">December 31, 2021</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: top; width: 88%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Beginning balance as of January 1, 2021</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">14.7</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: top; width: 88%;" valign="bottom">
          <div style="text-align: left; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Amount expensed during the year</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">13.5</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: top; width: 88%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: left; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Reserve adjustments during the year</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(1.8</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

  </tr>

  <tr>

    <td style="vertical-align: top; width: 88%;" valign="bottom">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Net amount expensed during the year</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">11.7</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: top; width: 88%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Amounts paid during the year</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(26.4</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

  </tr>

  <tr>

    <td style="vertical-align: top; width: 88%; padding-bottom: 4px;" valign="bottom">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Ending balance as of December 31, 2021</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#8212;</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>


</table>

<div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 12pt;"><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: left; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">The reserve adjustments during the period primarily related to forfeitures of severance and retention payments as a result of employee
    terminations before they earned the amounts.</div>
<span></span>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 810<br> -URI http://asc.fasb.org/topic&amp;trid=2197479<br></p></div>
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<span style="display: none;">v3.22.0.1</span><table class="report" border="0" cellspacing="2" id="idm139691015115032">
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<th class="tl" colspan="1" rowspan="2"><div style="width: 200px;"><strong>Severance and Retention Costs related to our Restructured Operations<br></strong></div></th>
<th class="th" colspan="1">12 Months Ended</th>
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<tr><th class="th"><div>Dec. 31, 2021</div></th></tr>
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<div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">8. Severance and Retention Costs related to our
    Restructured Operations</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;">Restructured European Operations</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">In the fourth quarter of 2020, </span>we
    entered into a distribution agreement with Sobi to commercialize TEGSEDI and WAYLIVRA in Europe. Under the distribution agreement, Sobi took over all material distribution operations at the end of January 2021. <span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">We remain the marketing authorization holder for TEGSEDI and WAYLIVRA in Europe. We will continue to maintain limited European operations including regulatory, manufacturing, and the
      management of relationships with key opinion leaders. We will also continue to lead the TEGSEDI and WAYLIVRA global commercial strategy.</span></div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">As a result of this change, we incurred severance and retention expenses of $14.2 million. During 2021 and 2020, we recorded $1.7 million and $12.5 million of severance and retention related costs in operating expenses, respectively. As of December 31, 2021, we have recognized all severance and
    retention costs related to this agreement.</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">The following table summarizes the
    severance and retention expenses related to our restructured European operations that we recognized for the periods indicated (in millions):</div>

<div><br/>
  </div>

<table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;">


  <tr>

    <td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">

        </td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Year Ended</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">December 31, 2021</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: top; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Year Ended</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">December 31, 2020</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 76%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">R&amp;D expenses</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">0.6</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">4.2</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 76%; padding-bottom: 2px;" valign="bottom">
          <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">SG&amp;A expenses</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">1.1</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">8.3</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 76%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Total</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">1.7</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">12.5</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>


</table>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">The following table summarizes the severance and retention reserve amounts related to our restructured European operations
    that we included in accrued compensation for the period indicated (in millions):</div>

<div style="text-align: justify;"><br/>
  </div>

<table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;">


  <tr>

    <td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">

        </td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Year Ended</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">December 31, 2021</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: top; width: 88%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Beginning balance as of January 1, 2021</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">12.4</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: top; width: 88%;" valign="bottom">
          <div style="text-align: left; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Amount expensed during the year</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">2.6</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: top; width: 88%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: left; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Reserve adjustments during the year</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(0.9</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

  </tr>

  <tr>

    <td style="vertical-align: top; width: 88%;" valign="bottom">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Net amount expensed during the year</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">1.7</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: top; width: 88%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Amounts paid during the year</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(14.1</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

  </tr>

  <tr>

    <td style="vertical-align: top; width: 88%; padding-bottom: 4px;" valign="bottom">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Ending balance as of December 31, 2021</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#8212;</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>


</table>

<div style="text-align: left;"><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: left; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">The reserve adjustments during the period primarily related to tax expense adjustments.</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;">Restructured North American TEGSEDI Operations</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">In April 2021, we entered into a distribution agreement with Sobi for TEGSEDI in North America. Under the terms of the
    distribution agreement, we will retain the marketing authorizations for TEGSEDI in the U.S. and Canada. We will continue to supply commercial product to Sobi and manage regulatory and manufacturing processes, as well as relationships with key opinion
    leaders. We will also continue to lead the TEGSEDI global commercial strategy. Sobi will otherwise have responsibility for commercializing TEGSEDI in the U.S. and Canada.</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">In connection with restructuring our North American TEGSEDI operations, or Restructured North American TEGSEDI Operations,
    we enacted a plan to reorganize our Akcea workforce in North America to better align with the needs of our business and to focus on our wholly owned pipeline.</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">The following table summarizes the severance expenses related to our
    Restructured North American TEGSEDI Operations that we recognized for the period indicated (in millions):</div>

<div style="text-align: justify;"><br/>
  </div>

<table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;">


  <tr>

    <td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">

        </td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Year Ended</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">December 31, 2021</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 88%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">R&amp;D expenses</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">2.3</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 88%; padding-bottom: 2px;" valign="bottom">
          <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">SG&amp;A expenses</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">7.1</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 88%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Total</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">9.4</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>


</table>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We recognized all severance expenses related to our Restructured North American
    TEGSEDI Operations during the three months ended June 30, 2021.</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">The following table summarizes the severance reserve amounts related to our
    Restructured North American TEGSEDI Operations that we included in accrued compensation for the period indicated (in millions):</div>

<div style="text-align: justify;"><br/>
  </div>

<table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;">


  <tr>

    <td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">

        </td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Year Ended</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">December 31, 2021</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: top; width: 88%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Beginning balance as of January 1, 2021</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#8212;</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: top; width: 88%;" valign="bottom">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Net amount expensed during the year</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

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          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">9.4</div>
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  <tr>

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          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Amounts paid during the year</div>
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    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(9.4</div>
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          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
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    <td style="vertical-align: top; width: 88%; padding-bottom: 4px;" valign="bottom">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Ending balance as of December 31, 2021</div>
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    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
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          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#8212;</div>
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    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom">&#160;</td>

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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The entire disclosure for restructuring and related activities. Description of restructuring activities such as exit and disposal activities, include facts and circumstances leading to the plan, the expected plan completion date, the major types of costs associated with the plan activities, total expected costs, the accrual balance at the end of the period, and the periods over which the remaining accrual will be settled.</p></div>
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<span style="display: none;">v3.22.0.1</span><table class="report" border="0" cellspacing="2" id="idm139691017167400">
<tr>
<th class="tl" colspan="1" rowspan="2"><div style="width: 200px;"><strong>Employment Benefits<br></strong></div></th>
<th class="th" colspan="1">12 Months Ended</th>
</tr>
<tr><th class="th"><div>Dec. 31, 2021</div></th></tr>
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<td class="text">&#160;<span></span>
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<td class="text">
<div style="text-align: justify; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">9. Employment Benefits</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We have employee 401(k) salary deferral plans covering all employees. Employees could make contributions by withholding a
    percentage of their salary up to the IRS annual limits of $20,500 and $27,000 in 2021 for employees under 50 years old and employees 50 years old or over,
    respectively. We made approximately $5.5 million, $5.7
    million and $6.4 million in matching contributions for the years ended December 31, 2021, 2020 and 2019, respectively.</div>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The entire disclosure for retirement benefits.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/exampleRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 715<br> -SubTopic 20<br> -Section 55<br> -Paragraph 17<br> -URI http://asc.fasb.org/extlink&amp;oid=123450688&amp;loc=d3e4179-114921<br><br>Reference 2: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 715<br> -SubTopic 20<br> -Section S99<br> -Paragraph 2<br> -URI http://asc.fasb.org/extlink&amp;oid=21916913&amp;loc=d3e273930-122802<br><br>Reference 3: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 715<br> -SubTopic 20<br> -Section 50<br> -Paragraph 1<br> -Subparagraph (d)(i)<br> -URI http://asc.fasb.org/extlink&amp;oid=123447040&amp;loc=d3e1928-114920<br><br>Reference 4: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 715<br> -SubTopic 20<br> -Section 50<br> -Paragraph 1<br> -Subparagraph (o)<br> -URI http://asc.fasb.org/extlink&amp;oid=123447040&amp;loc=d3e1928-114920<br><br>Reference 5: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 715<br> -SubTopic 20<br> -Section 50<br> -Paragraph 1<br> -Subparagraph (p)<br> -URI http://asc.fasb.org/extlink&amp;oid=123447040&amp;loc=d3e1928-114920<br><br>Reference 6: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 715<br> -SubTopic 70<br> -Section 50<br> -Paragraph 1<br> -URI http://asc.fasb.org/extlink&amp;oid=49170846&amp;loc=d3e28014-114942<br><br>Reference 7: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 715<br> -URI http://asc.fasb.org/topic&amp;trid=2235017<br><br>Reference 8: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 715<br> -SubTopic 60<br> -Section 50<br> -Paragraph 3<br> -Subparagraph (c)<br> -URI http://asc.fasb.org/extlink&amp;oid=6414203&amp;loc=d3e39689-114964<br><br>Reference 9: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 715<br> -SubTopic 20<br> -Section 50<br> -Paragraph 1<br> -Subparagraph (d)(iv)(03)<br> -URI http://asc.fasb.org/extlink&amp;oid=123447040&amp;loc=d3e1928-114920<br><br>Reference 10: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 715<br> -SubTopic 20<br> -Section 50<br> -Paragraph 1<br> -Subparagraph (q)<br> -URI http://asc.fasb.org/extlink&amp;oid=123447040&amp;loc=d3e1928-114920<br><br>Reference 11: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 715<br> -SubTopic 20<br> -Section 50<br> -Paragraph 1<br> -Subparagraph (r)(1)<br> -URI http://asc.fasb.org/extlink&amp;oid=123447040&amp;loc=d3e1928-114920<br><br>Reference 12: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 715<br> -SubTopic 20<br> -Section 50<br> -Paragraph 1<br> -Subparagraph (d)(iii)<br> -URI http://asc.fasb.org/extlink&amp;oid=123447040&amp;loc=d3e1928-114920<br><br>Reference 13: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 715<br> -SubTopic 20<br> -Section 50<br> -Paragraph 1<br> -Subparagraph (l)<br> -URI http://asc.fasb.org/extlink&amp;oid=123447040&amp;loc=d3e1928-114920<br><br>Reference 14: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 715<br> -SubTopic 20<br> -Section 50<br> -Paragraph 1<br> -Subparagraph (r)(2)<br> -URI http://asc.fasb.org/extlink&amp;oid=123447040&amp;loc=d3e1928-114920<br></p></div>
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<span style="display: none;">v3.22.0.1</span><table class="report" border="0" cellspacing="2" id="idm139691013877624">
<tr>
<th class="tl" colspan="1" rowspan="2"><div style="width: 200px;"><strong>Legal Proceedings<br></strong></div></th>
<th class="th" colspan="1">12 Months Ended</th>
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<tr><th class="th"><div>Dec. 31, 2021</div></th></tr>
<tr class="re">
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<td class="text">&#160;<span></span>
</td>
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<tr class="ro">
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<td class="text">
<div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">10. Legal Proceedings</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">From time to time, we are involved in legal proceedings arising in the ordinary course of our business. Periodically, we
    evaluate the status of each legal matter and assess our potential financial exposure. If the potential loss from any legal proceeding is considered probable and the amount can be reasonably estimated, we accrue a liability for the estimated loss.
    Significant judgment is required to determine the probability of a loss and whether the amount of the loss is reasonably estimable. The outcome of any proceeding is not determinable in advance. As a result, the assessment of a potential liability and
    the amount of accruals recorded are based only on the information available to us at the time. As additional information becomes available, we reassess the potential liability related to the legal proceeding, and may revise our estimates.</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">On August 5, 2021, </span>four<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> purported former stockholders of Akcea filed an action in the Delaware
      Court of Chancery captioned John Makris, et al. v. Ionis Pharmaceuticals, Inc., et al., C.A. No. 2021-0681, or the &#8220;Delaware Action.&#8221;&#160; The plaintiffs in the Delaware Action assert claims against (i) former members of Akcea&#8217;s board of directors; and
      (ii) Ionis, or collectively, the &#8220;Defendants.&#8221; The plaintiffs assert putatively direct claims on behalf of a purported class of former Akcea stockholders. The plaintiffs in the Delaware Action assert that the Defendants breached their fiduciary
      duties in connection with the October 2020 take-private transaction that we and Akcea entered into, in which Akcea became a wholly-owned subsidiary of Ionis. We believe that the claims asserted in the Delaware Action are without merit and filed a
      motion to dismiss the claims in November 2021. Briefing on the motion to dismiss is ongoing, and pursuant to an agreed-upon scheduling order that has been entered by the Court, argument on the motion to dismiss is expected later in the first quarter
      of 2022.</span></div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">On January 19, 2022, a purported stockholder of Ionis filed a stockholder derivative complaint in the Delaware Court of Chancery captioned
    Leo Shumacher, et al. v. Joseph Loscalzo, et al., C.A. No. 2022-0059, or the &#8220;Action.&#8221; The complaint names as defendants the current members of Ionis&#8217; board of directors, collectively the Directors. The company is a nominal defendant. Plaintiff asserts
    a breach of fiduciary duty claim against the Directors for awarding and receiving allegedly excessive compensation. Plaintiff also asserts an unjust enrichment claim against the non-employee Directors as a result of the compensation they received. The
    complaint seeks, among other things, damages, restitution, attorneys&#8217; fees and costs, and such other relief as deemed just and proper by the court. Defendants have not yet responded to the complaint in this Action.</div>
<span></span>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The entire disclosure for legal proceedings, legal contingencies, litigation, regulatory and environmental matters and other contingencies.</p></div>
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<span style="display: none;">v3.22.0.1</span><table class="report" border="0" cellspacing="2" id="idm139691017201912">
<tr>
<th class="tl" colspan="1" rowspan="2"><div style="width: 200px;"><strong>Fourth Quarter Financial Data (Unaudited)<br></strong></div></th>
<th class="th" colspan="1">12 Months Ended</th>
</tr>
<tr><th class="th"><div>Dec. 31, 2021</div></th></tr>
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<td class="text">&#160;<span></span>
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<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_QuarterlyFinancialInformationTextBlock', window );">Fourth Quarter Financial Data (Unaudited)</a></td>
<td class="text">
<div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">11. Fourth Quarter Financial Data (Unaudited)</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">The following financial information reflects all normal recurring adjustments, which are,
    in the opinion of management, necessary for a fair statement of the results of the interim periods. Summarized fourth quarter data for 2021
    and 2020 are as follows (in thousands, except per share data).</div>

<div><br/>
  </div>

<table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;">


  <tr>

    <td style="vertical-align: bottom; border-bottom: #000000 2px solid;" valign="bottom">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Three Months Ended December 31,</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2021</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2020</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 76%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Revenue</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">440,006</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">290,281</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 76%;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Operating expenses</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">219,403</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">312,945</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 76%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Income (loss) from operations</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">220,603</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(22,664</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 76%;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Net income (loss)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">224,613</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(355,687</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 76%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Net income (loss) attributable to Ionis Pharmaceuticals, Inc. common stockholders</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">224,613</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(354,532</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 76%;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Basic net income (loss) per share (1) (2)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">1.59</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(2.54</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 76%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Diluted net income (loss) per share (1) (3)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">1.41</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(2.54</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

  </tr>


</table>

<div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">________________</div>

<table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">


  <tr>

    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(1)</td>

    <td style="width: auto; vertical-align: top; text-align: left;">
          <div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">We </span>compute net income (loss) per share independently for each quarter during <span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">the year.</span></div>
        </td>

  </tr>


</table>

<div><br/>
  </div>

<table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">


  <tr>

    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(2)</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">As discussed in Note 1, <span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Organization and Significant Accounting Policies, </span>we compute basic net income (loss) per share by dividing the total net income (loss)
            attributable to our common stockholders by our weighted-average number of common shares outstanding during the period. Our basic net income per share for the fourth quarter of 2021 was $1.59.</div>
        </td>

  </tr>


</table>

<div><br/>
  </div>

<div style="text-align: justify; margin-left: 18pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Our basic net loss per share calculation for the fourth quarter of 2020 considered our net loss for Ionis on a stand-alone
    basis plus our share of Akcea&#8217;s net loss for the period. To calculate the portion of Akcea&#8217;s net loss attributable to our ownership, we multiplied Akcea&#8217;s loss per share by the weighted average shares we owned in Akcea during the period. As a result of
    this calculation, our total net loss available to Ionis common stockholders for the calculation of net loss per share is different than net loss attributable to Ionis Pharmaceuticals, Inc. common stockholders in the consolidated statements of
    operations.</div>

<div><br/>
  </div>

<div style="text-align: justify; margin-left: 18pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Our basic net loss per share for the fourth quarter of 2020 was calculated as follows (in thousands, except per share amounts):</div>

<div><br/>
  </div>

<table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;">


  <tr>

    <td style="vertical-align: bottom; border-bottom: #000000 2px solid; white-space: nowrap;" valign="bottom">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Three Months Ended December 31, 2020</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Weighted</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Average Shares</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Owned in Akcea</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Akcea</span>&#8217;<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">s</span></div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Net Loss</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Per Share</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Basic Net Loss</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Per Share</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Calculation</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: top; width: 64%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Akcea&#8217;s net loss in the pre-merger period attributable to our ownership</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">77,095</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(0.05</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(3,603</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

  </tr>

  <tr>

    <td style="vertical-align: top; width: 64%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">
          <div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Akcea&#8217;s net loss in the post-merger period attributable to our ownership</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(85,987</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

  </tr>

  <tr>

    <td style="vertical-align: top; width: 64%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Akcea&#8217;s total net loss attributable to our ownership</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(89,590</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

  </tr>

  <tr>

    <td style="vertical-align: top; width: 64%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">
          <div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Ionis&#8217; stand-alone net loss</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(266,418</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

  </tr>

  <tr>

    <td style="vertical-align: top; width: 64%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Net loss available to Ionis common stockholders</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(356,008</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

  </tr>

  <tr>

    <td style="vertical-align: top; width: 64%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">
          <div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Weighted average shares outstanding</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">139,956</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: top; width: 64%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Basic net loss per share</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(2.54</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

  </tr>


</table>

<div><br/>
  </div>

<table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">


  <tr>

    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(3)</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We had net income available
            to Ionis common stockholders for the fourth quarter of 2021. As a result, we computed diluted net income per share using the weighted-average number of common shares and dilutive common equivalent shares outstanding during the period as follows (in thousands except per share amounts):</div>
        </td>

  </tr>


</table>

<div><br/>
  </div>

<table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;">


  <tr>

    <td style="vertical-align: bottom; border-bottom: #000000 2px solid;" valign="bottom">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Three Months Ended December 31, 2021</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Income</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">(Numerator)</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Shares</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">(Denominator)</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Per-Share</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Amount</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: top; width: 64%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Net income available to Ionis common stockholders</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">224,612</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">141,205</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">1.59</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: top; width: 64%;" valign="bottom">
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    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

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    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

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    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

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    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

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    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

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    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">&#160;</td>

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    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

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          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">716</div>
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    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

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    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">6,590</div>
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    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

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          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">105</div>
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    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">464</div>
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    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

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    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

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<span style="display: none;">v3.22.0.1</span><table class="report" border="0" cellspacing="2" id="idm139691008041592">
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<th class="tl" colspan="1" rowspan="2"><div style="width: 200px;"><strong>Organization and Significant Accounting Policies (Policies)<br></strong></div></th>
<th class="th" colspan="1">12 Months Ended</th>
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<tr><th class="th"><div>Dec. 31, 2021</div></th></tr>
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<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">In our consolidated financial statements we included the accounts of Ionis Pharmaceuticals, Inc. and the consolidated
    results of our subsidiary, Akcea Therapeutics, Inc. and its wholly owned subsidiaries (&#8220;we&#8221;, &#8220;us&#8221; or &#8220;our&#8221;). We formed Akcea in December 2014. In July 2017, Akcea completed an initial public offering, or IPO, which reduced our ownership of Akcea&#8217;s
    common stock below 100 percent. In October 2020, we completed a merger transaction with Akcea such that following the completion of the merger,
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<div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Basic and Diluted Net Income (Loss) per Share</div>

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<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;">Basic net income (loss) per share</div>

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  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We compute basic net income (loss) per share by dividing the total net income (loss) attributable to our common
    stockholders by our weighted-average number of common shares outstanding during the period. For the year ended December 31, 2021, we did not have to consider Akcea results separately in our calculation because we owned 100 percent of Akcea for the entire period. Our basic net loss per share for the year ended December 31, 2021 was $0.20.</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">For the years ended December 31, 2020 and 2019, we calculated total net income (loss) attributable to our common
    stockholders for each year using our net income (loss) for Ionis on a stand-alone basis plus our share of Akcea&#8217;s net income (loss) for the period. To calculate the portion of Akcea&#8217;s net income (loss) attributable to our ownership for each year, we
    multiplied Akcea&#8217;s income (loss) per share by the weighted average shares we owned in Akcea during the period. As a result of this calculation, our total net income (loss) available to Ionis common stockholders for the calculation of net income (loss)
    per share is different than net income (loss) attributable to Ionis Pharmaceuticals, Inc. common stockholders in our consolidated statements of operations for each year.</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We calculated our basic net loss per share for the year ended December 31, 2020 as follows (in thousands, except
    per share amounts):</div>

<div><br/>
  </div>

<table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;">


  <tr>

    <td style="vertical-align: bottom; border-bottom: #000000 2px solid; white-space: nowrap;" valign="bottom">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Year Ended December 31, 2020</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Weighted</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Average Shares</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Owned in Akcea</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Akcea</span>&#8217;<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">s</span></div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Net Loss</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Per Share</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Basic Net Loss</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Per Share</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Calculation</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: top; width: 64%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Akcea&#8217;s net loss in the pre-merger period attributable to our ownership</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">77,095</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(1.45</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(111,775</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

  </tr>

  <tr>

    <td style="vertical-align: top; width: 64%; white-space: nowrap;" valign="bottom">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Akcea&#8217;s net loss in the post-merger period attributable to our ownership</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(85,987</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

  </tr>

  <tr>

    <td style="vertical-align: top; width: 64%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Akcea&#8217;s total net loss attributable to our ownership</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(197,762</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

  </tr>

  <tr>

    <td style="vertical-align: top; width: 64%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">
          <div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Ionis&#8217; stand-alone net loss</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(246,702</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

  </tr>

  <tr>

    <td style="vertical-align: top; width: 64%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Net loss available to Ionis common stockholders</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(444,464</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

  </tr>

  <tr>

    <td style="vertical-align: top; width: 64%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">
          <div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Weighted average shares outstanding</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">139,612</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: top; width: 64%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Basic net loss per share</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(3.18</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

  </tr>


</table>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We calculated our basic net income per share for the year ended December 31, 2019 as follows (in thousands, except per share amounts):</div>

<div><br/>
  </div>

<table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;">


  <tr>

    <td style="vertical-align: bottom; border-bottom: #000000 2px solid; white-space: nowrap;" valign="bottom">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Year Ended December 31, 2019</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Weighted</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Average Shares</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Owned in Akcea</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Akcea</span>&#8217;<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">s</span></div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Net Income</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Per Share</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Basic Net Income</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Per Share</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Calculation</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: top; width: 64%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Common shares</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">70,100</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">0.49</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">34,073</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: top; width: 64%; white-space: nowrap;" valign="bottom">
          <div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Akcea&#8217;s net income attributable to our ownership</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">34,073</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: top; width: 64%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Ionis&#8217; stand-alone net income</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">246,487</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: top; width: 64%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">
          <div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Net income available to Ionis common stockholders</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">280,560</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: top; width: 64%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Weighted average shares outstanding</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">139,998</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: top; width: 64%; padding-bottom: 4px; white-space: nowrap;" valign="bottom">
          <div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Basic net income per share</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">2.00</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>


</table>

<div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 12pt;"><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;">Diluted net income (loss) per share</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">For the years ended December 31, 2021 and 2020, we incurred a net loss; therefore, we did not include dilutive common
    equivalent shares in the computation of diluted net loss per share because the effect would have been anti-dilutive. Common stock underlying the following would have had an anti-dilutive effect on net loss per share:</div>

<div><br/>
  </div>

<table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">


  <tr>

    <td style="width: 36pt;"/>

    <td style="width: 18pt; vertical-align: top; align: right; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;">0.125 percent<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> convertible senior notes, or </span>0.125%<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> Notes;</span></div>
        </td>

  </tr>


</table>

<table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">


  <tr>

    <td style="width: 36pt;"/>

    <td style="width: 18pt; vertical-align: top; align: right; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">Note hedges related to the </span>0.125%<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> Notes;</span></div>
        </td>

  </tr>


</table>

<table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">


  <tr>

    <td style="width: 36pt;"/>

    <td style="width: 18pt; vertical-align: top; align: right; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;">1 percent<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> convertible senior notes, or </span>1%<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> Notes;</span></div>
        </td>

  </tr>


</table>

<table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">


  <tr>

    <td style="width: 36pt;"/>

    <td style="width: 18pt; vertical-align: top; align: right; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Dilutive stock options;</div>
        </td>

  </tr>


</table>

<table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">


  <tr>

    <td style="width: 36pt;"/>

    <td style="width: 18pt; vertical-align: top; align: right; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Unvested restricted stock units, or RSUs;</div>
        </td>

  </tr>


</table>

<table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">


  <tr>

    <td style="width: 36pt;"/>

    <td style="width: 18pt; vertical-align: top; align: right; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Unvested performance restricted stock units, or PRSUs; and</div>
        </td>

  </tr>


</table>

<table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">


  <tr>

    <td style="width: 36pt;"/>

    <td style="width: 18pt; vertical-align: top; align: right; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Employee Stock Purchase Plan, or ESPP.</div>
        </td>

  </tr>


</table>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">For the year ended December 31, 2021, common stock underlying the following would also have had an anti-dilutive effect on
    net loss per share:</div>

<div><br/>
  </div>

<table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">


  <tr>

    <td style="width: 36pt;"/>

    <td style="width: 18pt; vertical-align: top; align: right; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;">0 percent<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> convertible senior notes, or </span>0%<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> Notes; and</span></div>
        </td>

  </tr>


</table>

<table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">


  <tr>

    <td style="width: 36pt;"/>

    <td style="width: 18pt; vertical-align: top; align: right; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">Note hedges related to the </span>0%<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> Notes.</span></div>
        </td>

  </tr>


</table>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Additionally as of December 31, 2021, we had warrants related to our 0 percent and 0.125 percent Notes outstanding. We will include the shares issuable
    under these warrants in our calculation of diluted earnings per share when the average market price per share of our common stock for the reporting period exceeds the strike price of the warrants.</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">For the
      year ended December 31, 2019, we reported net income available to Ionis common stockholders. As a result, we computed diluted net income per share using the weighted-average number of common shares and dilutive common equivalent shares outstanding
      during each period.</span> We calculated our diluted net income per share as follows <span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">(in thousands except per share amounts):</span></div>

<div><br/>
  </div>

<table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;">


  <tr>

    <td style="vertical-align: bottom; border-bottom: #000000 2px solid;" valign="bottom">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Year Ended December 31, 2019</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Net Income Available</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">to Ionis Common</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Stockholders</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">(Numerator)</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Shares</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">(Denominator)</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Per-Share</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Amount</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: top; width: 64%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Net income available to Ionis common stockholders</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">280,560</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">139,998</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">2.00</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: top; width: 64%;" valign="bottom">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Effect of dilutive securities:</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: top; width: 64%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: left; text-indent: -8.9pt; margin-left: 18pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Shares issuable upon exercise of stock options</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#8212;</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">2,090</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: top; width: 64%;" valign="bottom">
          <div style="text-align: left; text-indent: 0.1pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Shares issuable upon restricted stock award issuance</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#8212;</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">766</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: top; width: 64%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: left; text-indent: 9.1pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Shares issuable related to our ESPP</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#8212;</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">18</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: top; width: 64%;" valign="bottom">
          <div style="text-align: left; text-indent: 9.1pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">Shares issuable related to our </span>0.125<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> percent convertible notes</span></div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">860</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">217</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: top; width: 64%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: left; text-indent: 9.1pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Shares issuable related to our 1 percent convertible notes</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">9,527</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">10,075</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: top; width: 64%; padding-bottom: 4px;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">290,947</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">153,164</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">1.90</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>


</table>
<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerPolicyTextBlock', window );">Revenue Recognition</a></td>
<td class="text">
<div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Revenue Recognition</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="text-decoration: underline;">Our Revenue Sources</span></div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We generally recognize revenue when we have satisfied all contractual obligations and are reasonably assured of collecting
    the resulting receivable. We are often entitled to bill our customers and receive payment from our customers in advance of recognizing the revenue. In the instances in which we have received payment from our customers in advance of recognizing revenue,
    we include the amounts in deferred revenue on our consolidated balance sheet.</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">At contract inception, we analyze our collaboration arrangements to assess whether such arrangements involve joint
    operating activities performed by parties that are both active participants in the activities and exposed to significant risks and rewards dependent on the commercial success of such activities and therefore within the scope of ASC Topic 808,
    Collaborative Arrangements (ASC 808).&#160; For collaboration arrangements within the scope of ASC 808 that contain multiple elements, we first determine which elements of the collaboration reflect a vendor-customer relationship and therefore within the
    scope of ASC 606. When we determine elements of a collaboration do not reflect a vendor-customer relationship, we consistently apply the reasonable and rational policy election we made by analogizing to authoritative accounting literature.</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We evaluate the income statement classification for presentation of amounts due from or owed to other participants
    associated with multiple activities in a collaboration arrangement based on the nature of each separate activity. For example, in our eplontersen collaboration with AstraZeneca, we recognize funding received from AstraZeneca for co-development
    activities as revenue. While, we recognize cost sharing payments to and from AstraZeneca associated with co-commercialization activities and co-medical affairs activities as SG&amp;A expense and research and development expense, respectively.</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;">Commercial Revenue: SPINRAZA royalties and Licensing and other royalty revenue</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We earn commercial revenue primarily in the form of royalty payments on net sales of SPINRAZA. We will also recognize as
    commercial revenue sales milestone payments and royalties we earn under our other partnerships.</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;">Commercial Revenue: TEGSEDI and WAYLIVRA revenue, net</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We began commercializing TEGSEDI and WAYLIVRA in Europe in January 2021 and TEGSEDI in North America in April 2021 through distribution
    agreements with Swedish Orphan Biovitrum AB, or Sobi. Under our agreements, we are responsible for supplying finished goods inventory to Sobi and Sobi is responsible for selling each medicine to the end customer. As a result of these agreements, we
    earn a distribution fee on net sales from Sobi for each medicine.</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Prior to the second quarter of 2021 in North America, we sold TEGSEDI through exclusive distribution agreements with third-party logistics
    companies, or 3PLs, that took title to TEGSEDI. The 3PLs then distributed TEGSEDI to a specialty pharmacy and a specialty distributor, which we collectively refer to as wholesalers, who then distributed TEGSEDI to health care providers and patients. In
    the United States, or U.S., we had a single 3PL as our sole customer and in Canada we also had a single 3PL as our sole customer. Prior to 2021 in Europe, we sold TEGSEDI and WAYLIVRA to hospitals and pharmacies, which were our customers, using 3PLs as
    distributors.</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">Under our collaboration agreement with PTC
      Therapeutics International Limited, or PTC, PTC is responsible for commercializing TEGSEDI and WAYLIVRA in Latin America and Caribbean countries. In the third quarter of 2021, we earned a </span>$4 million milestone payment from PTC when WAYLIVRA was approved in Brazil, which we included in TEGSEDI and WAYLIVRA revenue in our consolidated statement of operations. Under our agreement, we
    started receiving royalties from PTC for TEGSEDI sales beginning in December 2021.</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: left; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;">Research and development revenue under collaborative agreements</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We often enter into collaboration agreements to license and sell our technology on an exclusive or non-exclusive basis.
    Our collaboration agreements typically contain multiple elements, or performance obligations, including technology licenses or options to obtain technology licenses, research and development, or R&amp;D, services, and manufacturing services.</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We provide details about our collaboration agreements in Note 6, <span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Collaborative Arrangements and Licensing Agreements.</span><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">&#160;</span>For each collaboration, we discuss our specific revenue
    recognition conclusions, including our significant performance obligations under each collaboration.</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: left; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="text-decoration: underline;">Steps to Recognize Revenue</span></div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We use a five-step process to determine the amount of revenue we should recognize and when we should recognize it. The
    five step process is as follows:</div>

<div><br/>
  </div>

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    <td style="width: 18pt; vertical-align: top; align: right; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic; font-weight: bold;">1.</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic; font-weight: bold;">Identify the contract</div>
        </td>

  </tr>


</table>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Accounting rules require us to first determine if we have a contract with our partner, including confirming that we have met each of the
    following criteria:</div>

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    <td style="width: 36pt;"/>

    <td style="width: 18pt; vertical-align: top; align: right; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We and our partner approved the contract and we are both committed to perform our obligations;</div>
        </td>

  </tr>


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    <td style="width: 36pt;"/>

    <td style="width: 18pt; vertical-align: top; align: right; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We have identified our rights, our partner&#8217;s rights and the payment terms;</div>
        </td>

  </tr>


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    <td style="width: 36pt;"/>

    <td style="width: 18pt; vertical-align: top; align: right; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We have concluded that the contract has commercial substance, meaning that the risk, timing, or amount of our future cash flows is expected to change as a result of the
            contract; and</div>
        </td>

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    <td style="width: 36pt;"/>

    <td style="width: 18pt; vertical-align: top; align: right; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We believe collectability of the consideration is probable.</div>
        </td>

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</table>

<div><br/>
  </div>

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    <td style="width: 36pt;"/>

    <td style="width: 18pt; vertical-align: top; align: right;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold; font-style: italic;">2.</span></td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic; font-weight: bold;">Identify the performance obligations</div>
        </td>

  </tr>


</table>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We next identify our performance obligations, which represent the distinct goods and services we are required to provide under the
    contract.</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">Often we enter into a collaboration agreement
      in which we provide our partner with an option to license a medicine in the future. We may also provide our partner with an option to request that we provide additional goods or services in the future, such as active pharmaceutical ingredient, or
      API. We evaluate whether these options are material rights at the inception of the agreement. If we determine an option is a material right, we will consider the option a separate performance obligation. Historically, we have concluded that the
      options we grant to license a medicine in the future or to provide additional goods and services as requested by our partner are not material rights because these items are contingent upon future events that may not occur and are not priced at a
      significant discount. When a partner exercises its option to license a medicine or requests additional goods or services, then we identify a new performance obligation for that item</span>.</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">In some cases, we deliver a license at the start of an agreement. If we determine that our partner has full use of the license and we do
    not have any additional material performance obligations related to the license after delivery, then we consider the license to be a separate performance obligation. For example, in the fourth quarter of 2021, we received a $200 million upfront payment when we entered into an agreement with AstraZeneca to jointly develop and commercialize eplontersen. We recognized the upfront
    payment in full in the fourth quarter of 2021 because we did not have any remaining performance obligations after we delivered the license to AstraZeneca.</div>

<div><br/>
  </div>

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    <td style="width: 18pt; vertical-align: top; align: right; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic; font-weight: bold;">3.</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic; font-weight: bold;">Determine the transaction price</div>
        </td>

  </tr>


</table>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We then determine the transaction price by reviewing the amount of consideration we are eligible to earn under the
        collaboration agreement, including any variable consideration. Under our collaboration agreements, consideration typically includes fixed consideration in the form of an upfront payment and variable consideration in the form of potential milestone
        payments, license fees and royalties. At the start of an agreement, our transaction price usually consists of only the upfront payment. We do not typically include any payments we may receive in the future in our initial transaction price because
        the payments are not probable and are contingent on certain future events. We reassess the total transaction price at each reporting period to determine if we should include additional payments in the transaction price.</div>

<div><br/>
    </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">Milestone payments are our most common type
      of variable consideration. We recognize milestone payments using the most likely amount method because we will either receive the milestone payment or we will not, which makes the potential milestone payment a binary event. The most likely amount
      method requires us to determine the likelihood of earning the milestone payment. We include a milestone payment in the transaction price once it is probable we will achieve the milestone event. Most often, we do not consider our milestone payments
      probable until we or our partner achieve the milestone event because the majority of our milestone payments are contingent upon events that are not within our control and/ or are usually based on scientific progress which is inherently uncertain. For
      example, in the fourth quarter of 2021, we earned</span> a $10 million <span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">milestone payment from AstraZeneca when AstraZeneca advanced a target for a metabolic disease. We did not consider the milestone payment probable until AstraZeneca achieved the milestone event because advancing the target was
      contingent on AstraZeneca initiating a Phase 1 study and was not within our control. We recognized the milestone payment in full in the period the milestone event was achieved because we did not have any remaining performance obligations related to
      the milestone payment</span>.</div>

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    <td style="width: 18pt; vertical-align: top; align: right; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic; font-weight: bold;">4.</td>

    <td style="width: auto; vertical-align: top; text-align: left;">
          <div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic; font-weight: bold;">Allocate the transaction price</div>
        </td>

  </tr>


</table>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Next, we allocate the transaction price to
        each of our performance obligations. When we have to allocate the transaction price to more than </span>one<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> performance obligation, we make estimates of the relative
        stand-alone selling price of each performance obligation because we do not typically sell our goods or services on a stand-alone basis. We then allocate the transaction price to each performance obligation based on the relative stand-alone selling
        price. We do not reallocate the transaction price after the start of an agreement to reflect subsequent changes in stand-alone selling prices.</span></div>

<div><br/>
    </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We may engage a </span>third<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> party, independent valuation specialist to assist us with determining a stand-alone selling price for collaborations in which we deliver a license at the start of an agreement.
      We estimate the stand-alone selling price of these licenses using valuation methodologies, such as the relief from royalty method. Under this method, we estimate the amount of income, net of taxes, for the license. We then discount the projected
      income to present value. The significant inputs we use to determine the projected income of a license could include</span>:</div>

<div><br/>
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    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Estimated future product sales;</div>
        </td>

  </tr>


</table>

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  <tr>

    <td style="width: 36pt;"/>

    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Estimated royalties we may receive from future product sales;</div>
        </td>

  </tr>


</table>

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  <tr>

    <td style="width: 36pt;"/>

    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Estimated contractual milestone payments we may receive;</div>
        </td>

  </tr>


</table>

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  <tr>

    <td style="width: 36pt;"/>

    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Expenses we expect to incur;</div>
        </td>

  </tr>


</table>

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  <tr>

    <td style="width: 36pt;"/>

    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Estimated income taxes; and</div>
        </td>

  </tr>


</table>

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  <tr>

    <td style="width: 36pt;"/>

    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">A discount rate.</div>
        </td>

  </tr>


</table>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We typically estimate the selling price of R&amp;D services by using our internal estimates of the cost to perform the
    specific services. The significant inputs we use to determine the selling price of our R&amp;D services include:</div>

<div><br/>
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    <td style="width: 36pt;"/>

    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">The number of internal hours we estimate we will spend performing these services;</div>
        </td>

  </tr>


</table>

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  <tr>

    <td style="width: 36pt;"/>

    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">The estimated cost of work we will perform;</div>
        </td>

  </tr>


</table>

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  <tr>

    <td style="width: 36pt;"/>

    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">The estimated cost of work that we will contract with third parties to perform; and</div>
        </td>

  </tr>


</table>

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  <tr>

    <td style="width: 36pt;"/>

    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">The estimated cost of API we will use.</div>
        </td>

  </tr>


</table>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">For purposes of determining the stand-alone selling price of the R&amp;D services we perform and the API we will deliver,
    accounting guidance requires us to include a markup for a reasonable profit margin.</div>

<div><br/>
  </div>

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  <tr>

    <td style="width: 36pt;"/>

    <td style="width: 18pt; vertical-align: top; align: right; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic; font-weight: bold;">5.</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic; font-weight: bold;">Recognize revenue</div>
        </td>

  </tr>


</table>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We recognize revenue in </span>one<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> of </span>two<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> ways, over time or at a point in time. We recognize revenue over time when we are
        executing on our performance obligation over time and our partner receives benefit over time. For example, we recognize revenue over time when we provide R&amp;D services. We recognize revenue at a point in time when our partner receives full use
        of an item at a specific point in time. For example, we recognize revenue at a point in time when we deliver a license or API to a partner.</span></div>

<div><br/>
    </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">For R&amp;D services that we recognize over
      time, we measure our progress using an input method. The input methods we use are based on the effort we expend or costs we incur toward the satisfaction of our performance obligation. We estimate the amount of effort we expend, including the time we
      estimate it will take us to complete the activities, or costs we incur in a given period, relative to the estimated total effort or costs to satisfy the performance obligation. This results in a percentage that we multiply by the transaction price to
      determine the amount of revenue we recognize each period. This approach requires us to make numerous estimates and use significant judgement. If our estimates or judgements change over the course of the collaboration, they may affect the timing and
      amount of revenue that we recognize in the current and future periods.</span> Refer to Note 6, <span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Collaborative Arrangements and Licensing Agreements</span>,
    for further discussion of the cumulative catch up adjustment we made.</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: left; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">The following are examples of when we typically recognize revenue based on the types of payments we receive.</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: left; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;"><span style="text-decoration: underline;">Commercial Revenue: SPINRAZA royalties and Licensing and other royalty revenue</span></div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We recognize royalty revenue, including
      royalties from SPINRAZA sales, in the period in which the counterparty sells the related product and recognizes the related revenue, which in certain cases may require us to estimate our royalty revenue</span>.</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: left; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;"><span style="text-decoration: underline;">Commercial Revenue: TEGSEDI and WAYLIVRA revenue, net</span></div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Under our distribution agreements with Sobi we concluded that our performance obligation is to provide services to
      Sobi over the term of the agreement, which includes supplying finished goods inventory to Sobi and because we retained the marketing authorization for TEGSEDI and WAYLIVRA we are responsible for leading the global commercial strategy for each
      medicine. We view this performance obligation as a series of distinct activities that are substantially the same. Therefore, we recognize as revenue the price Sobi pays us for the inventory when we deliver the finished goods inventory to Sobi. We
      also recognize distribution fee revenue based on Sobi&#8217;s net sales of TEGSEDI and WAYLIVRA in the period in which the sales occurred. Under our agreements with Sobi, Sobi does not generally have a right of return.</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">Prior to our distribution agreements with
      Sobi, we recognized TEGSEDI and WAYLIVRA commercial revenue in the period when our customer obtained control of our products, which occurred at a point in time upon transfer of title to the customer. We classified payments to customers or other
      parties in the distribution channel for services that were distinct and priced at fair value as selling, general and administrative, or SG&amp;A, expenses in our consolidated statements of operations. We classified payments to customers or other
      parties in the distribution channel that did not meet those criteria as a reduction of revenue, as discussed further below. We excluded from revenues taxes collected from customers relating to TEGSEDI and WAYLIVRA commercial revenue and remitted
      these amounts to governmental authorities</span>.</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;">Reserves for TEGSEDI and WAYLIVRA commercial revenue</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Prior to our distribution agreements with Sobi, we recorded TEGSEDI and WAYLIVRA commercial revenue at our net sales
      price, or transaction price. We included in our transaction price estimated reserves for discounts, returns, chargebacks, rebates and other allowances that we offered within contracts between us and our customers, wholesalers, distributors, health
      care providers and other indirect customers. We estimated our reserves using the amounts we have earned or we could claim on the associated sales. We classified our reserves as a reduction of accounts receivable when we were not required to make a
      payment or as a current liability when we were required to make a payment. In certain cases, our estimates included a range of possible outcomes that were probability weighted for relevant factors such as our historical experience, current
      contractual and statutory requirements, specific known market events and trends, industry data and forecasted customer buying and payment patterns. Overall, our reserves reflected our best estimates under the terms of our respective contracts. When
      calculating our reserves and related TEGSEDI and WAYLIVRA commercial revenue, we only recognized amounts to the extent that we considered it probable that we would not have to reverse a significant amount of the cumulative sales we previously
      recognized in a future period. Under our agreements with Sobi, we transferred all reserves to Sobi.</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: left; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">The following were the components of variable consideration related to TEGSEDI and WAYLIVRA product sales prior to our agreements with Sobi:</div>

<div><br/>
  </div>

<div style="text-align: justify; margin-left: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Chargebacks: </span><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">In the U.S., we estimated obligations resulting from contractual commitments with the government and other entities to sell products to qualified healthcare
      providers at prices lower than the list prices charged to our U.S. customer. Our U.S. customer charged us for the difference between what it paid for the product and the selling price to the qualified healthcare providers. We also estimated the
      amount of chargebacks related to our estimated product remaining in the distribution channel at the end of the reporting period that we expected our customer to sell to healthcare providers in future periods. We recorded these reserves as a reduction
      to contracts receivable on our consolidated balance sheet</span>.</div>

<div><br/>
  </div>

<div style="text-align: justify; margin-left: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic; color: #000000;">Government rebates</span><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">: We were subject to discount obligations under government programs, including Medicaid and Medicare programs in the U.S. and we recorded reserves for government
      rebates based on statutory discount rates and estimated utilization. We estimated Medicaid and Medicare rebates based on a range of possible outcomes that were probability weighted for the estimated payer mix. We recorded these reserves as an accrued
      liability on our consolidated balance sheet with a corresponding offset reducing our product sales in the same period we recognized the related sale. For Medicare, we also estimated the number of patients in the prescription drug coverage gap for
      whom we would owe an additional liability under the Medicare Part D program. On a quarterly basis, we updated our estimates and recorded any adjustments in the period that we identified the adjustments</span>.</div>

<div><br/>
  </div>

<div style="text-align: justify; margin-left: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Managed care rebates: </span><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">We were subject to rebates in connection with agreements with certain contracted commercial payers. We recorded these rebates as a liability on our consolidated
      balance sheet in the same period we recognized the related revenue. We estimated our managed care rebates based on our estimated payer mix and the applicable contractual rebate rate</span>.</div>

<div><br/>
  </div>

<div style="text-align: justify; margin-left: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Trade discounts: </span><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">We provided customary invoice discounts on product sales to our U.S. customer for prompt payment. We recorded this discount as a reduction of product sales in the
      period in which we recognized the related product revenue</span>.</div>

<div><br/>
  </div>

<div style="text-align: justify; margin-left: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Distribution services</span>: <span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">We received and paid for various distribution services from our U.S. and European customers (prior to our agreement with Sobi) and wholesalers in the U.S. We
      classified the costs for services we received that are either not distinct from the sale of the product or for which we could not reasonably estimate the fair value as a reduction of product sales. To the extent that the services we received are
      distinct from the sale of the product, we classified the costs for such services as SG&amp;A expenses.</span></div>

<div><br/>
  </div>

<div style="text-align: justify; margin-left: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Product returns: </span><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">Our U.S. customer had return rights and the wholesalers had limited return rights primarily related to the product&#8217;s expiration date. We estimated the amount of
      product sales that our customer may return. We recorded our return estimate as an accrued refund liability on our consolidated balance sheet with a corresponding offset reducing our product sales in the same period we recognized the related sale.
      Based on our distribution model for product sales, contractual inventory limits with our customer and wholesalers and the price of the product, we had minimal returns. Our European customers generally only took title to the product after they
      received an order and therefore they did not maintain excess inventory levels of our products. Accordingly, we had limited return risk in Europe and we did not estimate returns in Europe</span>.</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: left; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;"><span style="text-decoration: underline;">Research and development revenue under collaboration agreements:</span></div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: left; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;"><span style="text-decoration: underline;">Upfront payments</span></div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">When we enter into a collaboration agreement
      with an upfront payment, we typically record the entire upfront payment as deferred revenue if our only performance obligation is for R&amp;D services we will provide in the future. We amortize the upfront payment into revenue as we perform the
      R&amp;D services. For example, under our collaboration agreement with Roche to</span><span style="background-color: #FBFBFB; font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> develop IONIS-FB-L</span><sub style="color: #000000;">Rx</sub><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> for the treatment of complement-mediated diseases, we received a $</span>75<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> million upfront payment in the fourth quarter of 2018. We allocated the upfront payment to our
      single performance obligation, R&amp;D services. We are amortizing the $</span>75<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> million upfront payment using an input method over the estimated period of time we are providing R&amp;D services</span>.</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;"><span style="text-decoration: underline;">Milestone payments</span></div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We are required to include additional consideration in the transaction price when it is probable. We typically
        include milestone payments for R&amp;D services in the transaction price when they are achieved. We include these milestone payments when they are achieved because typically there is considerable uncertainty in the research and development
        processes that trigger these payments. Similarly, we include approval milestone payments in the transaction price once the medicine is approved by the applicable regulatory agency. We will recognize sales-based milestone payments in the period in
        which we achieve the milestone under the sales-based royalty exception allowed under accounting rules.</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">We recognize milestone payments that relate
      to an ongoing performance obligation over our period of performance. For example, in the fourth quarter of 2021, we achieved a</span> $7.5&#160;<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">million milestone payment from Biogen when we advanced</span>&#160;<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">a </span>target
    under our 2018 strategic collaboration.<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> We added this payment to the transaction price and allocated it to our R&amp;D services performance obligation. We are
      recognizing revenue related to this milestone payment over our estimated period of performance</span>.</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Conversely, we recognize in full those milestone payments that we earn based on our partners&#8217; activities when our partner achieves the
    milestone event and we do not have a performance obligation. For example, in the fourth quarter of 2021, we recognized $15 million in milestone
    payments when Biogen advanced two targets under our 2018 strategic collaboration. <span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">We concluded that the milestone payments were not related to our R&amp;D services performance obligation. Therefore, we recognized the milestone payments in full in the fourth quarter of 2021.</span></div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;"><span style="text-decoration: underline;">License fees</span></div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">We generally recognize as revenue the total
      amount we determine to be the relative stand-alone selling price of a license when we deliver the license to our partner. This is because our partner has full use of the license and we do not have any additional performance obligations related to the
      license after delivery. For example, in the fourth quarter of 2021, we earned a</span> $60&#160;<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">million license fee from Biogen when Biogen licensed ION306, an investigational medicine in development to treat SMA.</span></div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;"><span style="text-decoration: underline;">Sublicense fees</span></div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">We recognize sublicense fee revenue in the
      period in which a party, who has already licensed our technology, further licenses the technology to another party because we do not have any performance obligations related to the sublicense. </span>For example, in the fourth quarter of 2020, we
    earned a $41.2 million sublicense fee from Alnylam Pharmaceuticals for its sublicense of our technology to Sanofi Genzyme.</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic; font-weight: bold;">Amendments to Agreements</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">From time to time we amend our collaboration agreements. When this occurs, we are required to assess the following items
    to determine the accounting for the amendment:</div>

<div><br/>
  </div>

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  <tr>

    <td style="width: 36pt;"/>

    <td style="width: 18pt; vertical-align: top; align: right; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">1)</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;">If the additional goods and/or services are distinct from the other performance obligations in the original agreement; and</div>
        </td>

  </tr>


</table>

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  <tr>

    <td style="width: 36pt;"/>

    <td style="width: 18pt; vertical-align: top; align: right; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">2)</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;">If the goods and/or services are at a stand-alone selling price.</div>
        </td>

  </tr>


</table>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">If we conclude the goods and/or services in the amendment are distinct from the performance obligations in the
        original agreement and at a stand-alone selling price, we account for the amendment as a separate agreement. If we conclude the goods and/or services are not distinct and are sold at a stand-alone selling price, we then assess whether the remaining
        goods or services are distinct from those already provided. If the goods and/or services are distinct from what we have already provided, then we allocate the remaining transaction price from the original agreement and the additional transaction
        price from the amendment to the remaining goods and/or services. If the goods and/or services are not distinct from what we have already provided, we update the transaction price for our single performance obligation and recognize any change in our
        estimated revenue as a cumulative adjustment.</div>

<div><br/>
    </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">For example, in May 2015, we entered into an exclusive license agreement with Bayer to develop and commercialize IONIS-FXI<sub>Rx</sub>
    for the prevention of thrombosis. As part of the agreement, Bayer paid us a $100 million upfront payment. At the onset of the agreement, we were
    responsible for completing a Phase 2 study of IONIS-FXI<sub>Rx</sub> in people with end-stage renal disease on hemodialysis and for providing an initial supply of API. In February 2017, we amended our agreement with Bayer to advance IONIS-FXI<sub>Rx</sub>
    and to initiate development of fesomersen, which Bayer licensed. As part of the 2017 amendment, Bayer paid us $75 million. We are also eligible
    to receive milestone payments and tiered royalties on gross margins of IONIS-FXI<sub>Rx</sub> and fesomersen. Under the 2017 amendment, we concluded we had a new agreement with three performance obligations. These performance obligations were to deliver the license of fesomersen, to provide R&amp;D services and to deliver API. We allocated the $75 million transaction price to these performance obligations. Refer to Note 6, <span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Collaborative Arrangements and Licensing Agreements</span>, for further discussion of the Bayer collaboration.</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic; font-weight: bold;">Multiple agreements</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">From time to time, we may enter into separate agreements at or near the same time with the same partner. We evaluate such
    agreements to determine whether we should account for them individually as distinct arrangements or whether the separate agreements should be combined and accounted for together. We evaluate the following to determine the accounting for the agreements:</div>

<div><br/>
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    <td style="width: 18pt; vertical-align: top; align: right; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Whether the agreements were negotiated together with a single objective;</div>
        </td>

  </tr>


</table>

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    <td style="width: 36pt;"/>

    <td style="width: 18pt; vertical-align: top; align: right; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Whether the amount of consideration in one contract depends on the price or performance of the other agreement; or</div>
        </td>

  </tr>


</table>

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    <td style="width: 36pt;"/>

    <td style="width: 18pt; vertical-align: top; align: right; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Whether the goods and/or services promised under the agreements are a single performance obligation.</div>
        </td>

  </tr>


</table>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Our evaluation involves significant judgment to determine whether a group of agreements might be so closely related that accounting
    guidance requires us to account for them as a combined arrangement.</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">For example, in the second quarter of 2018, we entered into two separate agreements with Biogen at the same time: <span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">a new strategic neurology collaboration
      agreement and a stock purchase agreement, or SPA. We evaluated the Biogen agreements to determine whether we should treat the agreements separately or combine them. We considered that the agreements were negotiated concurrently and in contemplation
      of one another. Based on these facts and circumstances, we concluded that we should evaluate the provisions of the agreements on a combined basis.</span></div>
<span></span>
</td>
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<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ReceivablesPolicyTextBlock', window );">Contracts Receivable</a></td>
<td class="text">
<div style="display:none;"><br/></div>
<div style="text-align: left; text-indent: -54pt; margin-left: 54pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Contracts Receivable</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">Our contracts receivable balance represents
      the amounts we have billed our partners or customers and that are due to us unconditionally for goods we have delivered or services we have performed. When we bill our partners or customers with payment terms based on the passage of time, we consider
      the contracts receivable to be unconditional. We typically receive payment within one </span><span style="-sec-ix-hidden:Fact_e2c2673a057f412ebd5831ca8712546a">quarter</span><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> of billing our partner or customer</span>.</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">As of December 31, 2021, approximately 93.8 percent of our contracts receivables were from two significant customers. As of December 31, 2020, approximately 99.5 percent of our contracts receivables were from two
    significant customers.</div>
<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_TradeAndOtherAccountsReceivableUnbilledReceivablesPolicy', window );">Unbilled SPINRAZA Royalties</a></td>
<td class="text">
<div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Unbilled SPINRAZA Royalties</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Our unbilled SPINRAZA royalties represent our right to receive consideration from Biogen in advance of when we are
    eligible to bill Biogen for SPINRAZA royalties. We include these unbilled amounts in other current assets on our consolidated balance sheet.</div>
<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RevenueRecognitionPolicyTextBlock', window );">Deferred Revenue</a></td>
<td class="text">
<div style="display:none;"><br/></div>
<div style="text-align: left; text-indent: -54pt; margin-left: 54pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Deferred Revenue</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">We are often entitled to bill our customers
      and receive payment from our customers in advance of our obligation to provide services or transfer goods to our partners. In these instances, we include the amounts in deferred revenue on our consolidated balance sheet.</span> During the years ended
    December 31, 2021 and 2020, we recognized $98.1 million and $100.4 million of revenue from amounts that were in our beginning deferred revenue balance for each respective period. For further discussion, refer to our revenue recognition policy above.</div>
<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_CostOfSalesPolicyTextBlock', window );">Cost of Sales</a></td>
<td class="text">
<div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Cost of Sales</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Our cost of sales includes manufacturing costs, transportation and freight costs and indirect overhead costs associated with the
    manufacturing and distribution of our products. We also may include certain period costs related to manufacturing services and inventory adjustments in cost of sales. We also may include certain period costs related to manufacturing services and
    inventory adjustments in cost of sales.</div>
<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ResearchAndDevelopmentExpensePolicy', window );">Research and Development Expenses</a></td>
<td class="text">
<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Our research and development expenses include wages, benefits, facilities, supplies, external
    services, clinical trial and manufacturing costs and other expenses that are directly related to our research and development operations. We expense research and development costs as we incur them. When we make payments for research and development
    services prior to the services being rendered, we record those amounts as prepaid assets on our consolidated balance sheet and we expense them as the services are provided. For the years ended December 31, 2021, 2020 and 2019, research and development expenses were $638.2 million, $531.0 million and $461.5 million, respectively. A
    portion of the costs included in research and development expenses are costs associated with our partner agreements.</div>
<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_IntangibleAssetsFiniteLivedPolicy', window );">Patent Expenses</a></td>
<td class="text">
<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We capitalize costs consisting principally of outside legal costs and filing fees related to obtaining
    patents. We amortize patent costs over the useful life of the patent, beginning with the date the U.S. Patent and Trademark Office, or foreign equivalent, issues the patent. The weighted average remaining amortizable life of our issued patents was 10.2 years at December 31, 2021.</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">The cost of our patents capitalized on our consolidated balance sheet at December 31, 2021 and 2020 was $38.4 million and $37.0 million, respectively.
    Accumulated amortization related to patents was $9.4 million and $9.1 million at December 31, 2021 and 2020, respectively.</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Based on our existing patents, we estimate amortization expense related to patents in each of
    the next five years to be the following:</div>

<div><br/>
  </div>

<table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;">


  <tr>

    <td style="vertical-align: bottom; border-bottom: #000000 2px solid;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Year Ending December 31,</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Amortization</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">(in millions)</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 88%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="text-indent: 0pt;">2022</span></div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">2.2</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 88%;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="text-indent: 0pt;">2023</span></div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">2.1</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 88%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="text-indent: 0pt;">2024</span></div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">1.9</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 88%;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="text-indent: 0pt;">2025</span></div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">1.8</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 88%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="text-indent: 0pt;">2026</span></div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">1.8</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>


</table>

<div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 12pt;"><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We review our capitalized patent costs regularly to ensure that they include costs for patents and patent applications
    that have future value. When we identify patents and patent applications that we are not actively pursuing, we write off any associated costs. In 2021,
    2020 and 2019, patent expenses
    were $5.3 million, $4.1 million and $4.2 million, respectively, and included non-cash charges related to the write-down of our patent costs to their estimated net realizable values of $2.7 million, $1.9 million and $2.2 million, respectively.</div>
<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_LiabilityForClinicalDevelopmentCostsPolicyPolicyTextBlock', window );">Estimated Liability for Clinical Development Costs</a></td>
<td class="text">
<div style="display:none;"><br/></div>
<div style="text-align: left; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;">Estimated Liability for Clinical Development Costs</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We have numerous medicines in preclinical studies and/or clinical trials at clinical sites throughout the world. On at least a quarterly
    basis, we estimate our liability for preclinical and clinical development costs we have incurred and services that we have received but for which we have not yet been billed and maintain an accrual to cover these costs. These costs primarily relate to
    third-party clinical management costs, laboratory and analysis costs, toxicology studies and investigator grants. We estimate our liability using assumptions about study and patient activities and the related expected expenses for those activities
    determined based on the contracted fees with our service providers. The assumptions we use represent our best estimates of the activity and expenses at the time of our accrual and involve inherent uncertainties and the application of our judgment. Upon
    settlement, these costs may differ materially from the amounts accrued in our consolidated financial statements. Our historical accrual estimates have not been materially different from our actual amounts.</div>
<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ConsolidationSubsidiariesOrOtherInvestmentsConsolidatedEntitiesPolicy', window );">Noncontrolling Interest in Akcea Therapeutics, Inc.</a></td>
<td class="text">
<div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Noncontrolling Interest in Akcea Therapeutics, Inc.</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">Since Akcea&#8217;s IPO in July 2017 and prior to
      the Akcea Merger in October 2020, the shares of Akcea&#8217;s common stock third parties owned represented an interest in Akcea&#8217;s equity that we did not control. During this period our ownership ranged from </span>68 percent<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> to </span>77 percent<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">. However, as we maintained overall control of Akcea through our voting interest, we
      reflected the assets, liabilities and results of operations of Akcea in our consolidated financial statements. Since Akcea&#8217;s IPO in July 2017 and through the closing of the Akcea Merger, we reflected the noncontrolling interest attributable to other
      owners of Akcea&#8217;s common stock on a separate line on our statement of operations and a separate line within stockholders&#8217; equity in our consolidated balance sheet. In addition, through the closing of the Akcea Merger, we recorded a noncontrolling
      interest adjustment to account for the stock options Akcea granted, which if exercised, would have diluted our ownership in Akcea. This adjustment was a reclassification within stockholders&#8217; equity from additional paid-in capital to noncontrolling
      interest in Akcea equal to the amount of stock-based compensation expense Akcea had recognized. Additionally, w</span>e reflected changes in our ownership percentage in our financial statements as an adjustment to noncontrolling interest in the
    period the change occurred.</div>
<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ConcentrationRiskCreditRisk', window );">Concentration of Credit Risk</a></td>
<td class="text">
<div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Concentration of Credit Risk</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Financial instruments that potentially subject us to concentrations of credit risk consist primarily of cash equivalents,
    short-term investments and receivables. We place our cash equivalents and short-term investments with reputable financial institutions. We primarily invest our excess cash in commercial paper and debt instruments of the U.S. Treasury, financial
    institutions, corporations, and U.S. government agencies with strong credit ratings and an investment grade rating at or above A-1, P-1 or F-1 by Moody&#8217;s, Standard &amp; Poor&#8217;s, or S&amp;P, or Fitch, respectively. We have established guidelines
    relative to diversification and maturities that maintain safety and liquidity. We periodically review and modify these guidelines to maximize trends in yields and interest rates without compromising safety and liquidity.</div>
<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_InvestmentPolicyTextBlock', window );">Cash, Cash Equivalents and Investments</a></td>
<td class="text">
<div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Cash, Cash Equivalents and Investments</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We consider all liquid investments with maturities of three months or less when we purchase them to be cash equivalents.
    Our short-term investments have initial maturities of greater than three months from date of purchase. We classify our short-term debt investments as &#8220;available-for-sale&#8221; and carry them at fair market value based upon prices on the last day of the
    fiscal period for identical or similar items. We record unrealized gains and losses on debt securities as a separate component of comprehensive income (loss) and include net realized gains and losses in gain (loss) on investments in our consolidated
    statement of operations. We use the specific identification method to determine the cost of securities sold.</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We also have equity investments of less than 20 percent ownership in publicly and privately held biotechnology companies
      that we received as part of a technology license or partner agreement. At December 31, 2021, we held equity investments in three publicly held companies, Antisense Therapeutics Limited, or ATL, Bicycle Therapeutics plc, or Bicycle, and ProQR Therapeutics N.V., or ProQR. We
      also held equity investments in seven privately-held companies, Aro Biotherapeutics, Atlantic Pharmaceuticals Limited, Dynacure SAS, Empirico,
      Inc., Flamingo Therapeutics BV, YourBio Health, Inc. (formerly Seventh Sense Biosystems) and Suzhou-Ribo Life Science Co, Ltd.</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We are required to measure and record our equity investments at fair value and to recognize the changes in fair value in our consolidated
    statement of operations. We account for our equity investments in privately held companies at their cost minus impairments, plus or minus changes resulting from observable price changes in orderly transactions for the identical or similar investment of
    the same issuer. For example, d<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">uring 2020, we revalued our investments in </span>three<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> privately held companies, Dynacure, Suzhou-Ribo and Aro Biotherapeutics because the companies
      sold additional equity securities that were similar to the equity we own. As a result of these observable price changes, we recognized a $</span>6.3<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> million gain on our investment in Dynacure, a $</span>3.0<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> million gain on our investment in Suzhou-Ribo and a $</span>5.5<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> million gain on our investment in Aro Biotherapeutics in our consolidated statement of operations during 2020 because the sales were at higher prices compared to
      our recorded value.</span></div>
<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_InventoryPolicyTextBlock', window );">Inventory Valuation</a></td>
<td class="text">
<div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Inventory Valuation</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We reflect our inventory on our consolidated balance sheet at the lower of cost or net realizable value under the first-in, first-out
    method, or FIFO. We capitalize the costs of raw materials that we purchase for use in producing our medicines because until we use these raw materials, they have alternative future uses, which we refer to as clinical raw materials. We include in
    inventory raw material costs for medicines that we manufacture for our partners under contractual terms and that we use primarily in our clinical development activities and drug products. We can use each of our raw materials in multiple products and,
    as a result, each raw material has future economic value independent of the development status of any single medicine. For example, if one of our medicines failed, we could use the raw materials for that medicine to manufacture our other medicines. We
    expense these costs as R&amp;D expenses when we begin to manufacture API for a particular medicine if the medicine has not been approved for marketing by a regulatory agency. Our raw materials- commercial inventory includes API for our commercial
    medicines. We capitalize material, labor and overhead costs as part of our raw materials- commercial inventory.</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We review our inventory periodically and reduce the carrying value of items we consider to be slow moving or obsolete to
    their estimated net realizable value based on forecasted demand compared to quantities on hand. We consider several factors in estimating the net realizable value, including shelf life of our inventory, alternative uses for our medicines in development
    and historical write-offs. We recorded an <span style="-sec-ix-hidden:Fact_df7c1770e27a4789b9f7ad5345f29256"><span style="-sec-ix-hidden:Fact_7ba6995a24424942b581829d4ed245cc">insignificant</span></span> amount of inventory write-offs during the years ended December 31, 2021 and 2020.</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Our inventory consisted of the following (in thousands):</div>

<div><br/>
  </div>

<table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;">


  <tr>

    <td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">

        </td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="6" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">December 31,</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2021</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2020</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom;" valign="bottom">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Raw materials:</div>
        </td>

    <td colspan="1" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 76%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 19.4pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Raw materials- clinical</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">14,507</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">9,206</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 76%; padding-bottom: 2px;" valign="bottom">
          <div style="text-align: justify; text-indent: -18pt; margin-left: 28.4pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Raw materials- commercial</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">4,139</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">7,502</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 76%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 28.45pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Total raw materials</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">18,646</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">16,708</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 76%;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Work in process</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">5,770</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">2,252</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 76%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Finished goods</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">390</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">3,005</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 76%; padding-bottom: 4px;" valign="bottom">
          <div style="text-align: justify; margin-left: 28.45pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Total inventory</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">24,806</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">21,965</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>


</table>
<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_PropertyPlantAndEquipmentPolicyTextBlock', window );">Property, Plant and Equipment</a></td>
<td class="text">
<div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Property, Plant and Equipment</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We carry our property, plant and equipment at cost and depreciate it on the straight-line method
    over its estimated useful life, which consists of the following (in thousands):</div>

<div><br/>
  </div>

<table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;">


  <tr>

    <td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">

        </td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; white-space: nowrap;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Estimated Useful</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="6" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">December 31,</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Lives (in years)</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2021</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2020</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Computer software, laboratory, manufacturing and other equipment</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">3 to 10</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">72,802</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">68,990</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Building, building improvements and building systems</div>
        </td>

    <td colspan="1" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">15 to 40</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">144,046</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">137,879</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Land improvements</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="2" rowspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: rgb(0, 0, 0); font-family: 'Times New Roman',Times,serif; font-size: 10pt; text-align: center;">20</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">10,077</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">8,391</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Leasehold improvements</div>
        </td>

    <td colspan="1" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">5 to 15</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">20,144</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">17,263</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Furniture and fixtures</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">5 to 10</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">10,591</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">12,871</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 64%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">257,660</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">245,394</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Less accumulated depreciation</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(102,653</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(87,379</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 64%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">155,007</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">158,015</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Land</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">23,062</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">23,062</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 64%; padding-bottom: 4px;" valign="bottom">
          <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#160;Total</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">178,069</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">181,077</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>


</table>

<div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 12pt;"><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We depreciate our leasehold improvements using the shorter of the estimated useful life or remaining lease term.</div>
<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_FairValueOfFinancialInstrumentsPolicy', window );">Fair Value of Financial Instruments</a></td>
<td class="text">
<div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Fair Value of Financial Instruments</div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt;"><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We have estimated the fair value of our financial instruments. The amounts reported for cash, accounts receivable,
    accounts payable and accrued expenses approximate the fair value because of their short maturities. We report our investment securities at their estimated fair value based on quoted market prices for identical or similar instruments.</div>
<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_LesseeLeasesPolicyTextBlock', window );">Leases</a></td>
<td class="text">
<div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Leases</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We determine if an arrangement contains a lease at inception. We currently only have operating leases. We recognize a
    right-of-use operating lease asset and associated short- and long-term operating lease liability on our consolidated balance sheet for operating leases greater than one year. Our right-of-use assets represent our right to use an underlying asset for
    the lease term and our lease liabilities represent our obligation to make lease payments arising from the lease arrangement. We recognize our right-of-use operating lease assets and lease liabilities based on the present value of the future minimum
    lease payments we will pay over the lease term.<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">&#160;</span>We determine the lease term at the inception of each lease, and in certain cases our lease term could
    include renewal options if we concluded we were reasonably certain that we will exercise the renewal option. When we exercise a lease option that was not previously included in the initial lease term, we reassess our right-of-use asset and lease
    liabilities for the new lease term.</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">As our leases do not provide an interest rate implicit in the lease, we used our incremental borrowing rate, based on the
    information available on the date we adopted Topic 842 (January 2019), as of the lease inception date or at the lease option extension date in determining the present value of future payments. We recognize rent expense for our minimum lease payments on
    a straight-line basis over the expected term of our lease. We recognize period expenses, such as common area maintenance expenses, in the period we incur the expense.</div>
<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ImpairmentOrDisposalOfLongLivedAssetsIncludingIntangibleAssetsPolicyPolicyTextBlock', window );">Long-Lived Assets</a></td>
<td class="text">
<div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Long-Lived Assets</div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt;"><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We evaluate long-lived assets, which include property, plant and equipment and patent costs, for impairment on at least a
    quarterly basis and whenever events or changes in circumstances indicate that we may not be able to recover the carrying amount of such assets. We recorded charges of $2.7 million, $1.9 million and $2.2 million for the years ended December 31, 2021, 2020 and 2019, respectively, related to the
    write-down of patents.</div>
<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_UseOfEstimates', window );">Use of Estimates</a></td>
<td class="text">
<div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Use of Estimates</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We prepare our consolidated financial statements in conformity with accounting principles generally accepted in the U.S.
    that require us to make estimates and assumptions that affect the amounts reported in our consolidated financial statements and accompanying notes. Actual results could differ from our estimates.</div>
<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationOptionAndIncentivePlansPolicy', window );">Stock-Based Compensation Expense</a></td>
<td class="text">
<div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Stock-Based Compensation Expense</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We measure stock-based compensation expense for equity-classified awards, principally related to stock options, RSUs,
    PRSUs and stock purchase rights under our ESPP based on the estimated fair value of the award on the date of grant. We recognize the value of the portion of the award that we ultimately expect to vest as stock-based compensation expense over the
    requisite service period in our consolidated statements of operations. We reduce stock-based compensation expense for estimated forfeitures at the time of grant and revise in subsequent periods if actual forfeitures differ from those estimates. We use
    the Black-Scholes model to estimate the fair value of stock options granted and stock purchase rights under our ESPP.</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">On the grant date, we use our stock price and assumptions regarding a number of variables to determine the estimated fair
    value of stock-based payment awards. These variables include, but are not limited to, our expected stock price volatility over the term of the awards, and actual and projected employee stock option exercise behaviors. The expected term of stock options
    granted represents the period of time that we expect them to be outstanding. We estimate the expected term of options granted based on historical exercise patterns.</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We recognize compensation expense for stock options granted, RSUs, PRSUs and stock purchase rights under the ESPP using
    the accelerated multiple-option approach. Under the accelerated multiple-option approach (also known as the graded-vesting method), we recognize compensation expense over the requisite service period for each separately vesting tranche of the award as
    though the award were in substance multiple awards, which results in the expense being front-loaded over the vesting period.</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">In December 2020, we amended and restated the
      Akcea 2015 equity plan, including renaming the plan as the Ionis Pharmaceuticals, Inc. 2020 Equity Incentive Plan, or 2020 Plan. As a result, all employees are now under an Ionis stock plan and subject to the same Black-Scholes assumptions</span>.</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;">RSU&#8217;s:</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">The fair value of RSUs is based on the market price of our common stock on the date of grant. The RSUs we have granted to
    employees vest annually over a four-year period. The RSUs we granted to our board of directors prior to June 2020 vest annually over a four-year period. RSUs granted to our board of directors after June 2020 fully vest after one year.</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;">PRSU&#8217;s:</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Beginning in 2020, we added PRSU awards to the compensation for our Chief Executive Officer, Dr. Brett Monia. Under the
    terms of the grants, <span style="-sec-ix-hidden:Fact_65d15117ab79462e81dfb8bbb86a0107"><span style="-sec-ix-hidden:Fact_e9934b85c6af480197be8d0d8b5ea434"><span style="-sec-ix-hidden:Fact_5599af32346c4fce91fa6d27caf4b474">one third</span></span></span> of the PRSUs may vest at the end of three separate performance periods spread over the three years following the date of
    grant (i.e., the one-year period commencing on the date of grant and ending on the first anniversary of the date of grant; the two-year period commencing on the date of grant and ending on the second anniversary of the date of grant; and the three-year period commencing on the date of grant and ending on the third anniversary of the date of grant) based on our relative total shareholder return, or TSR, as compared to a
    peer group of companies, and as measured, in each case, at the end of the applicable performance period. Under the terms of the grants no number
    of PRSUs is guaranteed to vest and the actual number of PRSUs that will vest at the end of each performance period may be anywhere from zero to
    150 percent of the target number depending on our relative TSR.</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We determined the fair value of Dr. Monia&#8217;s PRSUs using a Monte Carlo model because the performance target is based on our
    relative TSR, which represents a market condition. We are recognizing the grant date fair value of these awards as stock-based compensation expense using the accelerated multiple-option approach over the vesting period. The weighted-average grant date
    fair value of PRSUs granted to Dr. Monia for the years ended December 31, 2021 and 2020 were $77.17 and $93.09 per share, respectively.</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">See Note 4, <span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Stockholders&#8217;
      Equity,</span> for additional information regarding our stock-based compensation plans.</div>
<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_StockholdersEquityPolicyTextBlock', window );">Accumulated Other Comprehensive Loss</a></td>
<td class="text">
<div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Accumulated Other Comprehensive Loss</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 12pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Accumulated
      other comprehensive loss is comprised of unrealized gains and losses on investments, net of taxes and currency translation adjustments. The following table summarizes changes in accumulated other comprehensive loss for the years ended December 31, 2021, 2020 and 2019 (in thousands):</span></div>

<div style="text-align: justify;"><br/>
  </div>

<table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;">


  <tr>

    <td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">

        </td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="10" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Year Ended December 31,</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2021</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2020</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2019</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Beginning balance accumulated other comprehensive loss</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(21,071</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(25,290</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(32,016</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 64%;" valign="bottom">
          <div style="text-align: left; text-indent: -9pt; margin-left: 18pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Unrealized gains (losses) on securities, net of tax (1)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(11,486</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">3,729</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">6,633</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: left; text-indent: -9pt; margin-left: 18pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Currency translation adjustment</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(111</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">617</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">93</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 64%; padding-bottom: 2px;" valign="bottom">
          <div style="text-align: left; text-indent: -9pt; margin-left: 18pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Adjustments to other comprehensive loss from purchase of noncontrolling interest of Akcea
            Therapeutics, Inc.</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#8212;</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(127</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#8212;</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Net other comprehensive loss for the period</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(11,597</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">4,219</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">6,726</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 64%; padding-bottom: 4px;" valign="bottom">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Ending balance accumulated other comprehensive loss</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(32,668</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(21,071</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(25,290</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

  </tr>


</table>

<div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">________________</div>

<div>
    <table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">


  <tr>

    <td style="width: 18pt; vertical-align: top; align: right;">
            <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(1)</div>
          </td>

    <td style="width: auto; vertical-align: top;">
            <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We did not have tax expense included in our other comprehensive loss for the years ended December 31, 2021 and 2020. For the year ended December 31,
              2019, we had a tax benefit of $1.4
              million included in other comprehensive loss.&#160;</div>
          </td>

  </tr>


</table>
    </div>
<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DebtPolicyTextBlock', window );">Convertible Debt</a></td>
<td class="text">
<div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Convertible Debt</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;">Adoption of ASU 2020-06</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">In August 2020, the FASB issued ASU 2020-06, which simplifies the accounting for convertible debt instruments, amends the
    guidance on derivative scope exceptions for contracts in an entity&#8217;s own equity, and modifies the guidance on diluted earnings per share calculations. We adopted ASU 2020-06 on January 1, 2021 under the full retrospective approach, which required us to
    revise our prior period financial statements. This guidance impacted our accounting for outstanding convertible debt. At January 1, 2021, we had two
    outstanding convertible notes, our 0.125% Notes, which mature in December 2024, and our 1% Notes, which matured in November 2021. In April 2021, we completed a $632.5 million
    offering of 0% Notes primarily to repurchase a majority of our 1% Notes. We accounted for our 0% Notes under ASU 2020-06 at issuance. Refer to Note
    3, <span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Long-Term Obligations and Commitments</span>, for further information.</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">The updated guidance eliminates the cash conversion accounting model we previously followed in Accounting Standard
    Codification, or ASC, 470-20, which required us to separate each of our convertible debt instruments at issuance into two units of accounting, a liability component, based on our nonconvertible debt borrowing rate at issuance, and an equity component.
    Under ASU 2020-06, we now account for each of our convertible debt instruments as a single unit of accounting, a liability, because we concluded that the conversion features do not require bifurcation as a derivative under ASC 815-15 and we did not
    issue our convertible debt instruments at a substantial premium. Since we adopted ASU 2020-06 using the full retrospective approach, we were required to apply the guidance to all convertible debt instruments we had outstanding as of January 1, 2019. We
    recomputed the basis of each convertible debt instrument as if we accounted for each as a single unit of accounting at issuance. This update included recalculating the amortization of debt issuance costs using an updated effective interest rate. As a
    result of adopting ASU 2020-06, we recorded a cumulative adjustment to decrease our additional paid in capital and our accumulated deficit at January 1, 2019. We have updated these financial statements to reflect the cumulative adjustment for the
    periods presented. We have labeled our prior period financial statements &#8220;as revised&#8221; to indicate the change required under the new accounting guidance. Below is a summary of the change in our balance sheet at December 31, 2020 and statement of
    operations from the years ended December 31, 2020 and 2019 under the ASC 470-20 legacy guidance compared to the new ASU 2020-06 guidance we adopted:</div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt;"><br/>
  </div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">The following table summarizes the adjustments we made to the consolidated balance sheet we
    originally reported at December 31, 2020 to adopt ASU 2020-06 (in thousands):</div>

<div><br/>
  </div>

<table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;">


  <tr>

    <td style="vertical-align: top; padding-bottom: 2px;" valign="bottom">

        </td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="10" style="vertical-align: top; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">December 31, 2020</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: top; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">As Previously</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Reported</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">ASU 2020-06</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Adjustment</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">As Revised</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: top; width: 64%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">1 percent convertible
            senior notes</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">293,161</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">15,648</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">308,809</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: top; width: 64%;" valign="bottom">
          <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">0.125 percent convertible
            senior notes</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">455,719</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">84,417</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">540,136</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: top; width: 64%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Additional paid-in-capital</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">2,113,646</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(218,127</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">1,895,519</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: top; width: 64%;" valign="bottom">
          <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Accumulated deficit</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(1,249,368</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">118,062</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(1,131,306</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

  </tr>


</table>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#160;<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">Under ASU 2020-06, our revised
      ending balances for our </span>1%<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> Notes and </span>0.125%<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> Notes as of December 31, 2020 represent the principal
      balance of each convertible debt instrument less debt issuance costs. Additionally, because we have deferred tax assets related to our convertible debt instruments, we also adjusted these amounts as part of our adoption of ASU 2020-06. However,
      because we have a full valuation allowance on our deferred tax assets, there was </span>no<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> impact to our consolidated balance sheet related to our deferred tax assets.</span></div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#160;<span style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; color: #000000;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">The following
      tables summarize the adjustments we made to the consolidated statement of operations we originally reported for the years ended December 31, 2020 and 2019 to adopt ASU 2020-06 (in thousands):</span></span></div>

<div><br/>
  </div>

<table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;">


  <tr>

    <td style="vertical-align: top; padding-bottom: 2px;" valign="bottom">

        </td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="10" style="vertical-align: top; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Year Ended December 31, 2020</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: top; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">As Previously</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Reported</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">ASU 2020-06</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Adjustment</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">As Revised</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: top; width: 64%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Interest expense</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(44,990</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">35,480</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(9,510</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

  </tr>

  <tr>

    <td style="vertical-align: top; width: 64%;" valign="bottom">
          <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Loss before income tax expense</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(170,032</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">35,480</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(134,552</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

  </tr>

  <tr>

    <td style="vertical-align: top; width: 64%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Income tax expense</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(316,734</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(28,457</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(345,191</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

  </tr>

  <tr>

    <td style="vertical-align: top; width: 64%;" valign="bottom">
          <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Net loss</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(486,766</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">7,023</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(479,743</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

  </tr>

  <tr>

    <td style="vertical-align: top; width: 64%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Net loss attributable to Ionis Pharmaceuticals, Inc. common stockholders</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(451,286</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">7,023</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(444,263</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

  </tr>

  <tr>

    <td style="vertical-align: top; width: 64%;" valign="bottom">
          <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Basic and diluted net loss per share</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(3.23</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">0.05</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(3.18</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

  </tr>


</table>

<div><br/>
  </div>

<table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;">


  <tr>

    <td style="vertical-align: top; padding-bottom: 2px;" valign="bottom">

        </td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="10" style="vertical-align: top; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Year Ended December 31, 2019</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: top; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">As Previously</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Reported</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">ASU 2020-06</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Adjustment</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">As Revised</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: top; width: 64%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Interest expense</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(48,768</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">36,328</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(12,440</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

  </tr>

  <tr>

    <td style="vertical-align: top; width: 64%;" valign="bottom">
          <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Loss on early retirement of debt</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(21,865</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(44,331</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(66,196</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

  </tr>

  <tr>

    <td style="vertical-align: top; width: 64%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Income before income tax benefit (expense)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">346,769</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(8,003</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">338,766</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: top; width: 64%;" valign="bottom">
          <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Income tax expense</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(43,507</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(8,000</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(51,507</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

  </tr>

  <tr>

    <td style="vertical-align: top; width: 64%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Net income</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">303,262</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(16,003</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">287,259</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: top; width: 64%;" valign="bottom">
          <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Net income attributable to Ionis Pharmaceuticals, Inc. common stockholders</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">294,146</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(16,003</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">278,143</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: top; width: 64%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Basic net income per share</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">2.12</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(0.12</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">2.00</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: top; width: 64%;" valign="bottom">
          <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Diluted net income per share</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">2.08</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(0.18</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">1.90</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>


</table>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Under ASU 2020-06, our revised interest expense is lower because we are no longer recording non-cash
    interest expense related to a debt discount. This decrease was partially offset by the increase in interest expense related to the amortization of debt issuance costs because we no longer allocate a portion of our debt issuance costs to stockholders&#8217;
    equity at issuance. Instead, the entire debt issuance costs were recorded as a contra-liability on our consolidated balance sheet at issuance and we are amortizing them over the contractual term using an updated effective interest rate. Our updated
    effective interest rates for our 1% Notes and 0.125%
    Notes were 1.4 percent and 0.5 percent,
    respectively.</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">The following tables summarize the adjustments we made to our consolidated statements of
    stockholders&#8217; equity we originally reported at December 31, 2020 and 2019 to adopt ASU 2020-06 (in thousands):</div>

<div><br/>
  </div>

<table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;">


  <tr>

    <td style="vertical-align: top; padding-bottom: 2px;" valign="bottom">

        </td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="10" style="vertical-align: top; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">December 31, 2020</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: top; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">As Previously</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Reported</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">ASU 2020-06</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Adjustment</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">As Revised</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: top; width: 64%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Additional paid-in-capital</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">2,113,646</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(218,127</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">1,895,519</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: top; width: 64%;" valign="bottom">
          <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Accumulated deficit</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(1,249,368</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">118,062</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(1,131,306</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

  </tr>

  <tr>

    <td style="vertical-align: top; width: 64%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Total stockholders&#8217; equity</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">843,347</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(100,065</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">743,282</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>


</table>

<div><br/>
  </div>

<table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;">


  <tr>

    <td style="vertical-align: top; padding-bottom: 2px;" valign="bottom">

        </td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="10" style="vertical-align: top; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">December 31, 2019</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: top; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">As Previously</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Reported</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">ASU 2020-06</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Adjustment</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">As Revised</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: top; width: 64%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Additional paid-in-capital</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">2,203,778</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(218,128</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">1,985,650</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: top; width: 64%;" valign="bottom">
          <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Accumulated deficit</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(707,534</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">111,039</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(596,495</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

  </tr>

  <tr>

    <td style="vertical-align: top; width: 64%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Total stockholders&#8217; equity</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">1,684,547</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(107,088</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">1,577,459</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>


</table>
<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DerivativesPolicyTextBlock', window );">Call Spread</a></td>
<td class="text">
<div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Call Spread</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">In conjunction with the issuance of our 0% Notes and 0.125% Notes in April 2021 and December 2019, respectively, we entered
    into call spread transactions, which were comprised of purchasing note hedges and selling warrants. We account for the note hedges and warrants as separate freestanding financial instruments and treat each instrument as a separate unit of accounting.
    We determined that the note hedges and warrants do not meet the definition of a liability using the guidance contained in ASC Topic 480; therefore, we account for the note hedges and warrants using the Derivatives and Hedging &#8211; Contracts in Entity&#8217;s
    Own Equity accounting guidance contained in ASC Topic 815. We determined that the note hedges and warrants meet the definition of a derivative, are indexed to our stock and meet the criteria to be classified in shareholders&#8217; equity. We recorded the
    aggregate amount paid for the note hedges and the aggregate amount received for the warrants as additional paid-in capital in our consolidated balance sheet. We reassess our ability to continue to classify the note hedges and warrants in shareholders&#8217;
    equity at each reporting period.</div>
<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_SegmentReportingPolicyPolicyTextBlock', window );">Segment Information</a></td>
<td class="text">
<div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Segment Information</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">In 2021, we began operating as a single segment, Ionis operations, because our chief decision maker reviews operating
    results on an aggregate basis and manages our operations as a <span style="-sec-ix-hidden:Fact_33bc30118e9548358994c912eadf2161">single</span> operating segment. Previously, we had operated as two operating segments, Ionis Core and Akcea Therapeutics. We completed the Akcea Merger in October 2020 and fully integrated Akcea&#8217;s operations into ours
    as of January 1, 2021<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">.</span></div>
<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_FairValueMeasurementPolicyPolicyTextBlock', window );">Fair Value Measurements</a></td>
<td class="text">
<div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Fair Value Measurements</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We use a three-tier fair value hierarchy to prioritize the inputs used in our fair value measurements. These tiers
    include: Level 1, defined as observable inputs such as quoted prices in active markets for identical assets, which includes our money market funds and treasury securities classified as available-for-sale securities and our investment in equity
    securities in publicly held biotechnology companies; Level 2, defined as inputs other than quoted prices in active markets that are either directly or indirectly observable, which includes our fixed income securities and commercial paper classified as
    available-for-sale securities; and Level 3, defined as unobservable inputs in which little or no market data exists, therefore requiring us to develop our own assumptions. We classify most of our securities as Level 2. We obtain the fair value of our
    Level 2 investments from our custodian bank or from a professional pricing service. We validate the fair value of our Level 2 investments by understanding the pricing model used by the custodian banks or professional pricing service provider and
    comparing that fair value to the fair value based on observable market prices.</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">The following tables present the major security types we held at December 31, 2021 and 2020&#160;<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">that we regularly measure and carry at fair value</span>. As of December 31, 2021, our Bicycle investment was subject to trading restrictions that extend to the third quarter of 2022; as
    a result, we included a lack of marketability discount in valuing this investment, which is a Level 3 input. As of December 31, 2020, we did not
    have any investments that we valued using Level 3 inputs. The following tables segregate each security type by the level within the fair value hierarchy of the valuation techniques we utilized to determine the respective securities&#8217; fair value (in
    thousands):</div>

<div><br/>
  </div>

<table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;">


  <tr>

    <td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">At</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">December 31, 2021</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Quoted Prices in</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Active Markets</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">(Level 1)</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Significant Other</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Observable Inputs</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">(Level 2)</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Significant</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Unobservable Inputs</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">(Level 3)</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 52%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Cash equivalents (1)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">541,199</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">541,199</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#8212;</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#8212;</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 52%;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Corporate debt securities (2)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">764,059</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#8212;</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">764,059</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#8212;</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 52%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Debt securities issued by U.S. government agencies (2)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">120,868</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#8212;</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">120,868</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#8212;</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 52%;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Debt securities issued by the U.S. Treasury (2)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">182,634</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
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    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#8212;</div>
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    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#8212;</div>
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    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

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  <tr>

    <td style="vertical-align: bottom; width: 52%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Debt securities issued by states of the U.S. and political subdivisions of the states (3)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">174,464</div>
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    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#8212;</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">174,464</div>
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    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#8212;</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 52%;" valign="bottom">
          <div>
            <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Other municipal debt securities (2)</div>
          </div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">6,099</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#8212;</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">6,099</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#8212;</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 52%; background-color: #CCEEFF;" valign="bottom">
          <div>
            <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Investment in Bicycle Therapeutics plc (4)</div>
          </div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">14,330</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#8212;</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#8212;</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">14,330</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 52%; padding-bottom: 2px;" valign="bottom">
          <div>
            <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Investment in ProQR Therapeutics N.V. (4)</div>
          </div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">3,875</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">3,875</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#8212;</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#8212;</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 52%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; text-indent: -8.9pt; margin-left: 22.55pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Total</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">1,807,528</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">727,708</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">1,065,490</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">14,330</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>


</table>

<div><br/>
  </div>

<table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;">


  <tr>

    <td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">

        </td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">At</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">December 31, 2020</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Quoted Prices in</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Active Markets</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">(Level 1)</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Significant Other</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Observable Inputs</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">(Level 2)</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Cash equivalents (1)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">221,125</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">221,125</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#8212;</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 64%;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Corporate debt securities (5)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">846,315</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#8212;</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">846,315</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Debt securities issued by U.S. government agencies (2)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">174,861</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#8212;</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">174,861</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 64%;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Debt securities issued by the U.S. Treasury (6)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">358,497</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">358,497</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#8212;</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Debt securities issued by states of the U.S. and political subdivisions of the states (2)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">136,309</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#8212;</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">136,309</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 64%;" valign="bottom">
          <div>
            <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Other municipal debt securities (2)</div>
          </div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">6,225</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#8212;</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">6,225</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">
          <div>
            <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Investment in ProQR Therapeutics N.V. (4)</div>
          </div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">2,031</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">2,031</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#8212;</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 64%; padding-bottom: 4px;" valign="bottom">
          <div style="text-align: justify; text-indent: -8.9pt; margin-left: 22.55pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Total</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">1,745,363</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">581,653</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">1,163,710</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>


</table>

<div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">________________</div>

<table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">


  <tr>

    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(1)</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Included in cash and cash
            equivalents on our consolidated balance sheet.</div>
        </td>

  </tr>


</table>

<div><br/>
  </div>

<table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">


  <tr>

    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(2)</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Included in short-term
            investments.</div>
        </td>

  </tr>


</table>

<div><br/>
  </div>

<table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">


  <tr>

    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(3)</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$2.3 million included in cash and cash equivalents on our consolidated balance sheet, with the difference included in short-term investments on our
            consolidated balance sheet.</div>
        </td>

  </tr>


</table>

<div><br/>
  </div>

<table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">


  <tr>

    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(4)</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Included in other current assets
            on our consolidated balance sheet.</div>
        </td>

  </tr>


</table>

<div><br/>
  </div>

<table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">


  <tr>

    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(5)</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$10.0 million included in cash and cash equivalents on our consolidated balance sheet, with the difference included in short-term investments on our
            consolidated balance sheet.</div>
        </td>

  </tr>


</table>

<div><br/>
  </div>

<table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">


  <tr>

    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(6)</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$17.5 million included in cash and cash equivalents on our consolidated balance sheet, with the difference included in short-term investments on our
            consolidated balance sheet.</div>
        </td>

  </tr>


</table>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;">Convertible Notes</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Our 0.125% Notes and 0% Notes had a fair value of $495.4 million and $559.2 million at December 31, 2021, respectively. We determine the fair value of our notes based on quoted market prices for these notes, which are Level 2
    measurements because the notes do not trade regularly.</div>
<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_IncomeTaxPolicyTextBlock', window );">Income Taxes</a></td>
<td class="text">
<div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Income Taxes</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We account for income taxes using the asset and liability method, which requires the recognition of deferred tax assets and liabilities
    for the expected future tax consequences of events that have been recognized in our financial statements or tax returns. In addition, deferred tax assets are recorded for the future benefit of utilizing net operating losses and research and development
    credit carryforwards. We record a valuation allowance when necessary to reduce our net deferred tax assets to the amount expected to be realized.</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We apply the authoritative accounting guidance prescribing a threshold and measurement attribute for the financial recognition and
    measurement of a tax position taken or expected to be taken in a tax return. We recognize liabilities for uncertain tax positions based on a two-step process. The first step is to evaluate the tax position for recognition by determining if the weight
    of available evidence indicates that it is more likely than not that the position will be sustained on audit, including resolution of related appeals or litigation processes, if any. The second step requires us to estimate and measure the tax benefit
    as the largest amount that is more than 50 percent likely to be realized upon ultimate settlement.</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We are required to use significant judgment in evaluating our uncertain tax positions and determining our provision for income taxes.
    Although we believe our reserves are reasonable, no assurance can be given that the final tax outcome of these matters will not be different from that which is reflected in our historical income tax provisions and accruals. We adjust these reserves for
    changing facts and circumstances, such as the closing of a tax audit or the refinement of an estimate. To the extent that the final tax outcome of these matters is different than the amounts recorded, such differences may impact the provision for
    income taxes in the period in which such determination is made.</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We are also required to use significant judgment in determining any valuation allowance recorded against our deferred tax assets. In
    assessing the need for a valuation allowance, we consider all available evidence, including scheduled reversal of deferred tax liabilities, past operating results, the feasibility of tax planning strategies and estimates of future taxable income. We
    base our estimates of future taxable income on assumptions that are consistent with our plans. The assumptions we use represent our best estimates and involve inherent uncertainties and the application of our judgment. Should actual amounts differ from
    our estimates, the amount of our tax expense and liabilities we recognize could be materially impacted. We record a valuation allowance to reduce the balance of our net deferred tax assets to the amount we believe is more-likely-than-not to be
    realized.</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We do not provide for a U.S. income tax liability and foreign withholding taxes on undistributed foreign earnings of our foreign
    subsidiaries.</div>
<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_NewAccountingPronouncementsPolicyPolicyTextBlock', window );">Impact of Recently Issued Accounting Standards</a></td>
<td class="text">
<div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Impact of Recently Issued Accounting Standards</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">As disclosed in the &#8220;Convertible Debt&#8221; policy above within this footnote, we adopted the simplified accounting for
    convertible debt instrument guidance (ASU 2020-06) on January 1, 2021. Refer to the section above for the impact of adoption. We do not expect any other recently issued accounting standards to have a material impact to our financial results.</div>
<span></span>
</td>
</tr>
</table>
<div style="display: none;">
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_LiabilityForClinicalDevelopmentCostsPolicyPolicyTextBlock">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Disclosure of accounting policy for estimating the liability for clinical development costs.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_LiabilityForClinicalDevelopmentCostsPolicyPolicyTextBlock</td>
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<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
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<td><strong> Data Type:</strong></td>
<td>dtr-types:textBlockItemType</td>
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<td><strong> Balance Type:</strong></td>
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<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_ConcentrationRiskCreditRisk">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Disclosure of accounting policy for credit risk.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 275<br> -SubTopic 10<br> -Section 50<br> -Paragraph 1<br> -Subparagraph (d)<br> -URI http://asc.fasb.org/extlink&amp;oid=99393423&amp;loc=d3e5967-108592<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 942<br> -SubTopic 825<br> -Section 50<br> -Paragraph 1<br> -URI http://asc.fasb.org/extlink&amp;oid=123345438&amp;loc=d3e61044-112788<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ConcentrationRiskCreditRisk</td>
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<tr>
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<td><strong> Period Type:</strong></td>
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</table>
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<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Disclosure of accounting policy regarding (1) the principles it follows in consolidating or combining the separate financial statements, including the principles followed in determining the inclusion or exclusion of subsidiaries or other entities in the consolidated or combined financial statements and (2) its treatment of interests (for example, common stock, a partnership interest or other means of exerting influence) in other entities, for example consolidation or use of the equity or cost methods of accounting.  The accounting policy may also address the accounting treatment for intercompany accounts and transactions, noncontrolling interest, and the income statement treatment in consolidation for issuances of stock by a subsidiary.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/exampleRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 235<br> -SubTopic 10<br> -Section 50<br> -Paragraph 4<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=123372394&amp;loc=d3e18823-107790<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 810<br> -SubTopic 10<br> -Section 50<br> -Paragraph 1<br> -URI http://asc.fasb.org/extlink&amp;oid=109239629&amp;loc=d3e5614-111684<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ConsolidationPolicyTextBlock</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
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<tr>
<td><strong> Data Type:</strong></td>
<td>dtr-types:textBlockItemType</td>
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<tr>
<td><strong> Balance Type:</strong></td>
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<tr>
<td><strong> Period Type:</strong></td>
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</tr>
</table></div>
</div></td></tr>
</table>
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<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Disclosure of accounting policy for subsidiaries or other investments that are consolidated, including the accounting treatment for intercompany accounts or transactions and any noncontrolling interest.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 810<br> -SubTopic 10<br> -Section 50<br> -Paragraph 1<br> -URI http://asc.fasb.org/extlink&amp;oid=109239629&amp;loc=d3e5614-111684<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ConsolidationSubsidiariesOrOtherInvestmentsConsolidatedEntitiesPolicy</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
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<tr>
<td><strong> Data Type:</strong></td>
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<td><strong> Balance Type:</strong></td>
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</tr>
<tr>
<td><strong> Period Type:</strong></td>
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</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_CostOfSalesPolicyTextBlock">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Disclosure of accounting policy for cost of product sold and service rendered.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2009/role/commonPracticeRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 705<br> -URI http://asc.fasb.org/topic&amp;trid=2122478<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_CostOfSalesPolicyTextBlock</td>
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<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
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<td><strong> Data Type:</strong></td>
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<td><strong> Balance Type:</strong></td>
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</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_DebtPolicyTextBlock">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Disclosure of accounting policy related to debt. Includes, but is not limited to, debt issuance costs, the effects of refinancings, method of amortizing debt issuance costs and original issue discount, and classifications of debt.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 470<br> -SubTopic 10<br> -Section 50<br> -Paragraph 1<br> -URI http://asc.fasb.org/extlink&amp;oid=123465755&amp;loc=d3e1835-112601<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_DebtPolicyTextBlock</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
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<td><strong> Balance Type:</strong></td>
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<tr>
<td><strong> Period Type:</strong></td>
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</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_DerivativesPolicyTextBlock">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Disclosure of accounting policy for its derivative instruments and hedging activities.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 815<br> -SubTopic 10<br> -Section 50<br> -Paragraph 2<br> -URI http://asc.fasb.org/extlink&amp;oid=125515794&amp;loc=d3e41620-113959<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 815<br> -SubTopic 10<br> -Section 50<br> -Paragraph 4<br> -URI http://asc.fasb.org/extlink&amp;oid=125515794&amp;loc=d3e41638-113959<br><br>Reference 3: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 815<br> -SubTopic 10<br> -Section 50<br> -Paragraph 1A<br> -URI http://asc.fasb.org/extlink&amp;oid=125515794&amp;loc=SL5579245-113959<br><br>Reference 4: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 815<br> -SubTopic 10<br> -Section 50<br> -Paragraph 7<br> -URI http://asc.fasb.org/extlink&amp;oid=125515794&amp;loc=d3e41675-113959<br><br>Reference 5: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 235<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.4-08(n))<br> -URI http://asc.fasb.org/extlink&amp;oid=120395691&amp;loc=d3e23780-122690<br><br>Reference 6: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 815<br> -SubTopic 10<br> -Section 50<br> -Paragraph 1<br> -URI http://asc.fasb.org/extlink&amp;oid=125515794&amp;loc=SL5579240-113959<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_DerivativesPolicyTextBlock</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
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</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
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</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_EarningsPerSharePolicyTextBlock">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Disclosure of accounting policy for computing basic and diluted earnings or loss per share for each class of common stock and participating security. Addresses all significant policy factors, including any antidilutive items that have been excluded from the computation and takes into account stock dividends, splits and reverse splits that occur after the balance sheet date of the latest reporting period but before the issuance of the financial statements.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 260<br> -SubTopic 10<br> -Section 50<br> -Paragraph 1<br> -Subparagraph (c)<br> -URI http://asc.fasb.org/extlink&amp;oid=124432515&amp;loc=d3e3550-109257<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 260<br> -SubTopic 10<br> -Section 50<br> -Paragraph 2<br> -URI http://asc.fasb.org/extlink&amp;oid=124432515&amp;loc=d3e3630-109257<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_EarningsPerSharePolicyTextBlock</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
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<tr>
<td><strong> Data Type:</strong></td>
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<tr>
<td><strong> Balance Type:</strong></td>
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<td><strong> Period Type:</strong></td>
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<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_FairValueMeasurementPolicyPolicyTextBlock">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Disclosure of accounting policy for fair value measurements of financial and non-financial assets, liabilities and instruments classified in shareholders' equity. Disclosures include, but are not limited to, how an entity that manages a group of financial assets and liabilities on the basis of its net exposure measures the fair value of those assets and liabilities.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_FairValueMeasurementPolicyPolicyTextBlock</td>
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<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
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<td><strong> Period Type:</strong></td>
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<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Disclosure of accounting policy for determining the fair value of financial instruments.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 820<br> -SubTopic 10<br> -Section 60<br> -Paragraph 1<br> -URI http://asc.fasb.org/extlink&amp;oid=7493716&amp;loc=d3e21868-110260<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 825<br> -SubTopic 10<br> -Section 50<br> -Paragraph 1<br> -URI http://asc.fasb.org/extlink&amp;oid=123594938&amp;loc=d3e13279-108611<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_FairValueOfFinancialInstrumentsPolicy</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
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<tr>
<td><strong> Data Type:</strong></td>
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</tr>
<tr>
<td><strong> Balance Type:</strong></td>
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<tr>
<td><strong> Period Type:</strong></td>
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</div></td></tr>
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<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_ImpairmentOrDisposalOfLongLivedAssetsIncludingIntangibleAssetsPolicyPolicyTextBlock">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Disclosure of accounting policy for the impairment and disposal of long-lived assets including goodwill and other intangible assets.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ImpairmentOrDisposalOfLongLivedAssetsIncludingIntangibleAssetsPolicyPolicyTextBlock</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
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<tr>
<td><strong> Balance Type:</strong></td>
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<tr>
<td><strong> Period Type:</strong></td>
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</div></td></tr>
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<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_IncomeTaxPolicyTextBlock">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Disclosure of accounting policy for income taxes, which may include its accounting policies for recognizing and measuring deferred tax assets and liabilities and related valuation allowances, recognizing investment tax credits, operating loss carryforwards, tax credit carryforwards, and other carryforwards, methodologies for determining its effective income tax rate and the characterization of interest and penalties in the financial statements.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section 45<br> -Paragraph 25<br> -URI http://asc.fasb.org/extlink&amp;oid=123427490&amp;loc=d3e32247-109318<br><br>Reference 2: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section 50<br> -Paragraph 20<br> -URI http://asc.fasb.org/extlink&amp;oid=121826272&amp;loc=d3e32847-109319<br><br>Reference 3: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section 50<br> -Paragraph 19<br> -URI http://asc.fasb.org/extlink&amp;oid=121826272&amp;loc=d3e32840-109319<br><br>Reference 4: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 220<br> -SubTopic 10<br> -Section 50<br> -Paragraph 1<br> -URI http://asc.fasb.org/extlink&amp;oid=124431353&amp;loc=SL116659661-227067<br><br>Reference 5: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section 50<br> -Paragraph 9<br> -URI http://asc.fasb.org/extlink&amp;oid=121826272&amp;loc=d3e32639-109319<br><br>Reference 6: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section 45<br> -Paragraph 28<br> -URI http://asc.fasb.org/extlink&amp;oid=123427490&amp;loc=d3e32280-109318<br><br>Reference 7: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section 50<br> -Paragraph 17<br> -Subparagraph (b)<br> -URI http://asc.fasb.org/extlink&amp;oid=121826272&amp;loc=d3e32809-109319<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_IncomeTaxPolicyTextBlock</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
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</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_IntangibleAssetsFiniteLivedPolicy">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Disclosure of accounting policy for finite-lived intangible assets. This accounting policy also might address: (1) the amortization method used; (2) the useful lives of such assets; and (3) how the entity assesses and measures impairment of such assets.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 926<br> -SubTopic 20<br> -Section 50<br> -Paragraph 5<br> -URI http://asc.fasb.org/extlink&amp;oid=120154696&amp;loc=d3e54445-107959<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 350<br> -SubTopic 30<br> -Section 50<br> -Paragraph 2<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=66006027&amp;loc=d3e16323-109275<br><br>Reference 3: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 920<br> -SubTopic 350<br> -Section 50<br> -Paragraph 4<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=120155617&amp;loc=SL120155638-234783<br><br>Reference 4: http://www.xbrl.org/2003/role/exampleRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 235<br> -SubTopic 10<br> -Section 50<br> -Paragraph 4<br> -Subparagraph (c)<br> -URI http://asc.fasb.org/extlink&amp;oid=123372394&amp;loc=d3e18823-107790<br><br>Reference 5: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 920<br> -SubTopic 350<br> -Section 50<br> -Paragraph 1<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=120155617&amp;loc=SL120155628-234783<br><br>Reference 6: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 920<br> -SubTopic 350<br> -Section 50<br> -Paragraph 1<br> -Subparagraph (b)<br> -URI http://asc.fasb.org/extlink&amp;oid=120155617&amp;loc=SL120155628-234783<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_IntangibleAssetsFiniteLivedPolicy</td>
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<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
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<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Disclosure of inventory accounting policy for inventory classes, including, but not limited to, basis for determining inventory amounts, methods by which amounts are added and removed from inventory classes, loss recognition on impairment of inventories, and situations in which inventories are stated above cost.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 330<br> -SubTopic 10<br> -Section 50<br> -Paragraph 4<br> -URI http://asc.fasb.org/extlink&amp;oid=116847112&amp;loc=d3e4556-108314<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 210<br> -SubTopic 10<br> -Section 50<br> -Paragraph 1<br> -URI http://asc.fasb.org/extlink&amp;oid=6361739&amp;loc=d3e7789-107766<br><br>Reference 3: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 912<br> -SubTopic 330<br> -Section 50<br> -Paragraph 1<br> -URI http://asc.fasb.org/extlink&amp;oid=6471895&amp;loc=d3e55923-109411<br><br>Reference 4: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 330<br> -SubTopic 10<br> -Section 50<br> -Paragraph 1<br> -URI http://asc.fasb.org/extlink&amp;oid=116847112&amp;loc=d3e4492-108314<br><br>Reference 5: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 270<br> -SubTopic 10<br> -Section 45<br> -Paragraph 6<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=124437754&amp;loc=d3e543-108305<br><br>Reference 6: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 330<br> -URI http://asc.fasb.org/topic&amp;trid=2126998<br><br>Reference 7: http://www.xbrl.org/2003/role/exampleRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 235<br> -SubTopic 10<br> -Section 50<br> -Paragraph 4<br> -Subparagraph (d)<br> -URI http://asc.fasb.org/extlink&amp;oid=123372394&amp;loc=d3e18823-107790<br><br>Reference 8: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 210<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.5-02.6(b))<br> -URI http://asc.fasb.org/extlink&amp;oid=120391452&amp;loc=d3e13212-122682<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_InventoryPolicyTextBlock</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
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<tr>
<td><strong> Period Type:</strong></td>
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</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_InvestmentPolicyTextBlock">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Disclosure of accounting policy for investment in financial asset.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2009/role/commonPracticeRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 944<br> -SubTopic 220<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.7-04(3)(b))<br> -URI http://asc.fasb.org/extlink&amp;oid=120400993&amp;loc=SL114874131-224263<br><br>Reference 2: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 323<br> -SubTopic 10<br> -Section 50<br> -Paragraph 3<br> -Subparagraph (a)(2)<br> -URI http://asc.fasb.org/extlink&amp;oid=114001798&amp;loc=d3e33918-111571<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_InvestmentPolicyTextBlock</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
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<tr>
<td><strong> Data Type:</strong></td>
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<tr>
<td><strong> Balance Type:</strong></td>
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</tr>
<tr>
<td><strong> Period Type:</strong></td>
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</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_LesseeLeasesPolicyTextBlock">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Disclosure of accounting policy for leasing arrangement entered into by lessee.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 842<br> -SubTopic 20<br> -Section 50<br> -Paragraph 1<br> -Subparagraph (b)<br> -URI http://asc.fasb.org/extlink&amp;oid=123408670&amp;loc=SL77918666-209980<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
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</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
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</table>
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<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Disclosure of accounting policy pertaining to new accounting pronouncements that may impact the entity's financial reporting. Includes, but is not limited to, quantification of the expected or actual impact.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
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<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
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<td><strong> Data Type:</strong></td>
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<td><strong> Period Type:</strong></td>
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</table></div>
</div></td></tr>
</table>
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<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_OrganizationConsolidationAndPresentationOfFinancialStatementsAbstract</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
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<td><strong> Data Type:</strong></td>
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<td><strong> Period Type:</strong></td>
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</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_PropertyPlantAndEquipmentPolicyTextBlock">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Disclosure of accounting policy for long-lived, physical asset used in normal conduct of business and not intended for resale. Includes, but is not limited to, work of art, historical treasure, and similar asset classified as collections.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 958<br> -SubTopic 360<br> -Section 50<br> -Paragraph 1<br> -Subparagraph (d)<br> -URI http://asc.fasb.org/extlink&amp;oid=120429125&amp;loc=d3e99779-112916<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 210<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.5-02.13(a))<br> -URI http://asc.fasb.org/extlink&amp;oid=120391452&amp;loc=d3e13212-122682<br><br>Reference 3: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 958<br> -SubTopic 360<br> -Section 50<br> -Paragraph 6<br> -URI http://asc.fasb.org/extlink&amp;oid=120429125&amp;loc=d3e99893-112916<br><br>Reference 4: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 360<br> -SubTopic 10<br> -Section 50<br> -Paragraph 1<br> -URI http://asc.fasb.org/extlink&amp;oid=6391035&amp;loc=d3e2868-110229<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_PropertyPlantAndEquipmentPolicyTextBlock</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
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<td><strong> Data Type:</strong></td>
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<tr>
<td><strong> Balance Type:</strong></td>
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<td><strong> Period Type:</strong></td>
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</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_ReceivablesPolicyTextBlock">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Disclosure of accounting policy for receivable. Includes, but is not limited to, accounts receivable and financing receivable.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2009/role/commonPracticeRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 310<br> -SubTopic 10<br> -Section 50<br> -Paragraph 2<br> -URI http://asc.fasb.org/extlink&amp;oid=123577603&amp;loc=d3e5033-111524<br><br>Reference 2: http://www.xbrl.org/2009/role/commonPracticeRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 310<br> -SubTopic 20<br> -Section 50<br> -Paragraph 4<br> -URI http://asc.fasb.org/extlink&amp;oid=84159169&amp;loc=d3e10178-111534<br><br>Reference 3: http://www.xbrl.org/2009/role/commonPracticeRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 310<br> -SubTopic 20<br> -Section 50<br> -Paragraph 2<br> -URI http://asc.fasb.org/extlink&amp;oid=84159169&amp;loc=d3e10149-111534<br><br>Reference 4: http://www.xbrl.org/2009/role/commonPracticeRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 310<br> -SubTopic 20<br> -Section 50<br> -Paragraph 1<br> -URI http://asc.fasb.org/extlink&amp;oid=84159169&amp;loc=d3e10133-111534<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ReceivablesPolicyTextBlock</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Disclosure of accounting policy for costs it has incurred (1) in a planned search or critical investigation aimed at discovery of new knowledge with the hope that such knowledge will be useful in developing a new product or service, a new process or technique, or in bringing about a significant improvement to an existing product or process; or (2) to translate research findings or other knowledge into a plan or design for a new product or process or for a significant improvement to an existing product or process.</p></div>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Disclosure of accounting policy for revenue from contract with customer.</p></div>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Disclosure of accounting policy for revenue. Includes revenue from contract with customer and from other sources.</p></div>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Disclosure of accounting policy for segment reporting.</p></div>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Disclosure of accounting policy for award under share-based payment arrangement. Includes, but is not limited to, methodology and assumption used in measuring cost.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 718<br> -SubTopic 10<br> -Section 50<br> -Paragraph 2<br> -Subparagraph (b),(f)<br> -URI http://asc.fasb.org/extlink&amp;oid=120381028&amp;loc=d3e5070-113901<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 718<br> -SubTopic 10<br> -Section 50<br> -Paragraph 1<br> -URI http://asc.fasb.org/extlink&amp;oid=120381028&amp;loc=d3e5047-113901<br></p></div>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Disclosure of accounting policy for its capital stock transactions, including dividends and accumulated other comprehensive income.</p></div>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Disclosure of accounting policy for treatment of receivables that are billable but have not been billed as of the balance sheet date.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 310<br> -URI http://asc.fasb.org/topic&amp;trid=2196771<br></p></div>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Disclosure of accounting policy for the use of estimates in the preparation of financial statements in conformity with generally accepted accounting principles.</p></div>
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<th class="tl" colspan="1" rowspan="2"><div style="width: 200px;"><strong>Organization and Significant Accounting Policies (Tables)<br></strong></div></th>
<th class="th" colspan="1">12 Months Ended</th>
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<td class="text">
<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We calculated our basic net loss per share for the year ended December 31, 2020 as follows (in thousands, except
    per share amounts):</div>

<div><br/>
  </div>

<table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;">


  <tr>

    <td style="vertical-align: bottom; border-bottom: #000000 2px solid; white-space: nowrap;" valign="bottom">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Year Ended December 31, 2020</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Weighted</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Average Shares</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Owned in Akcea</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Akcea</span>&#8217;<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">s</span></div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Net Loss</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Per Share</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Basic Net Loss</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Per Share</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Calculation</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: top; width: 64%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Akcea&#8217;s net loss in the pre-merger period attributable to our ownership</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">77,095</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(1.45</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(111,775</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

  </tr>

  <tr>

    <td style="vertical-align: top; width: 64%; white-space: nowrap;" valign="bottom">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Akcea&#8217;s net loss in the post-merger period attributable to our ownership</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(85,987</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

  </tr>

  <tr>

    <td style="vertical-align: top; width: 64%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Akcea&#8217;s total net loss attributable to our ownership</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(197,762</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

  </tr>

  <tr>

    <td style="vertical-align: top; width: 64%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">
          <div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Ionis&#8217; stand-alone net loss</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(246,702</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

  </tr>

  <tr>

    <td style="vertical-align: top; width: 64%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Net loss available to Ionis common stockholders</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(444,464</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

  </tr>

  <tr>

    <td style="vertical-align: top; width: 64%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">
          <div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Weighted average shares outstanding</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">139,612</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: top; width: 64%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Basic net loss per share</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(3.18</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

  </tr>


</table>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We calculated our basic net income per share for the year ended December 31, 2019 as follows (in thousands, except per share amounts):</div>

<div><br/>
  </div>

<table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;">


  <tr>

    <td style="vertical-align: bottom; border-bottom: #000000 2px solid; white-space: nowrap;" valign="bottom">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Year Ended December 31, 2019</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Weighted</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Average Shares</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Owned in Akcea</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Akcea</span>&#8217;<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">s</span></div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Net Income</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Per Share</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Basic Net Income</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Per Share</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Calculation</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: top; width: 64%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Common shares</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">70,100</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">0.49</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">34,073</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: top; width: 64%; white-space: nowrap;" valign="bottom">
          <div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Akcea&#8217;s net income attributable to our ownership</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">34,073</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: top; width: 64%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Ionis&#8217; stand-alone net income</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">246,487</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: top; width: 64%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">
          <div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Net income available to Ionis common stockholders</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">280,560</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: top; width: 64%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Weighted average shares outstanding</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">139,998</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: top; width: 64%; padding-bottom: 4px; white-space: nowrap;" valign="bottom">
          <div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Basic net income per share</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">2.00</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>


</table>
<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ScheduleOfEarningsPerShareBasicAndDilutedTableTextBlock', window );">Basic and Diluted Net Income Per Share</a></td>
<td class="text">
<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">For the
      year ended December 31, 2019, we reported net income available to Ionis common stockholders. As a result, we computed diluted net income per share using the weighted-average number of common shares and dilutive common equivalent shares outstanding
      during each period.</span> We calculated our diluted net income per share as follows <span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">(in thousands except per share amounts):</span></div>

<div><br/>
  </div>

<table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;">


  <tr>

    <td style="vertical-align: bottom; border-bottom: #000000 2px solid;" valign="bottom">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Year Ended December 31, 2019</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Net Income Available</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">to Ionis Common</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Stockholders</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">(Numerator)</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Shares</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">(Denominator)</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Per-Share</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Amount</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: top; width: 64%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Net income available to Ionis common stockholders</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">280,560</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">139,998</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">2.00</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: top; width: 64%;" valign="bottom">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Effect of dilutive securities:</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: top; width: 64%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: left; text-indent: -8.9pt; margin-left: 18pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Shares issuable upon exercise of stock options</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#8212;</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">2,090</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: top; width: 64%;" valign="bottom">
          <div style="text-align: left; text-indent: 0.1pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Shares issuable upon restricted stock award issuance</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#8212;</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">766</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: top; width: 64%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: left; text-indent: 9.1pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Shares issuable related to our ESPP</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#8212;</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">18</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: top; width: 64%;" valign="bottom">
          <div style="text-align: left; text-indent: 9.1pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">Shares issuable related to our </span>0.125<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> percent convertible notes</span></div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">860</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">217</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: top; width: 64%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: left; text-indent: 9.1pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Shares issuable related to our 1 percent convertible notes</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">9,527</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">10,075</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: top; width: 64%; padding-bottom: 4px;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">290,947</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">153,164</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">1.90</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>


</table>
<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ScheduleofFiniteLivedIntangibleAssetsFutureAmortizationExpenseTableTextBlock', window );">Amortization Expense for Patents</a></td>
<td class="text">
<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Based on our existing patents, we estimate amortization expense related to patents in each of
    the next five years to be the following:</div>

<div><br/>
  </div>

<table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;">


  <tr>

    <td style="vertical-align: bottom; border-bottom: #000000 2px solid;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Year Ending December 31,</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Amortization</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">(in millions)</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 88%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="text-indent: 0pt;">2022</span></div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">2.2</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 88%;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="text-indent: 0pt;">2023</span></div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">2.1</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 88%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="text-indent: 0pt;">2024</span></div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">1.9</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 88%;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="text-indent: 0pt;">2025</span></div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">1.8</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 88%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="text-indent: 0pt;">2026</span></div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">1.8</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>


</table>
<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ScheduleOfAccruedLiabilitiesTableTextBlock', window );">Accrued Liabilities</a></td>
<td class="text">
<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Our accrued liabilities consisted of the following (in thousands):</div>

<div><br/>
  </div>

<table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;">


  <tr>

    <td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">

        </td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="6" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">December 31,</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2021</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2020</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 76%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Clinical expenses</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">65,730</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">39,477</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 76%;" valign="bottom">
          <div style="text-align: left; text-indent: -18pt; margin-left: 18pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">In-licensing expenses</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">8,044</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">8,264</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 76%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: left; text-indent: -18pt; margin-left: 18pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Commercial expenses</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">2,471</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">11,559</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 76%; padding-bottom: 2px;" valign="bottom">
          <div style="text-align: left; text-indent: -18pt; margin-left: 18pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Other miscellaneous expenses</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">12,315</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">30,861</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 76%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Total accrued liabilities</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">88,560</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">90,161</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>


</table>
<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ScheduleOfInventoryCurrentTableTextBlock', window );">Inventory</a></td>
<td class="text">
<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Our inventory consisted of the following (in thousands):</div>

<div><br/>
  </div>

<table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;">


  <tr>

    <td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">

        </td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="6" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">December 31,</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2021</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2020</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom;" valign="bottom">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Raw materials:</div>
        </td>

    <td colspan="1" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 76%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 19.4pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Raw materials- clinical</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">14,507</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">9,206</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 76%; padding-bottom: 2px;" valign="bottom">
          <div style="text-align: justify; text-indent: -18pt; margin-left: 28.4pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Raw materials- commercial</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">4,139</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">7,502</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 76%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 28.45pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Total raw materials</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">18,646</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">16,708</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 76%;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Work in process</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">5,770</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">2,252</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 76%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Finished goods</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">390</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">3,005</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 76%; padding-bottom: 4px;" valign="bottom">
          <div style="text-align: justify; margin-left: 28.45pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Total inventory</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">24,806</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">21,965</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>


</table>
<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_PropertyPlantAndEquipmentTextBlock', window );">Property, Plant and Equipment</a></td>
<td class="text">
<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We carry our property, plant and equipment at cost and depreciate it on the straight-line method
    over its estimated useful life, which consists of the following (in thousands):</div>

<div><br/>
  </div>

<table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;">


  <tr>

    <td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">

        </td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; white-space: nowrap;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Estimated Useful</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="6" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">December 31,</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Lives (in years)</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2021</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2020</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Computer software, laboratory, manufacturing and other equipment</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; background-color: #CCEEFF;" valign="bottom">
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    <td colspan="1" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
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    <td colspan="1" style="vertical-align: bottom; text-align: right; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">72,802</div>
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    <td colspan="1" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
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    <td colspan="1" style="vertical-align: bottom; text-align: right; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">68,990</div>
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    <td colspan="1" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom;" valign="bottom">
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    <td colspan="1" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom;" valign="bottom">
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    <td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">144,046</div>
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    <td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">137,879</div>
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    <td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Land improvements</div>
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    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="2" rowspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: rgb(0, 0, 0); font-family: 'Times New Roman',Times,serif; font-size: 10pt; text-align: center;">20</div>
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    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">10,077</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">8,391</div>
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    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Leasehold improvements</div>
        </td>

    <td colspan="1" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">5 to 15</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">20,144</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">17,263</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Furniture and fixtures</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">5 to 10</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">10,591</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">12,871</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 64%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">257,660</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">245,394</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Less accumulated depreciation</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(102,653</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(87,379</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 64%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">155,007</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">158,015</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Land</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">23,062</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">23,062</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 64%; padding-bottom: 4px;" valign="bottom">
          <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#160;Total</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">178,069</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">181,077</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>


</table>
<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ScheduleOfAccumulatedOtherComprehensiveIncomeLossTableTextBlock', window );">Changes in Accumulated Other Comprehensive Loss</a></td>
<td class="text">
<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 12pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Accumulated
      other comprehensive loss is comprised of unrealized gains and losses on investments, net of taxes and currency translation adjustments. The following table summarizes changes in accumulated other comprehensive loss for the years ended December 31, 2021, 2020 and 2019 (in thousands):</span></div>

<div style="text-align: justify;"><br/>
  </div>

<table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;">


  <tr>

    <td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">

        </td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="10" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Year Ended December 31,</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2021</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2020</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2019</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Beginning balance accumulated other comprehensive loss</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(21,071</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(25,290</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(32,016</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 64%;" valign="bottom">
          <div style="text-align: left; text-indent: -9pt; margin-left: 18pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Unrealized gains (losses) on securities, net of tax (1)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(11,486</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">3,729</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">6,633</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: left; text-indent: -9pt; margin-left: 18pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Currency translation adjustment</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(111</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">617</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">93</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 64%; padding-bottom: 2px;" valign="bottom">
          <div style="text-align: left; text-indent: -9pt; margin-left: 18pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Adjustments to other comprehensive loss from purchase of noncontrolling interest of Akcea
            Therapeutics, Inc.</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#8212;</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(127</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#8212;</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Net other comprehensive loss for the period</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(11,597</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">4,219</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">6,726</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 64%; padding-bottom: 4px;" valign="bottom">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Ending balance accumulated other comprehensive loss</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(32,668</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(21,071</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(25,290</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

  </tr>


</table>

<div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">________________</div>

<div>
    <table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">


  <tr>

    <td style="width: 18pt; vertical-align: top; align: right;">
            <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(1)</div>
          </td>

    <td style="width: auto; vertical-align: top;">
            <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We did not have tax expense included in our other comprehensive loss for the years ended December 31, 2021 and 2020. For the year ended December 31,
              2019, we had a tax benefit of $1.4
              million included in other comprehensive loss.&#160;</div>
          </td>

  </tr>


</table>
    </div>
<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ScheduleOfNewAccountingPronouncementsAndChangesInAccountingPrinciplesTextBlock', window );">Adoption of ASU 2020-06</a></td>
<td class="text">
<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">The following table summarizes the adjustments we made to the consolidated balance sheet we
    originally reported at December 31, 2020 to adopt ASU 2020-06 (in thousands):</div>

<div><br/>
  </div>

<table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;">


  <tr>

    <td style="vertical-align: top; padding-bottom: 2px;" valign="bottom">

        </td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="10" style="vertical-align: top; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">December 31, 2020</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: top; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">As Previously</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Reported</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">ASU 2020-06</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Adjustment</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">As Revised</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: top; width: 64%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">1 percent convertible
            senior notes</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">293,161</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">15,648</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">308,809</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: top; width: 64%;" valign="bottom">
          <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">0.125 percent convertible
            senior notes</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">455,719</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">84,417</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">540,136</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: top; width: 64%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Additional paid-in-capital</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">2,113,646</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(218,127</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">1,895,519</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: top; width: 64%;" valign="bottom">
          <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Accumulated deficit</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(1,249,368</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">118,062</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(1,131,306</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

  </tr>


</table>

<div><br/>
  </div>
<span style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; color: #000000;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">The following
      tables summarize the adjustments we made to the consolidated statement of operations we originally reported for the years ended December 31, 2020 and 2019 to adopt ASU 2020-06 (in thousands):</span></span>
<div><br/>
  </div>

<table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;">


  <tr>

    <td style="vertical-align: top; padding-bottom: 2px;" valign="bottom">

        </td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="10" style="vertical-align: top; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Year Ended December 31, 2020</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: top; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">As Previously</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Reported</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">ASU 2020-06</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Adjustment</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">As Revised</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: top; width: 64%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Interest expense</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(44,990</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">35,480</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(9,510</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

  </tr>

  <tr>

    <td style="vertical-align: top; width: 64%;" valign="bottom">
          <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Loss before income tax expense</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(170,032</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">35,480</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(134,552</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

  </tr>

  <tr>

    <td style="vertical-align: top; width: 64%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Income tax expense</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(316,734</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(28,457</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(345,191</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

  </tr>

  <tr>

    <td style="vertical-align: top; width: 64%;" valign="bottom">
          <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Net loss</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(486,766</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">7,023</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(479,743</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

  </tr>

  <tr>

    <td style="vertical-align: top; width: 64%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Net loss attributable to Ionis Pharmaceuticals, Inc. common stockholders</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(451,286</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">7,023</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(444,263</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

  </tr>

  <tr>

    <td style="vertical-align: top; width: 64%;" valign="bottom">
          <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Basic and diluted net loss per share</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(3.23</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">0.05</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(3.18</div>
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    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

  </tr>


</table>

<div><br/>
  </div>

<table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;">


  <tr>

    <td style="vertical-align: top; padding-bottom: 2px;" valign="bottom">

        </td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="10" style="vertical-align: top; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Year Ended December 31, 2019</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: top; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">As Previously</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Reported</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">ASU 2020-06</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Adjustment</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">As Revised</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: top; width: 64%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Interest expense</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(48,768</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">36,328</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(12,440</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

  </tr>

  <tr>

    <td style="vertical-align: top; width: 64%;" valign="bottom">
          <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Loss on early retirement of debt</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(21,865</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(44,331</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(66,196</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

  </tr>

  <tr>

    <td style="vertical-align: top; width: 64%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Income before income tax benefit (expense)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">346,769</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(8,003</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">338,766</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: top; width: 64%;" valign="bottom">
          <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Income tax expense</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(43,507</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(8,000</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(51,507</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

  </tr>

  <tr>

    <td style="vertical-align: top; width: 64%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Net income</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">303,262</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(16,003</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">287,259</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: top; width: 64%;" valign="bottom">
          <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Net income attributable to Ionis Pharmaceuticals, Inc. common stockholders</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">294,146</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(16,003</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">278,143</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: top; width: 64%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Basic net income per share</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">2.12</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(0.12</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">2.00</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: top; width: 64%;" valign="bottom">
          <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Diluted net income per share</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">2.08</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(0.18</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">1.90</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>


</table>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">The following tables summarize the adjustments we made to our consolidated statements of
    stockholders&#8217; equity we originally reported at December 31, 2020 and 2019 to adopt ASU 2020-06 (in thousands):</div>

<div><br/>
  </div>

<table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;">


  <tr>

    <td style="vertical-align: top; padding-bottom: 2px;" valign="bottom">

        </td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="10" style="vertical-align: top; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">December 31, 2020</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: top; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">As Previously</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Reported</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">ASU 2020-06</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Adjustment</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">As Revised</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: top; width: 64%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Additional paid-in-capital</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">2,113,646</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(218,127</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">1,895,519</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: top; width: 64%;" valign="bottom">
          <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Accumulated deficit</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(1,249,368</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">118,062</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(1,131,306</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

  </tr>

  <tr>

    <td style="vertical-align: top; width: 64%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Total stockholders&#8217; equity</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">843,347</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(100,065</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">743,282</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>


</table>

<div><br/>
  </div>

<table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;">


  <tr>

    <td style="vertical-align: top; padding-bottom: 2px;" valign="bottom">

        </td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="10" style="vertical-align: top; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">December 31, 2019</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: top; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">As Previously</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Reported</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">ASU 2020-06</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Adjustment</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">As Revised</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: top; width: 64%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Additional paid-in-capital</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">2,203,778</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(218,128</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">1,985,650</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: top; width: 64%;" valign="bottom">
          <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Accumulated deficit</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(707,534</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">111,039</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(596,495</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

  </tr>

  <tr>

    <td style="vertical-align: top; width: 64%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Total stockholders&#8217; equity</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">1,684,547</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(107,088</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">1,577,459</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>


</table>
<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_FairValueAssetsMeasuredOnRecurringBasisTextBlock', window );">Assets Measured at Fair Value on a Recurring Basis</a></td>
<td class="text">
<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">The following tables present the major security types we held at December 31, 2021 and 2020&#160;<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">that we regularly measure and carry at fair value</span>. As of December 31, 2021, our Bicycle investment was subject to trading restrictions that extend to the third quarter of 2022; as
    a result, we included a lack of marketability discount in valuing this investment, which is a Level 3 input. As of December 31, 2020, we did not
    have any investments that we valued using Level 3 inputs. The following tables segregate each security type by the level within the fair value hierarchy of the valuation techniques we utilized to determine the respective securities&#8217; fair value (in
    thousands):</div>

<div><br/>
  </div>

<table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;">


  <tr>

    <td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">At</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">December 31, 2021</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Quoted Prices in</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Active Markets</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">(Level 1)</div>
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    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

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          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Observable Inputs</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">(Level 2)</div>
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    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Significant</div>
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          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">(Level 3)</div>
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    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 52%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Cash equivalents (1)</div>
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    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
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    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">541,199</div>
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    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
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    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">541,199</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#8212;</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#8212;</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 52%;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Corporate debt securities (2)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">764,059</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#8212;</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">764,059</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#8212;</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 52%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Debt securities issued by U.S. government agencies (2)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">120,868</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#8212;</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">120,868</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#8212;</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 52%;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Debt securities issued by the U.S. Treasury (2)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">182,634</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">182,634</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#8212;</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#8212;</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 52%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Debt securities issued by states of the U.S. and political subdivisions of the states (3)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">174,464</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#8212;</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">174,464</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#8212;</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 52%;" valign="bottom">
          <div>
            <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Other municipal debt securities (2)</div>
          </div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">6,099</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#8212;</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">6,099</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#8212;</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 52%; background-color: #CCEEFF;" valign="bottom">
          <div>
            <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Investment in Bicycle Therapeutics plc (4)</div>
          </div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">14,330</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#8212;</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#8212;</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">14,330</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 52%; padding-bottom: 2px;" valign="bottom">
          <div>
            <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Investment in ProQR Therapeutics N.V. (4)</div>
          </div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">3,875</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">3,875</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#8212;</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#8212;</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 52%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; text-indent: -8.9pt; margin-left: 22.55pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Total</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">1,807,528</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
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    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">727,708</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">1,065,490</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">14,330</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>


</table>

<div><br/>
  </div>

<table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;">


  <tr>

    <td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">

        </td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">At</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">December 31, 2020</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Quoted Prices in</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Active Markets</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">(Level 1)</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Significant Other</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Observable Inputs</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">(Level 2)</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Cash equivalents (1)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">221,125</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">221,125</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#8212;</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 64%;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Corporate debt securities (5)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">846,315</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#8212;</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">846,315</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Debt securities issued by U.S. government agencies (2)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">174,861</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#8212;</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">174,861</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 64%;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Debt securities issued by the U.S. Treasury (6)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">358,497</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">358,497</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#8212;</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Debt securities issued by states of the U.S. and political subdivisions of the states (2)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">136,309</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#8212;</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">136,309</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 64%;" valign="bottom">
          <div>
            <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Other municipal debt securities (2)</div>
          </div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">6,225</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#8212;</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">6,225</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">
          <div>
            <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Investment in ProQR Therapeutics N.V. (4)</div>
          </div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">2,031</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">2,031</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#8212;</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 64%; padding-bottom: 4px;" valign="bottom">
          <div style="text-align: justify; text-indent: -8.9pt; margin-left: 22.55pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Total</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">1,745,363</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">581,653</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">1,163,710</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>


</table>

<div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">________________</div>

<table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">


  <tr>

    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(1)</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Included in cash and cash
            equivalents on our consolidated balance sheet.</div>
        </td>

  </tr>


</table>

<div><br/>
  </div>

<table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">


  <tr>

    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(2)</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Included in short-term
            investments.</div>
        </td>

  </tr>


</table>

<div><br/>
  </div>

<table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">


  <tr>

    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(3)</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$2.3 million included in cash and cash equivalents on our consolidated balance sheet, with the difference included in short-term investments on our
            consolidated balance sheet.</div>
        </td>

  </tr>


</table>

<div><br/>
  </div>

<table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">


  <tr>

    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(4)</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Included in other current assets
            on our consolidated balance sheet.</div>
        </td>

  </tr>


</table>

<div><br/>
  </div>

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  <tr>

    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(5)</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$10.0 million included in cash and cash equivalents on our consolidated balance sheet, with the difference included in short-term investments on our
            consolidated balance sheet.</div>
        </td>

  </tr>


</table>

<div><br/>
  </div>

<table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">


  <tr>

    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(6)</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$17.5 million included in cash and cash equivalents on our consolidated balance sheet, with the difference included in short-term investments on our
            consolidated balance sheet.</div>
        </td>

  </tr>


</table>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 820<br> -SubTopic 10<br> -Section 50<br> -Paragraph 2<br> -Subparagraph (b)<br> -URI http://asc.fasb.org/extlink&amp;oid=123874694&amp;loc=d3e19207-110258<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 820<br> -SubTopic 10<br> -Section 50<br> -Paragraph 2<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=123874694&amp;loc=d3e19207-110258<br></p></div>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Tabular disclosure of physical assets used in the normal conduct of business and not intended for resale. Includes, but is not limited to, balances by class of assets, depreciation and depletion expense and method used, including composite depreciation, and accumulated deprecation.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 210<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.5-02(13))<br> -URI http://asc.fasb.org/extlink&amp;oid=120391452&amp;loc=d3e13212-122682<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 360<br> -SubTopic 10<br> -Section 50<br> -Paragraph 1<br> -URI http://asc.fasb.org/extlink&amp;oid=6391035&amp;loc=d3e2868-110229<br></p></div>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Tabular disclosure of the components of accrued liabilities.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Tabular disclosure of the components of accumulated other comprehensive income (loss).</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2009/role/commonPracticeRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 830<br> -SubTopic 30<br> -Section 50<br> -Paragraph 1<br> -URI http://asc.fasb.org/extlink&amp;oid=6450520&amp;loc=d3e32583-110901<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 220<br> -SubTopic 10<br> -Section 45<br> -Paragraph 14A<br> -URI http://asc.fasb.org/extlink&amp;oid=124509347&amp;loc=SL7669686-108580<br><br>Reference 3: http://www.xbrl.org/2009/role/commonPracticeRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 830<br> -SubTopic 30<br> -Section 45<br> -Paragraph 20<br> -URI http://asc.fasb.org/extlink&amp;oid=118261656&amp;loc=d3e32211-110900<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Tabular disclosure of an entity's basic and diluted earnings per share calculations, including a reconciliation of numerators and denominators of the basic and diluted per-share computations for income from continuing operations.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2009/role/commonPracticeRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 260<br> -SubTopic 10<br> -Section 50<br> -Paragraph 1<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=124432515&amp;loc=d3e3550-109257<br></p></div>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Tabular disclosure of the effect of income (loss) on basic earnings per share.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 260<br> -SubTopic 10<br> -Section 55<br> -Paragraph 52<br> -URI http://asc.fasb.org/extlink&amp;oid=125512782&amp;loc=d3e4984-109258<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 260<br> -SubTopic 10<br> -Section 50<br> -Paragraph 1<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=124432515&amp;loc=d3e3550-109257<br><br>Reference 3: http://www.xbrl.org/2009/role/commonPracticeRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 260<br> -SubTopic 10<br> -Section 45<br> -Paragraph 3<br> -URI http://asc.fasb.org/extlink&amp;oid=125511455&amp;loc=d3e1278-109256<br></p></div>
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<span style="display: none;">v3.22.0.1</span><table class="report" border="0" cellspacing="2" id="idm139691013168184">
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<th class="tl" colspan="1" rowspan="2"><div style="width: 200px;"><strong>Investments (Tables)<br></strong></div></th>
<th class="th" colspan="1">12 Months Ended</th>
</tr>
<tr><th class="th"><div>Dec. 31, 2021</div></th></tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_InvestmentsAbstract', window );"><strong>Investments [Abstract]</strong></a></td>
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<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_InvestmentsClassifiedByContractualMaturityDateTableTextBlock', window );">Contract Maturity of Available-for-Sale Securities</a></td>
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<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">The following table summarizes the contract maturity of the available-for-sale securities we held as of
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<div><br/>
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<table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;">


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          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="text-indent: 0pt;">One year</span> or less</div>
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    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">51</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">%</div>
        </td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 88%; background-color: #FFFFFF;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">After <span style="text-indent: 0pt;">one year</span> but within <span style="text-indent: 0pt;">two years</span></div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">34</div>
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    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">%</div>
        </td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 88%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">After <span style="text-indent: 0pt;">two years</span> but within <span style="text-indent: 0pt;"><span style="-sec-ix-hidden:Fact_5b50da2d62974df399b2ebfcfccf0c30">three and a half years</span></span></div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">15</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">%</div>
        </td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 88%; padding-bottom: 4px; background-color: #FFFFFF;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Total</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">100</div>
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    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">%</div>
        </td>

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<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_UnrealizedGainLossOnInvestmentsTableTextBlock', window );">Summary of Investments</a></td>
<td class="text">
<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">The following is a summary of our investments (in thousands):</div>

<div><br/>
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          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Amortized</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

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          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Gross Unrealized</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Estimated</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

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  <tr>

    <td style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">December 31, 2021</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"> Cost</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Gains</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Losses</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Fair Value</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom;" valign="bottom">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Available-for-sale securities:</div>
        </td>

    <td colspan="1" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 52%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Corporate debt securities (1)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">383,870</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">728</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(226</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">384,372</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 52%; background-color: #FFFFFF;" valign="bottom">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Debt securities issued by U.S. government agencies</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">48,493</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">19</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(18</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">48,494</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 52%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Debt securities issued by the U.S. Treasury (1)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">45,424</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#8212;</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(64</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">45,360</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 52%; padding-bottom: 2px; background-color: #FFFFFF;" valign="bottom">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Debt securities issued by states of the U.S. and political subdivisions of the states</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">134,770</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">45</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(37</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">134,778</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 52%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Total securities with a maturity of one year or less</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">612,557</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">792</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(345</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">613,004</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 52%; background-color: #FFFFFF;" valign="bottom">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Corporate debt securities</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">382,000</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">331</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(2,644</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">379,687</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 52%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Debt securities issued by U.S. government agencies</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">72,935</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#8212;</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(561</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">72,374</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 52%; background-color: #FFFFFF;" valign="bottom">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Debt securities issued by the U.S. Treasury</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">137,635</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">139</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(500</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">137,274</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 52%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Debt securities issued by states of the U.S. and political subdivisions of the states</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">39,909</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">1</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(224</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">39,686</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 52%; padding-bottom: 2px; background-color: #FFFFFF;" valign="bottom">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Other municipal debt securities</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">6,136</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#8212;</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(37</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">6,099</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 52%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Total securities with a maturity of more than one year</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">638,615</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">471</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(3,966</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">635,120</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 52%; padding-bottom: 2px; background-color: #FFFFFF;" valign="bottom">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Total available-for-sale securities</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">1,251,172</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">1,263</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(4,311</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">1,248,124</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 52%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Equity securities:</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 52%; background-color: #FFFFFF;" valign="bottom">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Total equity securities included in other current assets (2)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">11,897</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">7,145</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(837</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">18,205</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 52%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Total equity securities included in deposits and other assets (3)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">15,615</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">16,707</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#8212;</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">32,322</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 52%; padding-bottom: 2px; background-color: #FFFFFF;" valign="bottom">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Total equity securities</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">27,512</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">23,852</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(837</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">50,527</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 52%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Total available-for-sale and equity securities</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">1,278,684</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">25,115</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
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    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(5,148</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">1,298,651</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>


</table>

<div><br/>
  </div>

<table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;">


  <tr>

    <td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">

        </td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom;" valign="bottom">
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        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="6" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
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    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Estimated</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">December 31, 2020</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"> Cost</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Gains</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Losses</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Fair Value</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom;" valign="bottom">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Available-for-sale securities:</div>
        </td>

    <td colspan="1" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 52%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Corporate debt securities (1)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">514,182</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">2,194</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(41</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">516,335</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 52%; background-color: #FFFFFF;" valign="bottom">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Debt securities issued by U.S. government agencies</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">94,234</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">354</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(2</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">94,586</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 52%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Debt securities issued by the U.S. Treasury (1)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">307,576</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">233</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(9</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">307,800</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 52%; background-color: #FFFFFF;" valign="bottom">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Debt securities issued by states of the U.S. and political subdivisions of the states</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">104,271</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">196</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(12</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">104,455</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 52%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Other municipal debt securities</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">5,191</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#8212;</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(7</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">5,184</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 52%; padding-bottom: 2px; background-color: #FFFFFF;" valign="bottom">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Total securities with a maturity of one year or less</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">1,025,454</div>
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    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">2,977</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(71</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">1,028,360</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 52%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Corporate debt securities</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">325,079</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">4,941</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(40</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">329,980</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 52%; background-color: #FFFFFF;" valign="bottom">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Debt securities issued by U.S. government agencies</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">80,099</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">185</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(9</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">80,275</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 52%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Debt securities issued by the U.S. Treasury</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">50,318</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">383</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(4</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">50,697</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 52%; background-color: #FFFFFF;" valign="bottom">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Debt securities issued by states of the U.S. and political subdivisions of the states</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">31,779</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">91</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(16</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">31,854</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 52%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Other municipal debt securities</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">1,041</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#8212;</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#8212;</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">1,041</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 52%; padding-bottom: 2px; background-color: #FFFFFF;" valign="bottom">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Total securities with a maturity of more than one year</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">488,316</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">5,600</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(69</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">493,847</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 52%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Total available-for-sale securities</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">1,513,770</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">8,577</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(140</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">1,522,207</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 52%; background-color: #FFFFFF;" valign="bottom">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Equity securities:</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 52%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Total equity securities included in other current assets (2)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">4,712</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#8212;</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(2,681</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">2,031</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 52%; padding-bottom: 2px; background-color: #FFFFFF;" valign="bottom">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Total equity securities included in deposits and other assets (3)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">15,062</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">15,938</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#8212;</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">31,000</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 52%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Total equity securities</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">19,774</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">15,938</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(2,681</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">33,031</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 52%; padding-bottom: 4px; background-color: #FFFFFF;" valign="bottom">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Total available-for-sale and equity securities</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">1,533,544</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">24,515</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(2,821</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">1,555,238</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>


</table>

<div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">________________</div>

<table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">


  <tr>

    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(1)</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Includes investments classified
            as cash equivalents on our consolidated balance sheet.</div>
        </td>

  </tr>


</table>

<div><br/>
  </div>

<table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">


  <tr>

    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(2)</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Our equity securities included in other current
            assets consisted of our investments in publicly traded companies. We recognize publicly traded equity securities at fair value.</div>
        </td>

  </tr>


</table>

<div><br/>
  </div>

<table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">


  <tr>

    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(3)</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">Our equity securities included in deposits and other assets consisted of our investments in privately held companies. We recognize our private company equity securities at</span> cost minus
            impairments, plus or minus changes resulting from observable price changes in orderly transactions for the identical or similar investment of the same issuer<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> on our consolidated balance sheet.</span></div>
        </td>

  </tr>


</table>
<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ScheduleOfTemporaryImpairmentLossesInvestmentsTableTextBlock', window );">Temporarily Impaired Investments</a></td>
<td class="text">
<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">The following is a summary of our investments we
      considered to be temporarily impaired at&#160;</span>December 31, 2021<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">&#160;(in thousands). All of these investments have less than 12 months of temporary impairment. We believe that the decline in value of these securities is temporary and is primarily related to the change in market interest rates since
      purchase. We believe it is more likely than not that we will be able to hold our debt securities to maturity. Therefore, we anticipate full recovery of our debt securities&#8217; amortized cost basis at maturity.</span></div>

<div><br/>
  </div>

<table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;">


  <tr>

    <td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">

        </td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Number of</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Investments</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Estimated</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Fair Value</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

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    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

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          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">552,966</div>
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    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

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          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">15</div>
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    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

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    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

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          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
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        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

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          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">13</div>
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    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">134,987</div>
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    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(564</div>
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    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
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          <div style="text-align: left; text-indent: -11.2pt; margin-left: 11.2pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Debt securities issued by states of the U.S. and political subdivisions of the states</div>
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    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">425</div>
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    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">126,401</div>
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    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(261</div>
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    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
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    <td style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Other municipal debt securities</div>
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    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">2</div>
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    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">6,099</div>
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    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(37</div>
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    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
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          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Total temporarily impaired securities</div>
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    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" valign="bottom">&#160;</td>

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    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">727</div>
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    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
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    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">934,791</div>
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    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
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    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(4,311</div>
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    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
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<th class="tl" colspan="1" rowspan="2"><div style="width: 200px;"><strong>Long-Term Obligations and Commitments (Tables)<br></strong></div></th>
<th class="th" colspan="1">12 Months Ended</th>
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<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">The carrying value of our long-term obligations was as follows (in thousands):</div>

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    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="6" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">December 31,</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2021</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2020</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">(as revised*)</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 76%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="text-indent: 0pt;">0.125 percent</span> convertible senior notes</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">542,314</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">540,136</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 76%;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="text-indent: 0pt;">1 percent</span> convertible senior notes (1)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#8212;</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">308,809</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 76%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="text-indent: 0pt;">0 percent</span> convertible senior notes</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">619,119</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#8212;</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 76%;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Long-term mortgage debt</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">59,713</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">59,984</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 76%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Leases and other obligations</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">29,904</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">30,710</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 76%;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Total</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">1,251,050</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">939,639</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 76%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Less: current portion (1)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(3,526</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(316,110</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 76%; padding-bottom: 4px;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 18pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Total Long-Term Obligations</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">1,247,524</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">623,529</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>


</table>

<div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">________________</div>

<table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">


  <tr>

    <td style="width: 18pt; vertical-align: top; align: right; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(1)</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We classified the carrying value of
            our 1% Notes as a current liability on our consolidated balance sheet at December 31, 2020 because it matured in November 2021.</div>
        </td>

  </tr>


</table>
<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_ConvertibleNotesDisclosureLineItems', window );"><strong>Convertible Notes [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_srt_ContractualObligationFiscalYearMaturityScheduleTableTextBlock', window );">Maturity Schedules for Annual Debt and Other Obligations</a></td>
<td class="text">
<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Annual debt and other obligation
    maturities, including fixed and determinable interest, at December 31, 2021 are as follows (in thousands):</div>

<div><br/>
  </div>

<table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;">


  <tr>

    <td style="vertical-align: bottom; width: 88%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="text-indent: 0pt;">2022</span></div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">3,498</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 88%;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="text-indent: 0pt;">2023</span></div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">4,180</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 88%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="text-indent: 0pt;">2024</span></div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">4,180</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 88%;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="text-indent: 0pt;">2025</span></div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">1,184,820</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 88%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="text-indent: 0pt;">2026</span></div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">3,494</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 88%; padding-bottom: 2px;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Thereafter</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">57,439</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 88%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Subtotal</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">1,257,611</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 88%;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Less: current portion</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(3,526</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 88%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Less: fixed and determinable interest</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(15,498</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 88%;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Less: debt issuance costs</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(20,302</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 88%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Plus: lease liabilities</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">22,058</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 88%; padding-bottom: 2px;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Plus: other liabilities</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">7,181</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 88%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Total long-term debt</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">1,247,524</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>


</table>
<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_LesseeOperatingLeaseInformationTableTextBlock', window );">Amounts Related to Operating Leases</a></td>
<td class="text">
<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Amounts related to our operating leases were as follows (dollar amounts in millions):</div>

<div><br/>
  </div>

<table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;">


  <tr>

    <td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">

        </td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">At December 31, 2021</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 88%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Right-of-use operating lease assets (1)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">18.0</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 88%;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Operating lease liabilities (2)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">22.1</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Weighted average remaining lease term</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">6.6 years</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 88%;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Weighted average discount rate</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">6.0</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">%</div>
        </td>

  </tr>


</table>

<div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">________________</div>

<table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">


  <tr>

    <td style="width: 18pt; vertical-align: top; align: right; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(1)</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Included in <span style="-sec-ix-hidden:Fact_f81ca57385a04657b8ecd0f06d505159">deposits and other assets</span> on our consolidated balance sheet.</div>
        </td>

  </tr>


</table>

<div><br/>
  </div>

<table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">


  <tr>

    <td style="width: 18pt; vertical-align: top; align: right; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(2)</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Current portion of $2.6 million was included in <span style="-sec-ix-hidden:Fact_b2b58e46aca04158b3b03811dd0a9c0f">current portion of long-term obligations</span> on our consolidated balance sheet, with the difference included in <span style="-sec-ix-hidden:Fact_9c37cb3853f74a4f821bbe4ed37a06ba">long-term obligations</span>.</div>
        </td>

  </tr>


</table>
<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_LesseeOperatingLeaseLiabilityMaturityTableTextBlock', window );">Future Payments for Operating Lease Liabilities</a></td>
<td class="text">
<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">As of December 31, 2021, the future payments for our operating lease liabilities are as follows (in thousands):</div>

<div><br/>
  </div>

<table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;">


  <tr>

    <td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">

        </td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Operating</span> <span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Leases</span></div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 88%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Year ending December 31,</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">$</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 88%;" valign="bottom">
          <div style="text-align: justify; margin-left: 18.7pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">2022</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">4,075</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 88%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; text-indent: -0.2pt; margin-left: 18.7pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="text-indent: 0pt;">2023</span></div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">4,314</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 88%;" valign="bottom">
          <div style="text-align: justify; text-indent: -0.2pt; margin-left: 18.7pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="text-indent: 0pt;">2024</span></div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">4,223</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 88%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; margin-left: 18.7pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">2025</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">4,062</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 88%;" valign="bottom">
          <div style="text-align: justify; margin-left: 18.7pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">2026</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">3,778</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 88%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Thereafter</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">7,035</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 88%;" valign="bottom">
          <div style="text-align: left; margin-left: 18.7pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Total minimum lease payments</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">27,487</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 88%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Less:</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 88%; padding-bottom: 2px;" valign="bottom">
          <div style="text-align: left; margin-left: 18.7pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Imputed interest</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(5,429</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 88%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: left; margin-left: 36.7pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Total operating lease liabilities</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">22,058</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>


</table>
<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DebtInstrumentAxis=ions_ConvertibleSeniorNotes0PercentMember', window );">0% Notes [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_ConvertibleNotesDisclosureLineItems', window );"><strong>Convertible Notes [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ConvertibleDebtTableTextBlock', window );">Convertible Senior Notes</a></td>
<td class="text">
<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">At December 31, 2021,
    we had the following <span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">0%</span> Notes outstanding (amounts in
    millions except interest rate and price per share data):</div>

<div><br/>
  </div>

<table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;">


  <tr>

    <td style="vertical-align: top; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: top; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">0%</span> Notes</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: top; width: 88%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Outstanding principal balance</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">632.5</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: top; width: 88%;" valign="bottom">
          <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Unamortized debt issuance costs</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">13.4</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: top; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Maturity date</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: top; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="-sec-ix-hidden:Fact_7dc5959ba24b47e092541cc149b2023c">April 2026</span></div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: top;" valign="bottom">
          <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Interest rate</div>
        </td>

    <td colspan="1" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: top;" valign="bottom">
          <div style="text-align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">0 percent</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: top; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Effective interest rate</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: top; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">0.5 percent</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: top; width: 88%;" valign="bottom">
          <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Conversion price per share</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">57.84</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: top; width: 88%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Effective conversion price per share with call spread</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">76.39</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: top; width: 88%;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Total shares of common stock subject to conversion</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">10.9</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>


</table>
<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DebtInstrumentAxis=ions_ConvertibleSeniorNotes0125PercentMember', window );">0.125% Notes [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_ConvertibleNotesDisclosureLineItems', window );"><strong>Convertible Notes [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ConvertibleDebtTableTextBlock', window );">Convertible Senior Notes</a></td>
<td class="text">
<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">At December 31, 2021,
    we had the following 0.125% Notes outstanding with interest payable semi-annually (amounts in millions except interest rate and price per share
    data):</div>

<div><br/>
  </div>

<table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;">


  <tr>

    <td style="vertical-align: top; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: top; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">0.125%
            Notes</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: top; width: 88%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Outstanding principal balance</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">548.8</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: top; width: 88%;" valign="bottom">
          <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Unamortized debt issuance costs</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">6.5</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: top; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Maturity date</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: top; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="-sec-ix-hidden:Fact_ef7fbbee87c14676a78b2a22d99ec0ae">December 2024</span></div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: top;" valign="bottom">
          <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Interest rate</div>
        </td>

    <td colspan="1" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: top;" valign="bottom">
          <div style="text-align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">0.125 percent</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: top; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Effective interest rate</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: top; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">0.5 percent</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: top; width: 88%;" valign="bottom">
          <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Conversion price per share</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">83.28</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: top; width: 88%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Effective conversion price per share with call spread</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">123.38</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: top; width: 88%;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Total shares of common stock subject to conversion</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">6.6</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>


</table>
<span></span>
</td>
</tr>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Line items represent financial concepts included in a table. These concepts are used to disclose reportable information associated with domain members defined in one or many axes to the table.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Tabular disclosure of information on lessee's operating leases, including carrying value of right-of-use assets and lease liabilities, weighted-average remaining term and weighted-average discount rate.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
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    <td colspan="1" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 18pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Exercised</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(219</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">38.69</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 18pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Cancelled/forfeited/expired</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(1,513</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; padding-bottom: 2px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">54.65</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 52%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="text-indent: 0pt;">Outstanding at December 31, 2021</span></div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">14,089</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">54.04</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">3.89</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">1,131</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 52%; padding-bottom: 4px;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="text-indent: 0pt;">Exercisable at December 31, 2021</span></div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">9,175</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">53.65</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">2.94</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">1,067</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>


</table>
<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ScheduleOfSharebasedCompensationRestrictedStockAndRestrictedStockUnitsActivityTableTextBlock', window );">RSU Activity</a></td>
<td class="text">
<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">The following table summarizes the RSU activity for the year ended December 31, 2021 (in thousands, except per share data):</div>

<div><br/>
  </div>

<table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;">


  <tr>

    <td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">

        </td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Number</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">of Shares</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Weighted Average</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Grant Date Fair</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Value Per Share</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 76%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="text-indent: 0pt;">Non-vested at December 31, 2020</span></div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">2,374</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">58.81</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 76%;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 18pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Granted</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">1,548</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">57.69</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 76%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 18pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Vested</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(834</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">57.47</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 76%; padding-bottom: 2px;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 18pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Cancelled/forfeited</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(411</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">59.24</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 76%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="text-indent: 0pt;">Non-vested at December 31, 2021</span></div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">2,677</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">58.51</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>


</table>
<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ScheduleOfEmployeeServiceShareBasedCompensationAllocationOfRecognizedPeriodCostsTextBlock', window );">Stock-Based Compensation Expense</a></td>
<td class="text">
<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">The following table summarizes stock-based compensation expense for the years ended December 31, 2021, 2020 and 2019 (in thousands):</div>

<div><br/>
  </div>

<table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;">


  <tr>

    <td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">

        </td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="10" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Year Ended December 31,</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2021</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2020</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2019</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Cost of sales</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
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    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">456</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">1,991</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
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    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">438</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 64%;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Research, development and patent</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">87,522</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">115,584</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">95,348</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Selling, general and administrative</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">32,700</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">112,542</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">50,788</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 64%; padding-bottom: 4px;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Total</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">120,678</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">230,117</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">146,574</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>


</table>
<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ScheduleOfShareBasedPaymentAwardStockOptionsValuationAssumptionsTableTextBlock', window );">Weighted-Average Assumptions for Stock Options</a></td>
<td class="text">
<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;">Ionis Employee Stock Options:</div>

<div><br/>
  </div>

<table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;">


  <tr>

    <td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">

        </td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="10" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Year Ended December 31,</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2021</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2020</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2019</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Risk-free interest rate</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">0.6</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">%</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">1.5</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">%</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">2.3</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">%</div>
        </td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 64%;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Dividend yield</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">0.0</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">%</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">0.0</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">%</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">0.0</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">%</div>
        </td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Volatility</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">54.0</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">%</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">58.6</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">%</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">60.3</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">%</div>
        </td>

  </tr>

  <tr>

    <td style="vertical-align: bottom;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Expected life</div>
        </td>

    <td colspan="1" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom;" valign="bottom">
          <div style="text-align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">4.9 years</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom;" valign="bottom">
          <div style="text-align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">4.7 years</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom;" valign="bottom">
          <div style="text-align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">4.8 years</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>


</table>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;">Ionis Board of Director Stock Options:</div>

<div><br/>
  </div>

<table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;">


  <tr>

    <td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">

        </td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="10" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Year Ended December 31,</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2021</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2020</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2019</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Risk-free interest rate</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">1.2</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">%</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">0.5</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">%</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">1.9</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">%</div>
        </td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 64%;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Dividend yield</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">0.0</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">%</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">0.0</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">%</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">0.0</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">%</div>
        </td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Volatility</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">55.9</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">%</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">57.6</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">%</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">60.7</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">%</div>
        </td>

  </tr>

  <tr>

    <td style="vertical-align: bottom;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Expected life</div>
        </td>

    <td colspan="1" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom;" valign="bottom">
          <div style="text-align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">7.3 years</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom;" valign="bottom">
          <div style="text-align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">6.7 years</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom;" valign="bottom">
          <div style="text-align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">6.6 years</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>


</table>
<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ScheduleOfShareBasedPaymentAwardEmployeeStockPurchasePlanValuationAssumptionsTableTextBlock', window );">Weighted-Average Assumptions for ESPP</a></td>
<td class="text">
<div style="display:none;"><br/></div>
<div style="text-align: left; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;">Ionis ESPP:</div>

<div><br/>
  </div>

<table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;">


  <tr>

    <td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">

        </td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="10" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Year Ended December 31,</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2021</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2020</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2019</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Risk-free interest rate</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">0.1</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">%</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">0.8</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">%</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">2.4</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">%</div>
        </td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 64%;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Dividend yield</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">0.0</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">%</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">0.0</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">%</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">0.0</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">%</div>
        </td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Volatility</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">42.4</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">%</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">47.9</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">%</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">45.6</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">%</div>
        </td>

  </tr>

  <tr>

    <td style="vertical-align: bottom;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Expected life</div>
        </td>

    <td colspan="1" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom;" valign="bottom">
          <div style="text-align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">6 months</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom;" valign="bottom">
          <div style="text-align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">6 months</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom;" valign="bottom">
          <div style="text-align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">6 months</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>


</table>
<span></span>
</td>
</tr>
</table>
<div style="display: none;">
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    <td style="vertical-align: bottom; width: 64%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Income (loss) before income taxes</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(29,148</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(134,552</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">338,766</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>


</table>
<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ScheduleOfComponentsOfIncomeTaxExpenseBenefitTableTextBlock', window );">Income Tax Expense (Benefit)</a></td>
<td class="text">
<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Our income tax expense (benefit) was as follows (in thousands):</div>

<div><br/>
  </div>

<table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;">


  <tr>

    <td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">

        </td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="10" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Year Ended December 31,</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2021</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2020</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2019</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">(as revised*)</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">(as revised*)</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Current:</div>
        </td>

    <td colspan="1" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Federal</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(200</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(837</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">35,861</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 64%;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">State</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(690</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">3,782</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">14,329</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Foreign</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">339</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">518</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">413</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 64%;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Total current income tax expense (benefit)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(551</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">3,463</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">50,603</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 64%;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Deferred:</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Federal</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#8212;</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">341,728</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">904</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 64%; padding-bottom: 2px;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">State</div>
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    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#8212;</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#8212;</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#8212;</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">
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        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#8212;</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">341,728</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">904</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 64%; padding-bottom: 4px;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Total income tax expense (benefit)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(551</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">345,191</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">51,507</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>


</table>
<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ScheduleOfEffectiveIncomeTaxRateReconciliationTableTextBlock', window );">Reconciliation of Statutory to Effective Tax Rate</a></td>
<td class="text">
<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Our expense (benefit) for income taxes differs from the amount computed by applying the U.S. federal
    statutory rate to income (loss) before taxes. The sources and tax effects of the differences are as follows (in thousands):</div>

<div><br/>
  </div>

<table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;">


  <tr>

    <td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">

        </td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="22" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Year Ended December 31,</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="6" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2021</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="6" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2020</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="6" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2019</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="6" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="6" style="vertical-align: bottom;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">(as revised*)</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="6" style="vertical-align: bottom;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">(as revised*)</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="6" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="6" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="6" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Pre-tax income (loss)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(29,148</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(134,552</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">338,766</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 28%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Statutory rate</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(6,121</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">21.0</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">%</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(28,256</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">21.0</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">%</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">71,141</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">21.0</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">%</div>
        </td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 28%;" valign="bottom">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">State income tax net of federal benefit</div>
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    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
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    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
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    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)%</div>
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    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(37,705</div>
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    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
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    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">28.0</div>
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    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">%</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
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    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">14.5</div>
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    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">%</div>
        </td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 28%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Foreign</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">143</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(0.5</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)%</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">49</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">0.0</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">%</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">340</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">0.1</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">%</div>
        </td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 28%;" valign="bottom">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Net change in valuation allowance</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">2,885</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(9.9</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)%</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">460,898</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(342.5</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)%</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(37,314</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(11.0</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)%</div>
        </td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 28%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Loss on debt transactions</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">262</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(0.9</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)%</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#8212;</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#8212;</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">9,911</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">2.9</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">%</div>
        </td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 28%;" valign="bottom">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Impact from outside basis differences</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#8212;</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#8212;</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#8212;</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#8212;</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(16,344</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(4.8</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)%</div>
        </td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 28%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Tax credits</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(23,198</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">79.6</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">%</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(18,774</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">14.0</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
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    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
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    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
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    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(6.6</div>
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    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)%</div>
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  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 28%;" valign="bottom">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Deferred tax true-up</div>
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    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(24</div>
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    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
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    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
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    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">%</div>
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    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(206</div>
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    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
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    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">0.2</div>
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    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">%</div>
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    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">646</div>
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    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
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    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">%</div>
        </td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 28%; background-color: #CCEEFF;" valign="bottom">
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    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">12,838</div>
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    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(44.0</div>
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    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)%</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(32,951</div>
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    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">24.5</div>
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    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">%</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">1,248</div>
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    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">0.4</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">%</div>
        </td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 28%;" valign="bottom">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Non-deductible compensation</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">5,085</div>
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    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(17.4</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)%</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">7,931</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(5.9</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)%</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">3,361</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">1.0</div>
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    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">%</div>
        </td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 28%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Other non-deductible items</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">84</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(0.3</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)%</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">193</div>
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    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(0.1</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)%</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">329</div>
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    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">0.1</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">%</div>
        </td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 28%;" valign="bottom">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Stock-based compensation</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">4,720</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(16.2</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)%</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">17,435</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(13.0</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)%</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(4,837</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(1.4</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)%</div>
        </td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 28%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Foreign-derived intangible income benefit</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#8212;</div>
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    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

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          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#8212;</div>
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    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

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    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#8212;</div>
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    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#8212;</div>
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    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
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    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
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    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
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    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
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  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 28%;" valign="bottom">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Impacts from Akcea Merger</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#8212;</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#8212;</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(22,032</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">16.4</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">%</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#8212;</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#8212;</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 28%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Other</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(1,503</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">5.1</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">%</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(1,391</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">0.9</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">%</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(1,607</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(0.6</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)%</div>
        </td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 28%; padding-bottom: 4px;" valign="bottom">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Effective rate</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(551</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">1.9</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">%</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">345,191</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(256.5</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)%</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">51,507</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">15.2</div>
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    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">%</div>
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  </tr>


</table>
<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ScheduleOfDeferredTaxAssetsAndLiabilitiesTableTextBlock', window );">Deferred Tax Assets and Liabilities</a></td>
<td class="text">
<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Significant components of our deferred tax assets and liabilities as of December 31, 2021 and 2020 are as follows (in thousands):</div>

<div><br/>
  </div>

<table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;">


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    <td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">

        </td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="6" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Year Ended December 31,</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2021</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2020</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">(as revised*)</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Deferred Tax Assets:</div>
        </td>

    <td colspan="1" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 76%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Net operating loss carryovers</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">85,600</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
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    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">83,681</div>
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    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 76%;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Tax credits</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">269,538</div>
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    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">245,746</div>
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    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 76%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Deferred revenue</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">104,330</div>
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    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">124,452</div>
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    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 76%;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Stock-based compensation</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">86,611</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">80,055</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 76%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Intangible and capital assets</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">92,542</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">98,443</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 76%;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Convertible debt</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">45,681</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">22,395</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 76%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Interest expense limitation</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">6,996</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#8212;</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 76%; padding-bottom: 2px;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Other</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">15,048</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">13,402</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 76%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Total deferred tax assets</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">706,346</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">668,174</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 76%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 76%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Deferred Tax Liabilities:</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 76%;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Fixed assets</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(3,303</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(3,611</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 76%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Other</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(5,270</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(5,808</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 76%;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Net deferred tax asset</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">697,773</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">658,755</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 76%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Valuation allowance</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(697,773</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(658,755</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 76%; padding-bottom: 4px;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Total net deferred tax assets and liabilities</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#8212;</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#8212;</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>


</table>

<div><br/>
  </div>

<table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">


  <tr>

    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">*</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We revised our 2020 and 2019 amounts to reflect the simplified convertible instruments accounting guidance, which we adopted retrospectively. Refer to
            Note 1, <span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Organization and Significant Accounting Policies</span>, for further information.</div>
        </td>

  </tr>


</table>
<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ScheduleOfUnrecognizedTaxBenefitsRollForwardTableTextBlock', window );">Gross Unrecognized Tax Benefits</a></td>
<td class="text">
<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">The following table summarizes our gross unrecognized tax benefits <span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">(in thousands):</span></div>

<div><br/>
  </div>

<table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;">


  <tr>

    <td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">

        </td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="10" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Year Ended December 31,</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2021</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2020</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2019</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Beginning balance of unrecognized tax benefits</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">54,163</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">69,784</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">68,301</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 64%;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Decrease for prior period tax positions</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(695</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(24,154</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(867</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Increase for prior period tax positions</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">263</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">7,023</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">736</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 64%; padding-bottom: 2px;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Increase for current period tax positions</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">1,354</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">1,510</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">1,614</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 64%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Ending balance of unrecognized tax benefits</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">55,085</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">54,163</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">69,784</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>


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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Tabular disclosure of the components of income tax expense attributable to continuing operations for each year presented including, but not limited to: current tax expense (benefit), deferred tax expense (benefit), investment tax credits, government grants, the benefits of operating loss carryforwards, tax expense that results from allocating certain tax benefits either directly to contributed capital or to reduce goodwill or other noncurrent intangible assets of an acquired entity, adjustments of a deferred tax liability or asset for enacted changes in tax laws or rates or a change in the tax status of the entity, and adjustments of the beginning-of-the-year balances of a valuation allowance because of a change in circumstances that causes a change in judgment about the realizability of the related deferred tax asset in future years.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section 50<br> -Paragraph 9<br> -URI http://asc.fasb.org/extlink&amp;oid=121826272&amp;loc=d3e32639-109319<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Tabular disclosure of the components of net deferred tax asset or liability recognized in an entity's statement of financial position, including the following: the total of all deferred tax liabilities, the total of all deferred tax assets, the total valuation allowance recognized for deferred tax assets.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section 50<br> -Paragraph 2<br> -URI http://asc.fasb.org/extlink&amp;oid=121826272&amp;loc=d3e32537-109319<br></p></div>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Tabular disclosure of the reconciliation using percentage or dollar amounts of the reported amount of income tax expense attributable to continuing operations for the year to the amount of income tax expense that would result from applying domestic federal statutory tax rates to pretax income from continuing operations.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section 50<br> -Paragraph 12<br> -URI http://asc.fasb.org/extlink&amp;oid=121826272&amp;loc=d3e32687-109319<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
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<span style="display: none;">v3.22.0.1</span><table class="report" border="0" cellspacing="2" id="idm139691007389944">
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<th class="tl" colspan="1" rowspan="2"><div style="width: 200px;"><strong>Collaborative Arrangements and Licensing Agreements (Tables)<br></strong></div></th>
<th class="th" colspan="1">12 Months Ended</th>
</tr>
<tr><th class="th"><div>Dec. 31, 2021</div></th></tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_TypeOfArrangementAxis=ions_BiogenCollaborationsMember', window );">Biogen [Member]</a></td>
<td class="text">&#160;<span></span>
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<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CollaborativeArrangementsAndNonCollaborativeArrangementTransactionsDisclosureLineItems', window );"><strong>Collaborative Arrangements and Licensing Agreements [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
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<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">During the years ended December 31, 2021, 2020 and 2019, we earned the following revenue from our relationship with Biogen (in millions, except percentage amounts):</div>

<div><br/>
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<table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;">


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          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Year Ended December 31,</div>
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    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

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  <tr>

    <td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

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          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2021</div>
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    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

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          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2020</div>
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    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2019</div>
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    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: left; text-indent: -27pt; margin-left: 27pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">SPINRAZA royalties (commercial revenue)</div>
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    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
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    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">267.8</div>
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    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
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    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">286.6</div>
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    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">293.0</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 64%; padding-bottom: 2px;" valign="bottom">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">R&amp;D revenue</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">161.0</div>
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    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">122.0</div>
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    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">180.6</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: left; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Total revenue from our relationship with Biogen</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">428.8</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">408.6</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">473.6</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 64%;" valign="bottom">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Percentage of total revenue</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">53</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">%</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">56</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">%</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">42</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">%</div>
        </td>

  </tr>


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<span></span>
</td>
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<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_TypeOfArrangementAxis=ions_AstrazenecaCollaborationsMember', window );">AstraZeneca [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CollaborativeArrangementsAndNonCollaborativeArrangementTransactionsDisclosureLineItems', window );"><strong>Collaborative Arrangements and Licensing Agreements [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
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<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_SchedulesOfConcentrationOfRiskByRiskFactorTextBlock', window );">Revenue from Collaborative Relationship</a></td>
<td class="text">
<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">During the years ended December 31, 2021, 2020 and 2019, we earned the following revenue from our relationship with AstraZeneca (in millions, except percentage amounts):</div>

<div><br/>
  </div>

<table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;">


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    <td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">

        </td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="10" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Year Ended December 31,</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2021</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2020</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2019</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: left; text-indent: -27pt; margin-left: 27pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">R&amp;D revenue</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">254.6</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">88.0</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">28.1</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 64%;" valign="bottom">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Percentage of total revenue</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">31</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">%</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">12</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">%</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">3</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">%</div>
        </td>

  </tr>


</table>
<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_TypeOfArrangementAxis=ions_BayerCollaborationsMember', window );">Bayer [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CollaborativeArrangementsAndNonCollaborativeArrangementTransactionsDisclosureLineItems', window );"><strong>Collaborative Arrangements and Licensing Agreements [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_SchedulesOfConcentrationOfRiskByRiskFactorTextBlock', window );">Revenue from Collaborative Relationship</a></td>
<td class="text">
<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">During the years ended December 31, 2021, 2020 and 2019, we earned the following revenue from our relationship with Bayer (in millions, except percentage amounts):</div>

<div><br/>
  </div>

<table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;">


  <tr>

    <td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">

        </td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="10" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Year Ended December 31,</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2021</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2020</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2019</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: left; text-indent: -27pt; margin-left: 27pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">R&amp;D revenue</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">1.1</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">3.2</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">14.3</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 64%;" valign="bottom">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Percentage of total revenue</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">0</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">%</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">0</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">%</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">1</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">%</div>
        </td>

  </tr>


</table>
<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_TypeOfArrangementAxis=ions_GlaxoSmithKlineCollaborationMember', window );">GSK [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CollaborativeArrangementsAndNonCollaborativeArrangementTransactionsDisclosureLineItems', window );"><strong>Collaborative Arrangements and Licensing Agreements [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_SchedulesOfConcentrationOfRiskByRiskFactorTextBlock', window );">Revenue from Collaborative Relationship</a></td>
<td class="text">
<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">During the years ended December 31, 2021, 2020 and 2019, we earned the following revenue from our relationship with GSK (in millions, except percentage amounts):</div>

<div><br/>
  </div>

<table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;">


  <tr>

    <td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">

        </td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="10" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Year Ended December 31,</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2021</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2020</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2019</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: left; text-indent: -27pt; margin-left: 27pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">R&amp;D revenue</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#8212;</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">0.2</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">25.4</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 64%;" valign="bottom">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Percentage of total revenue</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#8212;</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">0</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">%</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">2</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">%</div>
        </td>

  </tr>


</table>
<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_TypeOfArrangementAxis=ions_NovartisCollaborationMember', window );">Novartis [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CollaborativeArrangementsAndNonCollaborativeArrangementTransactionsDisclosureLineItems', window );"><strong>Collaborative Arrangements and Licensing Agreements [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_SchedulesOfConcentrationOfRiskByRiskFactorTextBlock', window );">Revenue from Collaborative Relationship</a></td>
<td class="text">
<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">During the years ended December 31, 2021, 2020 and 2019, we earned the following revenue from our
    relationship with Novartis (in millions, except percentage amounts):</div>

<div><br/>
  </div>

<table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;">


  <tr>

    <td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">

        </td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="10" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Year Ended December 31,</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2021</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2020</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2019</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: left; text-indent: -27pt; margin-left: 27pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">R&amp;D revenue</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">25.5</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">1.0</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">187.4</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 64%;" valign="bottom">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Percentage of total revenue</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">3</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">%</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">0</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">%</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">17</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">%</div>
        </td>

  </tr>


</table>
<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_TypeOfArrangementAxis=ions_RocheCollaborationMember', window );">Roche [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CollaborativeArrangementsAndNonCollaborativeArrangementTransactionsDisclosureLineItems', window );"><strong>Collaborative Arrangements and Licensing Agreements [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_SchedulesOfConcentrationOfRiskByRiskFactorTextBlock', window );">Revenue from Collaborative Relationship</a></td>
<td class="text">
<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">During the years ended December 31, 2021, 2020 and 2019, we earned the following revenue from our relationship with Roche (in millions, except percentage amounts):</div>

<div><br/>
  </div>

<table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;">


  <tr>

    <td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">

        </td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="10" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Year Ended December 31,</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2021</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2020</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2019</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: left; text-indent: -27pt; margin-left: 27pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">R&amp;D revenue</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">17.2</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">5.9</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">57.0</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 64%;" valign="bottom">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Percentage of total revenue</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">2</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">%</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">1</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">%</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">5</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">%</div>
        </td>

  </tr>


</table>
<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_TypeOfArrangementAxis=ions_AlnylamPharmaceuticalsIncMember', window );">Alnylam [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CollaborativeArrangementsAndNonCollaborativeArrangementTransactionsDisclosureLineItems', window );"><strong>Collaborative Arrangements and Licensing Agreements [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_SchedulesOfConcentrationOfRiskByRiskFactorTextBlock', window );">Revenue from Collaborative Relationship</a></td>
<td class="text">
<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">During the years ended December 31, <span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">2021</span>, <span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">2020</span> and <span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">2019</span>, we
      earned the following revenue from our relationship with Alnylam (in millions, except percentage amounts):</div>

<div><br/>
    </div>

<table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;">


  <tr>

    <td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">

        </td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="10" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Year Ended December 31,</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2021</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2020</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2019</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: left; text-indent: -27pt; margin-left: 27pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">R&amp;D revenue</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#8212;</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">47.9</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">24.1</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 64%;" valign="bottom">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Percentage of total revenue</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#8212;</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">7</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">%</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">2</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">%</div>
        </td>

  </tr>


</table>
<span></span>
</td>
</tr>
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<div style="display: none;">
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<th class="tl" colspan="1" rowspan="2"><div style="width: 200px;"><strong>Akcea Merger (Tables)<br></strong></div></th>
<th class="th" colspan="1">12 Months Ended</th>
</tr>
<tr><th class="th"><div>Dec. 31, 2021</div></th></tr>
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<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">The following table summarizes the severance and retention expenses related to the Akcea Merger that we recognized for the periods indicated (in
    millions):</div>

<div style="text-align: justify;"><br/>
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<table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;">


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        </td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Year Ended</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">December 31, 2021</div>
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    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: top; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Year Ended</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">December 31, 2020</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

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          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">R&amp;D expenses</div>
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    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">5.1</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">3.9</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

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          <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">SG&amp;A expenses</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">6.6</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">11.4</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 76%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Total</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">11.7</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">15.3</div>
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    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

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<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">The following table summarizes the severance and retention reserve amounts related to the Akcea Merger that we included in
    accrued compensation for the period indicated (in millions):</div>

<div style="text-align: justify;"><br/>
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<table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;">


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    <td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">

        </td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Year Ended</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">December 31, 2021</div>
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    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

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    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

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    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

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          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(26.4</div>
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<span style="display: none;">v3.22.0.1</span><table class="report" border="0" cellspacing="2" id="idm139691013939960">
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<th class="tl" colspan="1" rowspan="2"><div style="width: 200px;"><strong>Severance and Retention Costs related to our Restructured Operations (Tables)<br></strong></div></th>
<th class="th" colspan="1">12 Months Ended</th>
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<tr><th class="th"><div>Dec. 31, 2021</div></th></tr>
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<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">The following table summarizes the
    severance and retention expenses related to our restructured European operations that we recognized for the periods indicated (in millions):</div>

<div><br/>
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<table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;">


  <tr>

    <td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">

        </td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

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          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Year Ended</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">December 31, 2021</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: top; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Year Ended</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">December 31, 2020</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 76%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">R&amp;D expenses</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">0.6</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">4.2</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 76%; padding-bottom: 2px;" valign="bottom">
          <div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">SG&amp;A expenses</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">1.1</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">8.3</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 76%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Total</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">1.7</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">12.5</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

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  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">The following table summarizes the severance and retention reserve amounts related to our restructured European operations
    that we included in accrued compensation for the period indicated (in millions):</div>

<div style="text-align: justify;"><br/>
  </div>

<table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;">


  <tr>

    <td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">

        </td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Year Ended</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">December 31, 2021</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: top; width: 88%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Beginning balance as of January 1, 2021</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">12.4</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: top; width: 88%;" valign="bottom">
          <div style="text-align: left; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Amount expensed during the year</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">2.6</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: top; width: 88%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: left; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Reserve adjustments during the year</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(0.9</div>
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    <td colspan="1" style="vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

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    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

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          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(14.1</div>
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    <td style="vertical-align: top; width: 88%; padding-bottom: 4px;" valign="bottom">
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        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
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          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#8212;</div>
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<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RestructuringCostAndReserveAxis=ions_RestructuredNorthAmericanTegsediOperationsMember', window );">Restructured North American TEGSEDI Operations [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_SeveranceAndRetentionCostsLineItems', window );"><strong>Severance and Retention Costs [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ScheduleOfRestructuringAndRelatedCostsTextBlock', window );">Severance and Retention Costs</a></td>
<td class="text">
<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">The following table summarizes the severance expenses related to our
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<div style="text-align: justify;"><br/>
  </div>

<table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;">


  <tr>

    <td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">

        </td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Year Ended</div>
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        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 88%; background-color: #CCEEFF;" valign="bottom">
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        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">2.3</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 88%; padding-bottom: 2px;" valign="bottom">
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        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" valign="bottom">&#160;</td>

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        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 88%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom">
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    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
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    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">9.4</div>
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    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

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<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">The following table summarizes the severance reserve amounts related to our
    Restructured North American TEGSEDI Operations that we included in accrued compensation for the period indicated (in millions):</div>

<div style="text-align: justify;"><br/>
  </div>

<table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;">


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    <td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">

        </td>

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    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: top; width: 88%; background-color: #CCEEFF;" valign="bottom">
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          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#8212;</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: top; width: 88%;" valign="bottom">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Net amount expensed during the year</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

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        </td>

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          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(9.4</div>
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  <tr>

    <td style="vertical-align: top; width: 88%; padding-bottom: 4px;" valign="bottom">
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    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom">&#160;</td>

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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Line items represent financial concepts included in a table. These concepts are used to disclose reportable information associated with domain members defined in one or many axes to the table.</p></div>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Tabular disclosure of costs incurred for restructuring including, but not limited to, exit and disposal activities, remediation, implementation, integration, asset impairment, and charges against earnings from the write-down of assets.</p></div>
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<span style="display: none;">v3.22.0.1</span><table class="report" border="0" cellspacing="2" id="idm139691013053464">
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<th class="tl" colspan="1" rowspan="2"><div style="width: 200px;"><strong>Fourth Quarter Financial Data (Unaudited) (Tables)<br></strong></div></th>
<th class="th" colspan="1">12 Months Ended</th>
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<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">The following financial information reflects all normal recurring adjustments, which are,
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  <tr>

    <td style="vertical-align: bottom; border-bottom: #000000 2px solid;" valign="bottom">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Three Months Ended December 31,</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2021</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2020</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 76%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Revenue</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">440,006</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">290,281</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 76%;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Operating expenses</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">219,403</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">312,945</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 76%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Income (loss) from operations</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">220,603</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(22,664</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 76%;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Net income (loss)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">224,613</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(355,687</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 76%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Net income (loss) attributable to Ionis Pharmaceuticals, Inc. common stockholders</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">224,613</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(354,532</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 76%;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Basic net income (loss) per share (1) (2)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">1.59</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(2.54</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 76%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Diluted net income (loss) per share (1) (3)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">1.41</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(2.54</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

  </tr>


</table>

<div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">________________</div>

<table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">


  <tr>

    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(1)</td>

    <td style="width: auto; vertical-align: top; text-align: left;">
          <div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">We </span>compute net income (loss) per share independently for each quarter during <span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">the year.</span></div>
        </td>

  </tr>


</table>

<div><br/>
  </div>

<table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">


  <tr>

    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(2)</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">As discussed in Note 1, <span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Organization and Significant Accounting Policies, </span>we compute basic net income (loss) per share by dividing the total net income (loss)
            attributable to our common stockholders by our weighted-average number of common shares outstanding during the period. Our basic net income per share for the fourth quarter of 2021 was $1.59.</div>
        </td>

  </tr>


</table>

<div><br/>
  </div>

<div style="text-align: justify; margin-left: 18pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Our basic net loss per share calculation for the fourth quarter of 2020 considered our net loss for Ionis on a stand-alone
    basis plus our share of Akcea&#8217;s net loss for the period. To calculate the portion of Akcea&#8217;s net loss attributable to our ownership, we multiplied Akcea&#8217;s loss per share by the weighted average shares we owned in Akcea during the period. As a result of
    this calculation, our total net loss available to Ionis common stockholders for the calculation of net loss per share is different than net loss attributable to Ionis Pharmaceuticals, Inc. common stockholders in the consolidated statements of
    operations.</div>

<div><br/>
  </div>

<div style="text-align: justify; margin-left: 18pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Our basic net loss per share for the fourth quarter of 2020 was calculated as follows (in thousands, except per share amounts):</div>

<div><br/>
  </div>

<table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;">


  <tr>

    <td style="vertical-align: bottom; border-bottom: #000000 2px solid; white-space: nowrap;" valign="bottom">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Three Months Ended December 31, 2020</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Weighted</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Average Shares</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Owned in Akcea</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Akcea</span>&#8217;<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">s</span></div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Net Loss</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Per Share</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Basic Net Loss</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Per Share</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Calculation</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: top; width: 64%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Akcea&#8217;s net loss in the pre-merger period attributable to our ownership</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">77,095</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(0.05</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(3,603</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

  </tr>

  <tr>

    <td style="vertical-align: top; width: 64%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">
          <div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Akcea&#8217;s net loss in the post-merger period attributable to our ownership</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(85,987</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

  </tr>

  <tr>

    <td style="vertical-align: top; width: 64%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Akcea&#8217;s total net loss attributable to our ownership</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(89,590</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

  </tr>

  <tr>

    <td style="vertical-align: top; width: 64%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">
          <div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Ionis&#8217; stand-alone net loss</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(266,418</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

  </tr>

  <tr>

    <td style="vertical-align: top; width: 64%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Net loss available to Ionis common stockholders</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(356,008</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

  </tr>

  <tr>

    <td style="vertical-align: top; width: 64%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">
          <div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Weighted average shares outstanding</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">139,956</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: top; width: 64%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Basic net loss per share</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(2.54</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">)</div>
        </td>

  </tr>


</table>

<div><br/>
  </div>

<table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">


  <tr>

    <td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">(3)</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We had net income available
            to Ionis common stockholders for the fourth quarter of 2021. As a result, we computed diluted net income per share using the weighted-average number of common shares and dilutive common equivalent shares outstanding during the period as follows (in thousands except per share amounts):</div>
        </td>

  </tr>


</table>

<div><br/>
  </div>

<table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;">


  <tr>

    <td style="vertical-align: bottom; border-bottom: #000000 2px solid;" valign="bottom">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Three Months Ended December 31, 2021</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Income</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">(Numerator)</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Shares</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">(Denominator)</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom">&#160;</td>

    <td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Per-Share</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Amount</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: top; width: 64%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Net income available to Ionis common stockholders</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">224,612</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">141,205</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">1.59</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: top; width: 64%;" valign="bottom">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Effect of dilutive securities:</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>

  <tr>

    <td style="vertical-align: top; width: 64%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: left; text-indent: -9pt; margin-left: 21pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Shares issuable upon exercise of stock options</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#8212;</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">46</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

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  <tr>

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<span style="display: none;">v3.22.0.1</span><table class="report" border="0" cellspacing="2" id="idm139691007925048">
<tr>
<th class="tl" colspan="1" rowspan="2"><div style="width: 200px;"><strong>Organization and Significant Accounting Policies, Basic Net Income (Loss) per Share (Details) - USD ($)<br> $ / shares in Units, shares in Thousands, $ in Thousands</strong></div></th>
<th class="th" colspan="1">1 Months Ended</th>
<th class="th" colspan="1">2 Months Ended</th>
<th class="th" colspan="4">3 Months Ended</th>
<th class="th" colspan="1">10 Months Ended</th>
<th class="th" colspan="3">12 Months Ended</th>
<th class="th" colspan="1"></th>
</tr>
<tr>
<th class="th"><div>Oct. 31, 2020</div></th>
<th class="th"><div>Dec. 31, 2020</div></th>
<th class="th" colspan="2"><div>Dec. 31, 2021</div></th>
<th class="th" colspan="2"><div>Dec. 31, 2020</div></th>
<th class="th"><div>Oct. 31, 2020</div></th>
<th class="th"><div>Dec. 31, 2021</div></th>
<th class="th"><div>Dec. 31, 2020</div></th>
<th class="th"><div>Dec. 31, 2019</div></th>
<th class="th"><div>Sep. 30, 2020</div></th>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_EarningsPerShareBasicAbstract', window );"><strong>Basic Net Income (Loss) per Share [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_EarningsPerShareBasic', window );">Basic net income (loss) per share (in dollars per share)</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 1.59<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"><sup>[1],[2]</sup></td>
<td class="num">$ (2.54)<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"><sup>[1],[2]</sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="num">$ (0.20)<span></span>
</td>
<td class="num">$ (3.18)<span></span>
</td>
<td class="nump">$ 2.00<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_NetIncomeLoss', window );">Net loss</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 224,613<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="num">$ (354,532)<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="num">$ (28,597)<span></span>
</td>
<td class="num">$ (444,263)<span></span>
</td>
<td class="nump">$ 278,143<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_NetIncomeLossAvailableToCommonStockholdersBasic', window );">Income (loss) available to Ionis common stockholders</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 224,612<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="num">$ (356,008)<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="num">$ (444,464)<span></span>
</td>
<td class="nump">$ 280,560<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_WeightedAverageNumberOfSharesOutstandingBasic', window );">Weighted average shares outstanding (in shares)</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">141,205<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">139,956<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">141,021<span></span>
</td>
<td class="nump">139,612<span></span>
</td>
<td class="nump">139,998<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_StatementBusinessSegmentsAxis=ions_IonisCoreMember', window );">Ionis [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_EarningsPerShareBasicAbstract', window );"><strong>Basic Net Income (Loss) per Share [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_NetIncomeLoss', window );">Net loss</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="num">$ (266,418)<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="num">$ (246,702)<span></span>
</td>
<td class="nump">$ 246,487<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_srt_OwnershipAxis=ions_AkceaTherapeuticsIncMember', window );">Akcea [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ProceedsFromIssuanceOrSaleOfEquityAbstract', window );"><strong>Basic Net Income (Loss) per Share [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_MinorityInterestOwnershipPercentageByParent', window );">Percentage ownership</a></td>
<td class="nump">100.00%<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">100.00%<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">100.00%<span></span>
</td>
<td class="nump">100.00%<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">76.00%<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_EarningsPerShareBasicAbstract', window );"><strong>Basic Net Income (Loss) per Share [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_WeightedAverageNumberOfSharesOwnedInSubsidiary', window );">Weighted average shares owned in Akcea (in shares)</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">77,095<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_EarningsPerShareBasic', window );">Basic net income (loss) per share (in dollars per share)</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="num">$ (0.05)<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_NetIncomeLoss', window );">Net loss</a></td>
<td class="num">$ (3,603)<span></span>
</td>
<td class="num">$ (85,987)<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="num">$ (89,590)<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_srt_ConsolidatedEntitiesAxis=ions_AkceaTherapeuticsIncMember', window );">Akcea [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_EarningsPerShareBasicAbstract', window );"><strong>Basic Net Income (Loss) per Share [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_WeightedAverageNumberOfSharesOwnedInSubsidiary', window );">Weighted average shares owned in Akcea (in shares)</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">77,095<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">70,100<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_EarningsPerShareBasic', window );">Basic net income (loss) per share (in dollars per share)</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="num">$ (1.45)<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 0.49<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_NetIncomeLoss', window );">Net loss</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="num">$ (85,987)<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="num">$ (111,775)<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="num">$ (197,762)<span></span>
</td>
<td class="nump">$ 34,073<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr><td colspan="12"></td></tr>
<tr><td colspan="12"><table class="outerFootnotes" width="100%">
<tr class="outerFootnote">
<td style="vertical-align: top; width: 12pt;" valign="top">[1]</td>
<td style="vertical-align: top;" valign="top"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">We </span>compute net income (loss) per share independently for each quarter during <span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">the year.</span></td>
</tr>
<tr class="outerFootnote">
<td style="vertical-align: top; width: 12pt;" valign="top">[2]</td>
<td style="vertical-align: top;" valign="top">As discussed in Note 1, Organization and Significant Accounting Policies, we compute basic net income (loss) per share by dividing the total net income (loss)
            attributable to our common stockholders by our weighted-average number of common shares outstanding during the period. Our basic net income per share for the fourth quarter of 2021 was $1.59.Our basic net loss per share calculation for the fourth quarter of 2020 considered our net loss for Ionis on a stand-alone
    basis plus our share of Akcea&#8217;s net loss for the period. To calculate the portion of Akcea&#8217;s net loss attributable to our ownership, we multiplied Akcea&#8217;s loss per share by the weighted average shares we owned in Akcea during the period. As a result of
    this calculation, our total net loss available to Ionis common stockholders for the calculation of net loss per share is different than net loss attributable to Ionis Pharmaceuticals, Inc. common stockholders in the consolidated statements of
    operations.</td>
</tr>
</table></td></tr>
</table>
<div style="display: none;">
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_WeightedAverageNumberOfSharesOwnedInSubsidiary">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Number of shares owned in the subsidiary during the reporting period determined by relating the portion of time within a reporting period that shares have been owned to the total time in that period.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_WeightedAverageNumberOfSharesOwnedInSubsidiary</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:sharesItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_EarningsPerShareBasic">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The amount of net income (loss) for the period per each share of common stock or unit outstanding during the reporting period.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 815<br> -SubTopic 40<br> -Section 65<br> -Paragraph 1<br> -Subparagraph (e)(4)<br> -URI http://asc.fasb.org/extlink&amp;oid=123482062&amp;loc=SL123482106-238011<br><br>Reference 2: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 250<br> -SubTopic 10<br> -Section 50<br> -Paragraph 3<br> -URI http://asc.fasb.org/extlink&amp;oid=124431687&amp;loc=d3e22583-107794<br><br>Reference 3: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 250<br> -SubTopic 10<br> -Section 50<br> -Paragraph 11<br> -Subparagraph (b)<br> -URI http://asc.fasb.org/extlink&amp;oid=124431687&amp;loc=d3e22694-107794<br><br>Reference 4: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 260<br> -SubTopic 10<br> -Section 45<br> -Paragraph 10<br> -URI http://asc.fasb.org/extlink&amp;oid=125511455&amp;loc=d3e1448-109256<br><br>Reference 5: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 250<br> -SubTopic 10<br> -Section 50<br> -Paragraph 4<br> -URI http://asc.fasb.org/extlink&amp;oid=124431687&amp;loc=d3e22595-107794<br><br>Reference 6: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 250<br> -SubTopic 10<br> -Section 50<br> -Paragraph 11<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=124431687&amp;loc=d3e22694-107794<br><br>Reference 7: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 260<br> -SubTopic 10<br> -Section 45<br> -Paragraph 7<br> -URI http://asc.fasb.org/extlink&amp;oid=125511455&amp;loc=d3e1337-109256<br><br>Reference 8: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 815<br> -SubTopic 40<br> -Section 65<br> -Paragraph 1<br> -Subparagraph (f)<br> -URI http://asc.fasb.org/extlink&amp;oid=123482062&amp;loc=SL123482106-238011<br><br>Reference 9: http://www.xbrl.org/2003/role/exampleRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 260<br> -SubTopic 10<br> -Section 55<br> -Paragraph 52<br> -URI http://asc.fasb.org/extlink&amp;oid=125512782&amp;loc=d3e4984-109258<br><br>Reference 10: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 944<br> -SubTopic 220<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.7-04(23))<br> -URI http://asc.fasb.org/extlink&amp;oid=120400993&amp;loc=SL114874131-224263<br><br>Reference 11: 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10<br> -Section S99<br> -Paragraph 2<br> -Subparagraph (SX 210.5-03(25))<br> -URI http://asc.fasb.org/extlink&amp;oid=123367319&amp;loc=SL114868664-224227<br><br>Reference 15: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 260<br> -SubTopic 10<br> -Section 45<br> -Paragraph 2<br> -URI http://asc.fasb.org/extlink&amp;oid=125511455&amp;loc=d3e1252-109256<br><br>Reference 16: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 260<br> -SubTopic 10<br> -Section 45<br> -Paragraph 60B<br> -Subparagraph (d)<br> -URI http://asc.fasb.org/extlink&amp;oid=125511455&amp;loc=SL5780133-109256<br><br>Reference 17: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 942<br> -SubTopic 220<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.9-04(27))<br> -URI http://asc.fasb.org/extlink&amp;oid=120399700&amp;loc=SL114874048-224260<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_EarningsPerShareBasic</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>dtr-types:perShareItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_EarningsPerShareBasicAbstract">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_EarningsPerShareBasicAbstract</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:stringItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_MinorityInterestOwnershipPercentageByParent">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The parent entity's interest in net assets of the subsidiary, expressed as a percentage.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_MinorityInterestOwnershipPercentageByParent</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>dtr-types:percentItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_NetIncomeLoss">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The portion of profit or loss for the period, net of income taxes, which is attributable to the parent.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 942<br> -SubTopic 220<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.9-04(22))<br> -URI http://asc.fasb.org/extlink&amp;oid=120399700&amp;loc=SL114874048-224260<br><br>Reference 2: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 280<br> -SubTopic 10<br> -Section 50<br> -Paragraph 32<br> -Subparagraph (f)<br> -URI http://asc.fasb.org/extlink&amp;oid=123359005&amp;loc=d3e8933-108599<br><br>Reference 3: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 250<br> -SubTopic 10<br> -Section 50<br> -Paragraph 4<br> -URI 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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount, after deduction of tax, noncontrolling interests, dividends on preferred stock and participating securities; of income (loss) available to common shareholders.</p></div>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Number of [basic] shares or units, after adjustment for contingently issuable shares or units and other shares or units not deemed outstanding, determined by relating the portion of time within a reporting period that common shares or units have been outstanding to the total time in that period.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 260<br> -SubTopic 10<br> -Section 50<br> -Paragraph 1<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=124432515&amp;loc=d3e3550-109257<br><br>Reference 2: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 260<br> -SubTopic 10<br> -Section 45<br> -Paragraph 10<br> -URI http://asc.fasb.org/extlink&amp;oid=125511455&amp;loc=d3e1448-109256<br></p></div>
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<span style="display: none;">v3.22.0.1</span><table class="report" border="0" cellspacing="2" id="idm139691003584568">
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<th class="th" colspan="4">3 Months Ended</th>
<th class="th" colspan="3">12 Months Ended</th>
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<th class="th" colspan="2"><div>Dec. 31, 2021</div></th>
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<td class="num">$ (356,008)<span></span>
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<td class="text">&#160;<span></span>
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<td class="text">&#160;<span></span>
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<td class="text">&#160;<span></span>
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<td class="text">&#160;<span></span>
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<td class="text">&#160;<span></span>
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<td class="text">&#160;<span></span>
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<td class="text">&#160;<span></span>
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<td class="nump">139,998<span></span>
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<td class="text">&#160;<span></span>
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<td class="text">&#160;<span></span>
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<td class="text">&#160;<span></span>
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<td class="text">&#160;<span></span>
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<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_IncrementalCommonSharesAttributableToEmployeeStockPurchasePlan', window );">Shares issuable related to our ESPP (in shares)</a></td>
<td class="nump">34<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">18<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rou">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_WeightedAverageNumberOfDilutedSharesOutstanding', window );">Shares used in computing diluted net income per share (in shares)</a></td>
<td class="nump">160,340<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">141,021<span></span>
</td>
<td class="nump">139,612<span></span>
</td>
<td class="nump">153,164<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_EarningsPerShareAbstract', window );"><strong>Per-Share Amount [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_EarningsPerShareBasic', window );">Basic net income per share (in dollars per share)</a></td>
<td class="nump">$ 1.59<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"><sup>[1],[2]</sup></td>
<td class="num">$ (2.54)<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"><sup>[1],[2]</sup></td>
<td class="num">$ (0.20)<span></span>
</td>
<td class="num">$ (3.18)<span></span>
</td>
<td class="nump">$ 2.00<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_EarningsPerShareDiluted', window );">Diluted net income (loss) per share (in dollars per share)</a></td>
<td class="nump">$ 1.41<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"><sup>[1],[3]</sup></td>
<td class="num">$ (2.54)<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"><sup>[1]</sup></td>
<td class="num">$ (0.20)<span></span>
</td>
<td class="num">$ (3.18)<span></span>
</td>
<td class="nump">$ 1.90<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DebtInstrumentAxis=ions_ConvertibleSeniorNotes0125PercentMember', window );">0.125% Notes [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_EarningsPerShareDilutedAbstract', window );"><strong>Diluted Net Income per Share [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DebtInstrumentInterestRateStatedPercentage', window );">Interest rate on convertible senior notes</a></td>
<td class="nump">0.125%<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">0.125%<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">0.125%<span></span>
</td>
<td class="nump">0.125%<span></span>
</td>
<td class="nump">0.125%<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_NetIncomeLossAvailableToCommonStockholdersDilutedAbstract', window );"><strong>Net Income (Numerator) [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DilutiveSecuritiesEffectOnBasicEarningsPerShareOther', window );">Shares issuable related to our convertible notes</a></td>
<td class="nump">$ 716<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 860<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_WeightedAverageNumberDilutedSharesOutstandingAdjustmentAbstract', window );"><strong>Effect of Diluted Securities [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_IncrementalCommonSharesAttributableToConversionOfDebtSecurities', window );">Shares issuable related to our convertible notes (in shares)</a></td>
<td class="nump">6,590<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">217<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DebtInstrumentAxis=ions_ConvertibleSeniorNotes1PercentMember', window );">1% Notes [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_EarningsPerShareDilutedAbstract', window );"><strong>Diluted Net Income per Share [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DebtInstrumentInterestRateStatedPercentage', window );">Interest rate on convertible senior notes</a></td>
<td class="nump">1.00%<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">1.00%<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">1.00%<span></span>
</td>
<td class="nump">1.00%<span></span>
</td>
<td class="nump">1.00%<span></span>
</td>
<td class="nump">1.00%<span></span>
</td>
<td class="nump">1.00%<span></span>
</td>
<td class="nump">1.00%<span></span>
</td>
<td class="nump">1.00%<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_NetIncomeLossAvailableToCommonStockholdersDilutedAbstract', window );"><strong>Net Income (Numerator) [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DilutiveSecuritiesEffectOnBasicEarningsPerShareOther', window );">Shares issuable related to our convertible notes</a></td>
<td class="nump">$ 105<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 9,527<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_WeightedAverageNumberDilutedSharesOutstandingAdjustmentAbstract', window );"><strong>Effect of Diluted Securities [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_IncrementalCommonSharesAttributableToConversionOfDebtSecurities', window );">Shares issuable related to our convertible notes (in shares)</a></td>
<td class="nump">464<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">10,075<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DebtInstrumentAxis=ions_ConvertibleSeniorNotes0PercentMember', window );">0% Notes [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_EarningsPerShareDilutedAbstract', window );"><strong>Diluted Net Income per Share [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DebtInstrumentInterestRateStatedPercentage', window );">Interest rate on convertible senior notes</a></td>
<td class="nump">0.00%<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">0.00%<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">0.00%<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">0.00%<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_NetIncomeLossAvailableToCommonStockholdersDilutedAbstract', window );"><strong>Net Income (Numerator) [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DilutiveSecuritiesEffectOnBasicEarningsPerShareOther', window );">Shares issuable related to our convertible notes</a></td>
<td class="nump">$ 777<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_WeightedAverageNumberDilutedSharesOutstandingAdjustmentAbstract', window );"><strong>Effect of Diluted Securities [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_IncrementalCommonSharesAttributableToConversionOfDebtSecurities', window );">Shares issuable related to our convertible notes (in shares)</a></td>
<td class="nump">10,936<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AwardTypeAxis=us-gaap_EmployeeStockOptionMember', window );">Stock Options [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_WeightedAverageNumberDilutedSharesOutstandingAdjustmentAbstract', window );"><strong>Effect of Diluted Securities [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_IncrementalCommonSharesAttributableToShareBasedPaymentArrangements', window );">Shares issuable related to stock-based compensation (in shares)</a></td>
<td class="nump">46<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">2,090<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AwardTypeAxis=us-gaap_RestrictedStockMember', window );">Restricted Stock Awards [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_WeightedAverageNumberDilutedSharesOutstandingAdjustmentAbstract', window );"><strong>Effect of Diluted Securities [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_IncrementalCommonSharesAttributableToShareBasedPaymentArrangements', window );">Shares issuable related to stock-based compensation (in shares)</a></td>
<td class="nump">1,065<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">766<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
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<tr><td colspan="12"></td></tr>
<tr><td colspan="12"><table class="outerFootnotes" width="100%">
<tr class="outerFootnote">
<td style="vertical-align: top; width: 12pt;" valign="top">[1]</td>
<td style="vertical-align: top;" valign="top"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">We </span>compute net income (loss) per share independently for each quarter during <span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">the year.</span></td>
</tr>
<tr class="outerFootnote">
<td style="vertical-align: top; width: 12pt;" valign="top">[2]</td>
<td style="vertical-align: top;" valign="top">As discussed in Note 1, Organization and Significant Accounting Policies, we compute basic net income (loss) per share by dividing the total net income (loss)
            attributable to our common stockholders by our weighted-average number of common shares outstanding during the period. Our basic net income per share for the fourth quarter of 2021 was $1.59.Our basic net loss per share calculation for the fourth quarter of 2020 considered our net loss for Ionis on a stand-alone
    basis plus our share of Akcea&#8217;s net loss for the period. To calculate the portion of Akcea&#8217;s net loss attributable to our ownership, we multiplied Akcea&#8217;s loss per share by the weighted average shares we owned in Akcea during the period. As a result of
    this calculation, our total net loss available to Ionis common stockholders for the calculation of net loss per share is different than net loss attributable to Ionis Pharmaceuticals, Inc. common stockholders in the consolidated statements of
    operations.</td>
</tr>
<tr class="outerFootnote">
<td style="vertical-align: top; width: 12pt;" valign="top">[3]</td>
<td style="vertical-align: top;" valign="top">We had net income available
            to Ionis common stockholders for the fourth quarter of 2021. As a result, we computed diluted net income per share using the weighted-average number of common shares and dilutive common equivalent shares outstanding during the period</td>
</tr>
</table></td></tr>
</table>
<div style="display: none;">
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<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Additional shares included in the calculation of diluted EPS as a result of the potentially dilutive effect of shares issuable related to employee stock purchase plan.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
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<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Contractual interest rate for funds borrowed, under the debt agreement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 470<br> -SubTopic 20<br> -Section 50<br> -Paragraph 1B<br> -Subparagraph (b)<br> -URI http://asc.fasb.org/extlink&amp;oid=123466505&amp;loc=SL123495323-112611<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 210<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.5-02.22(a)(1))<br> -URI http://asc.fasb.org/extlink&amp;oid=120391452&amp;loc=d3e13212-122682<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of increase (decrease) to net income used for calculating diluted earnings per share (EPS), resulting from the assumed exercise of dilutive convertible securities excluding adjustments related to ESOP convertible preferred stock, stock options, and restrictive stock units.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_DilutiveSecuritiesEffectOnBasicEarningsPerShareOther</td>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
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<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The amount of net income (loss) for the period per each share of common stock or unit outstanding during the reporting period.</p></div>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_EarningsPerShareBasic</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>dtr-types:perShareItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
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</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_EarningsPerShareDiluted">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The amount of net income (loss) for the period available to each share of common stock or common unit outstanding during the reporting period and to each share or unit that would have been outstanding assuming the issuance of common shares or units for all dilutive potential common shares or units outstanding during the reporting period.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/exampleRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 260<br> -SubTopic 10<br> -Section 55<br> -Paragraph 52<br> -URI http://asc.fasb.org/extlink&amp;oid=125512782&amp;loc=d3e4984-109258<br><br>Reference 2: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 250<br> -SubTopic 10<br> -Section 50<br> -Paragraph 7<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=124431687&amp;loc=d3e22644-107794<br><br>Reference 3: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 260<br> -SubTopic 10<br> -Section 55<br> -Paragraph 15<br> -URI http://asc.fasb.org/extlink&amp;oid=125512782&amp;loc=d3e3842-109258<br><br>Reference 4: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 260<br> -SubTopic 10<br> -Section 45<br> -Paragraph 2<br> -URI http://asc.fasb.org/extlink&amp;oid=125511455&amp;loc=d3e1252-109256<br><br>Reference 5: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 250<br> -SubTopic 10<br> -Section 50<br> -Paragraph 11<br> -Subparagraph (b)<br> -URI http://asc.fasb.org/extlink&amp;oid=124431687&amp;loc=d3e22694-107794<br><br>Reference 6: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 250<br> -SubTopic 10<br> -Section 50<br> -Paragraph 4<br> -URI http://asc.fasb.org/extlink&amp;oid=124431687&amp;loc=d3e22595-107794<br><br>Reference 7: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 250<br> -SubTopic 10<br> -Section 50<br> -Paragraph 3<br> -URI http://asc.fasb.org/extlink&amp;oid=124431687&amp;loc=d3e22583-107794<br><br>Reference 8: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 260<br> -SubTopic 10<br> -Section 45<br> -Paragraph 60B<br> -Subparagraph (d)<br> -URI http://asc.fasb.org/extlink&amp;oid=125511455&amp;loc=SL5780133-109256<br><br>Reference 9: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 815<br> -SubTopic 40<br> -Section 65<br> -Paragraph 1<br> -Subparagraph (f)<br> -URI http://asc.fasb.org/extlink&amp;oid=123482062&amp;loc=SL123482106-238011<br><br>Reference 10: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 942<br> -SubTopic 220<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.9-04(27))<br> -URI http://asc.fasb.org/extlink&amp;oid=120399700&amp;loc=SL114874048-224260<br><br>Reference 11: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 260<br> -SubTopic 10<br> -Section 50<br> -Paragraph 1<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=124432515&amp;loc=d3e3550-109257<br><br>Reference 12: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 944<br> -SubTopic 220<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.7-04(23))<br> -URI http://asc.fasb.org/extlink&amp;oid=120400993&amp;loc=SL114874131-224263<br><br>Reference 13: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 250<br> -SubTopic 10<br> -Section 50<br> -Paragraph 11<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=124431687&amp;loc=d3e22694-107794<br><br>Reference 14: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 260<br> -SubTopic 10<br> -Section 45<br> -Paragraph 7<br> -URI http://asc.fasb.org/extlink&amp;oid=125511455&amp;loc=d3e1337-109256<br><br>Reference 15: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 815<br> -SubTopic 40<br> -Section 65<br> -Paragraph 1<br> -Subparagraph (e)(4)<br> -URI http://asc.fasb.org/extlink&amp;oid=123482062&amp;loc=SL123482106-238011<br><br>Reference 16: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 220<br> -SubTopic 10<br> -Section S99<br> -Paragraph 2<br> -Subparagraph (SX 210.5-03(25))<br> -URI http://asc.fasb.org/extlink&amp;oid=123367319&amp;loc=SL114868664-224227<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_EarningsPerShareDiluted</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>dtr-types:perShareItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_EarningsPerShareDilutedAbstract">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_EarningsPerShareDilutedAbstract</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:stringItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
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<tr>
<td><strong> Period Type:</strong></td>
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</tr>
</table></div>
</div></td></tr>
</table>
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<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Additional shares included in the calculation of diluted EPS as a result of the potentially dilutive effect of convertible debt securities using the if-converted method.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 260<br> -SubTopic 10<br> -Section 45<br> -Paragraph 40<br> -Subparagraph (c)<br> -URI http://asc.fasb.org/extlink&amp;oid=125511455&amp;loc=d3e1930-109256<br><br>Reference 2: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 260<br> -SubTopic 10<br> -Section 45<br> -Paragraph 42<br> -URI http://asc.fasb.org/extlink&amp;oid=125511455&amp;loc=d3e2029-109256<br><br>Reference 3: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 260<br> -SubTopic 10<br> -Section 50<br> -Paragraph 1<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=124432515&amp;loc=d3e3550-109257<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_IncrementalCommonSharesAttributableToConversionOfDebtSecurities</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:sharesItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_IncrementalCommonSharesAttributableToShareBasedPaymentArrangements">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Additional shares included in the calculation of diluted EPS as a result of the potentially dilutive effect of share based payment arrangements using the treasury stock method.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 260<br> -SubTopic 10<br> -Section 45<br> -Paragraph 22<br> -URI http://asc.fasb.org/extlink&amp;oid=125511455&amp;loc=d3e1707-109256<br><br>Reference 2: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 260<br> -SubTopic 10<br> -Section 50<br> -Paragraph 1<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=124432515&amp;loc=d3e3550-109257<br><br>Reference 3: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 260<br> -SubTopic 10<br> -Section 45<br> -Paragraph 28A<br> -URI http://asc.fasb.org/extlink&amp;oid=125511455&amp;loc=d3e1500-109256<br><br>Reference 4: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 260<br> -SubTopic 10<br> -Section 45<br> -Paragraph 23<br> -Subparagraph (c)<br> -URI http://asc.fasb.org/extlink&amp;oid=125511455&amp;loc=d3e1757-109256<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_IncrementalCommonSharesAttributableToShareBasedPaymentArrangements</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:sharesItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_NetIncomeLossAvailableToCommonStockholdersBasic">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount, after deduction of tax, noncontrolling interests, dividends on preferred stock and participating securities; of income (loss) available to common shareholders.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 250<br> -SubTopic 10<br> -Section 50<br> -Paragraph 4<br> -URI http://asc.fasb.org/extlink&amp;oid=124431687&amp;loc=d3e22595-107794<br><br>Reference 2: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 260<br> -SubTopic 10<br> -Section 45<br> -Paragraph 10<br> -URI http://asc.fasb.org/extlink&amp;oid=125511455&amp;loc=d3e1448-109256<br><br>Reference 3: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 250<br> -SubTopic 10<br> -Section 50<br> -Paragraph 11<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=124431687&amp;loc=d3e22694-107794<br><br>Reference 4: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 260<br> -SubTopic 10<br> -Section 45<br> -Paragraph 11<br> -URI http://asc.fasb.org/extlink&amp;oid=125511455&amp;loc=d3e1377-109256<br><br>Reference 5: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 260<br> -SubTopic 10<br> -Section 50<br> -Paragraph 1<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=124432515&amp;loc=d3e3550-109257<br><br>Reference 6: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 280<br> -SubTopic 10<br> -Section 50<br> -Paragraph 22<br> -URI http://asc.fasb.org/extlink&amp;oid=123359005&amp;loc=d3e8736-108599<br><br>Reference 7: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 250<br> -SubTopic 10<br> -Section 50<br> -Paragraph 11<br> -Subparagraph (b)<br> -URI http://asc.fasb.org/extlink&amp;oid=124431687&amp;loc=d3e22694-107794<br><br>Reference 8: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 260<br> -SubTopic 10<br> -Section 45<br> -Paragraph 60B<br> -Subparagraph (c)<br> -URI http://asc.fasb.org/extlink&amp;oid=125511455&amp;loc=SL5780133-109256<br><br>Reference 9: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 280<br> -SubTopic 10<br> -Section 50<br> -Paragraph 32<br> -Subparagraph (f)<br> -URI http://asc.fasb.org/extlink&amp;oid=123359005&amp;loc=d3e8933-108599<br><br>Reference 10: http://www.xbrl.org/2003/role/exampleRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 280<br> -SubTopic 10<br> -Section 50<br> -Paragraph 31<br> -URI http://asc.fasb.org/extlink&amp;oid=123359005&amp;loc=d3e8924-108599<br><br>Reference 11: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 280<br> -SubTopic 10<br> -Section 50<br> -Paragraph 30<br> -Subparagraph (b)<br> -URI http://asc.fasb.org/extlink&amp;oid=123359005&amp;loc=d3e8906-108599<br><br>Reference 12: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 250<br> -SubTopic 10<br> -Section 50<br> -Paragraph 3<br> -URI http://asc.fasb.org/extlink&amp;oid=124431687&amp;loc=d3e22583-107794<br><br>Reference 13: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 280<br> -SubTopic 10<br> -Section 50<br> -Paragraph 32<br> -Subparagraph (c)<br> -URI http://asc.fasb.org/extlink&amp;oid=123359005&amp;loc=d3e8933-108599<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_NetIncomeLossAvailableToCommonStockholdersBasic</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_NetIncomeLossAvailableToCommonStockholdersDiluted">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount, after deduction of tax, noncontrolling interests, dividends on preferred stock and participating securities, and addition from assumption of issuance of common shares for dilutive potential common shares; of income (loss) available to common shareholders.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 260<br> -SubTopic 10<br> -Section 45<br> -Paragraph 40<br> -Subparagraph (b)(2)<br> -URI http://asc.fasb.org/extlink&amp;oid=125511455&amp;loc=d3e1930-109256<br><br>Reference 2: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 260<br> -SubTopic 10<br> -Section 45<br> -Paragraph 40<br> -Subparagraph (b)(3)<br> -URI http://asc.fasb.org/extlink&amp;oid=125511455&amp;loc=d3e1930-109256<br><br>Reference 3: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 260<br> -SubTopic 10<br> -Section 45<br> -Paragraph 60B<br> -Subparagraph (c)<br> -URI http://asc.fasb.org/extlink&amp;oid=125511455&amp;loc=SL5780133-109256<br><br>Reference 4: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 260<br> -SubTopic 10<br> -Section 50<br> -Paragraph 1<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=124432515&amp;loc=d3e3550-109257<br><br>Reference 5: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 260<br> -SubTopic 10<br> -Section 45<br> -Paragraph 40<br> -Subparagraph (b)(1)<br> -URI http://asc.fasb.org/extlink&amp;oid=125511455&amp;loc=d3e1930-109256<br><br>Reference 6: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 260<br> -SubTopic 10<br> -Section 45<br> -Paragraph 16<br> -URI http://asc.fasb.org/extlink&amp;oid=125511455&amp;loc=d3e1505-109256<br><br>Reference 7: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 260<br> -SubTopic 10<br> -Section 45<br> -Paragraph 40<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=125511455&amp;loc=d3e1930-109256<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_NetIncomeLossAvailableToCommonStockholdersDiluted</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_NetIncomeLossAvailableToCommonStockholdersDilutedAbstract">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_NetIncomeLossAvailableToCommonStockholdersDilutedAbstract</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
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<td style="white-space:nowrap;">us-gaap_WeightedAverageNumberDilutedSharesOutstandingAdjustmentAbstract</td>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The average number of shares or units issued and outstanding that are used in calculating diluted EPS or earnings per unit (EPU), determined based on the timing of issuance of shares or units in the period.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 260<br> -SubTopic 10<br> -Section 50<br> -Paragraph 1<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=124432515&amp;loc=d3e3550-109257<br><br>Reference 2: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 260<br> -SubTopic 10<br> -Section 45<br> -Paragraph 16<br> -URI http://asc.fasb.org/extlink&amp;oid=125511455&amp;loc=d3e1505-109256<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_WeightedAverageNumberOfDilutedSharesOutstanding</td>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Number of [basic] shares or units, after adjustment for contingently issuable shares or units and other shares or units not deemed outstanding, determined by relating the portion of time within a reporting period that common shares or units have been outstanding to the total time in that period.</p></div>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
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<th class="th" colspan="4">1 Months Ended</th>
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<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerAbstract', window );"><strong>Revenue Recognition [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax', window );">Revenue</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 55,500<span></span>
</td>
<td class="nump">$ 69,999<span></span>
</td>
<td class="nump">$ 42,253<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_TypeOfArrangementAxis=ions_PtcTherapeuticsCollaborationMember', window );">PTC Therapeutics [Member] | TEGSEDI and WAYLIVRA [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerAbstract', window );"><strong>Revenue Recognition [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax', window );">Revenue</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 4,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_TypeOfArrangementAxis=ions_AstrazenecaCollaborationEplontersenMember', window );">AstraZeneca [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerAbstract', window );"><strong>Revenue Recognition [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax', window );">Revenue</a></td>
<td class="nump">$ 200,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_UpfrontPaymentReceived', window );">Upfront payment received</a></td>
<td class="nump">$ 200,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_RevenueFromContractWithCustomerNumberOfSeparatePerformanceObligations', window );">Number of separate performance obligations | PerformanceObligation</a></td>
<td class="nump">1<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">1<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">1<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_RevenueFromContractWithCustomerTransactionPrice', window );">Transaction price</a></td>
<td class="nump">$ 200,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 200,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 200,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_TypeOfArrangementAxis=ions_AstrazenecaCollaborationEplontersenMember', window );">AstraZeneca [Member] | Eplontersen [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerAbstract', window );"><strong>Revenue Recognition [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax', window );">Revenue</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">200,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_TypeOfArrangementAxis=ions_AstrazenecaCollaborationCardiovascularRenalAndMetabolicDiseasesMember', window );">AstraZeneca [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerAbstract', window );"><strong>Revenue Recognition [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax', window );">Revenue</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">10,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 10,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_UpfrontPaymentReceived', window );">Upfront payment received</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 65,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_RevenueFromContractWithCustomerNumberOfSeparatePerformanceObligations', window );">Number of separate performance obligations | PerformanceObligation</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">1<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_RevenueFromContractWithCustomerTransactionPrice', window );">Transaction price</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 65,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_TypeOfArrangementAxis=ions_RocheCollaborationIonisFbLForComplementMediatedDiseasesMember', window );">Roche IONIS-FB-L for Complement-Mediated Diseases [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerAbstract', window );"><strong>Revenue Recognition [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax', window );">Revenue</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="num">$ (9,200)<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_UpfrontPaymentReceived', window );">Upfront payment received</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 75,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_RevenueFromContractWithCustomerNumberOfSeparatePerformanceObligations', window );">Number of separate performance obligations | PerformanceObligation</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">1<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_RevenueFromContractWithCustomerTransactionPrice', window );">Transaction price</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 75,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_TypeOfArrangementAxis=ions_BiogenCollaboration2018StrategicNeurologyMember', window );">Biogen 2018 Strategic Neurology [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerAbstract', window );"><strong>Revenue Recognition [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax', window );">Revenue</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">15,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_UpfrontPaymentReceived', window );">Upfront payment received</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 375,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_RevenueFromContractWithCustomerTransactionPriceAdditions', window );">Milestone payment received and added to transaction price</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 7,500<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_NumberOfNewTargetsAdvanced', window );">Number of new targets advanced | Target</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">2<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_RevenueFromContractWithCustomerNumberOfSeparatePerformanceObligations', window );">Number of separate performance obligations | PerformanceObligation</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">1<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_RevenueFromContractWithCustomerTransactionPrice', window );">Transaction price</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 552,000<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_TypeOfArrangementAxis=ions_BiogenCollaborationNewAntisenseMedicinesForTreatmentOfSmaMember', window );">Biogen Treatment of SMA [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerAbstract', window );"><strong>Revenue Recognition [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax', window );">Revenue</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 8,300<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_UpfrontPaymentReceived', window );">Upfront payment received</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 25,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_RevenueFromContractWithCustomerNumberOfSeparatePerformanceObligations', window );">Number of separate performance obligations | PerformanceObligation</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">1<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_RevenueFromContractWithCustomerTransactionPrice', window );">Transaction price</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 25,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_TypeOfArrangementAxis=ions_BiogenCollaborationNewAntisenseMedicinesForTreatmentOfSmaMember', window );">Biogen Treatment of SMA [Member] | ION306 [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerAbstract', window );"><strong>Revenue Recognition [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax', window );">Revenue</a></td>
<td class="nump">$ 60,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 60,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_TypeOfArrangementAxis=ions_AlnylamCollaborationMember', window );">Alnylam [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerAbstract', window );"><strong>Revenue Recognition [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax', window );">Revenue</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 41,200<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_TypeOfArrangementAxis=ions_BayerCollaborationIonisFxiMember', window );">Bayer [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerAbstract', window );"><strong>Revenue Recognition [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_UpfrontPaymentReceived', window );">Upfront payment received</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 100,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 100,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_RevenueFromContractWithCustomerNumberOfSeparatePerformanceObligations', window );">Number of separate performance obligations | PerformanceObligation</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">3<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_TypeOfArrangementAxis=ions_BayerCollaborationIonisFxiAmendmentMember', window );">Bayer [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerAbstract', window );"><strong>Revenue Recognition [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_UpfrontPaymentReceived', window );">Upfront payment received</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 75,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_RevenueFromContractWithCustomerNumberOfSeparatePerformanceObligations', window );">Number of separate performance obligations | PerformanceObligation</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">3<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_RevenueFromContractWithCustomerTransactionPrice', window );">Transaction price</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 75,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
</table>
<div style="display: none;">
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_NumberOfAgreementsWithCollaborationPartner">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The number of agreements entered into with the collaboration partner.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_NumberOfAgreementsWithCollaborationPartner</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:integerItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_NumberOfNewTargetsAdvanced">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The number of new targets advanced during the period under the collaboration agreement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_NumberOfNewTargetsAdvanced</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:integerItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_RevenueFromContractWithCustomerNumberOfSeparatePerformanceObligations">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The number of separate performance obligations under the collaboration agreement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_RevenueFromContractWithCustomerNumberOfSeparatePerformanceObligations</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:integerItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_RevenueFromContractWithCustomerTransactionPrice">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The amount of consideration the Company earned or is eligible to earn under the collaboration agreement, including any variable consideration.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_RevenueFromContractWithCustomerTransactionPrice</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_RevenueFromContractWithCustomerTransactionPriceAdditions">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The additional amount of consideration the Company earned under the collaboration agreement that is added to the transaction price.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_RevenueFromContractWithCustomerTransactionPriceAdditions</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_UpfrontPaymentReceived">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The amount of upfront payments received during the period under the collaboration agreement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_UpfrontPaymentReceived</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_RevenueFromContractWithCustomerAbstract">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_RevenueFromContractWithCustomerAbstract</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:stringItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount, excluding tax collected from customer, of revenue from satisfaction of performance obligation by transferring promised good or service to customer. Tax collected from customer is tax assessed by governmental authority that is both imposed on and concurrent with specific revenue-producing transaction, including, but not limited to, sales, use, value added and excise.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 280<br> -SubTopic 10<br> -Section 50<br> -Paragraph 30<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=123359005&amp;loc=d3e8906-108599<br><br>Reference 2: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 280<br> -SubTopic 10<br> -Section 50<br> -Paragraph 40<br> -URI http://asc.fasb.org/extlink&amp;oid=123359005&amp;loc=d3e9031-108599<br><br>Reference 3: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 280<br> -SubTopic 10<br> -Section 50<br> -Paragraph 41<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=123359005&amp;loc=d3e9038-108599<br><br>Reference 4: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 280<br> -SubTopic 10<br> -Section 50<br> -Paragraph 32<br> -Subparagraph (b)<br> -URI http://asc.fasb.org/extlink&amp;oid=123359005&amp;loc=d3e8933-108599<br><br>Reference 5: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 280<br> -SubTopic 10<br> -Section 50<br> -Paragraph 32<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=123359005&amp;loc=d3e8933-108599<br><br>Reference 6: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 606<br> -SubTopic 10<br> -Section 50<br> -Paragraph 4<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=123351226&amp;loc=SL49130543-203045<br><br>Reference 7: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 280<br> -SubTopic 10<br> -Section 50<br> -Paragraph 22<br> -Subparagraph (b)<br> -URI http://asc.fasb.org/extlink&amp;oid=123359005&amp;loc=d3e8736-108599<br><br>Reference 8: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 280<br> -SubTopic 10<br> -Section 50<br> -Paragraph 22<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=123359005&amp;loc=d3e8736-108599<br><br>Reference 9: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 280<br> -SubTopic 10<br> -Section 50<br> -Paragraph 42<br> -URI http://asc.fasb.org/extlink&amp;oid=123359005&amp;loc=d3e9054-108599<br><br>Reference 10: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 606<br> -SubTopic 10<br> -Section 50<br> -Paragraph 5<br> -URI http://asc.fasb.org/extlink&amp;oid=123351226&amp;loc=SL49130545-203045<br><br>Reference 11: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 924<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SAB Topic 11.L)<br> -URI http://asc.fasb.org/extlink&amp;oid=6472922&amp;loc=d3e499488-122856<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_srt_MajorCustomersAxis=ions_BiogenIncMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">srt_MajorCustomersAxis=ions_BiogenIncMember</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td></td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_srt_ProductOrServiceAxis=us-gaap_ProductMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">srt_ProductOrServiceAxis=us-gaap_ProductMember</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td></td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_TypeOfArrangementAxis=ions_PtcTherapeuticsCollaborationMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_TypeOfArrangementAxis=ions_PtcTherapeuticsCollaborationMember</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td></td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_TypeOfArrangementAxis=ions_AstrazenecaCollaborationEplontersenMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_TypeOfArrangementAxis=ions_AstrazenecaCollaborationEplontersenMember</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td></td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_srt_ProductOrServiceAxis=ions_EplontersenMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">srt_ProductOrServiceAxis=ions_EplontersenMember</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td></td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_TypeOfArrangementAxis=ions_AstrazenecaCollaborationCardiovascularRenalAndMetabolicDiseasesMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_TypeOfArrangementAxis=ions_AstrazenecaCollaborationCardiovascularRenalAndMetabolicDiseasesMember</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td></td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_TypeOfArrangementAxis=ions_RocheCollaborationIonisFbLForComplementMediatedDiseasesMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_TypeOfArrangementAxis=ions_RocheCollaborationIonisFbLForComplementMediatedDiseasesMember</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td></td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_TypeOfArrangementAxis=ions_BiogenCollaboration2018StrategicNeurologyMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_TypeOfArrangementAxis=ions_BiogenCollaboration2018StrategicNeurologyMember</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td></td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_TypeOfArrangementAxis=ions_BiogenCollaborationNewAntisenseMedicinesForTreatmentOfSmaMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_TypeOfArrangementAxis=ions_BiogenCollaborationNewAntisenseMedicinesForTreatmentOfSmaMember</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td></td>
</tr>
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<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_srt_ProductOrServiceAxis=ions_Ion306Member">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">srt_ProductOrServiceAxis=ions_Ion306Member</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td></td>
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<tr>
<td><strong> Data Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td></td>
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<tr>
<td><strong> Period Type:</strong></td>
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</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_TypeOfArrangementAxis=ions_AlnylamCollaborationMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_TypeOfArrangementAxis=ions_AlnylamCollaborationMember</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
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<tr>
<td><strong> Data Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
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</tr>
</table></div>
</div></td></tr>
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<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_TypeOfArrangementAxis=ions_BayerCollaborationIonisFxiMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_TypeOfArrangementAxis=ions_BayerCollaborationIonisFxiMember</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td></td>
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<td><strong> Data Type:</strong></td>
<td>na</td>
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<tr>
<td><strong> Balance Type:</strong></td>
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<tr>
<td><strong> Period Type:</strong></td>
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<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_TypeOfArrangementAxis=ions_BayerCollaborationIonisFxiAmendmentMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_TypeOfArrangementAxis=ions_BayerCollaborationIonisFxiAmendmentMember</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td></td>
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<td><strong> Data Type:</strong></td>
<td>na</td>
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<tr>
<td><strong> Balance Type:</strong></td>
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<DOCUMENT>
<TYPE>XML
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<FILENAME>R34.htm
<DESCRIPTION>IDEA: XBRL DOCUMENT
<TEXT>
<html>
<head>
<title></title>
<link rel="stylesheet" type="text/css" href="report.css">
<script type="text/javascript" src="Show.js">/* Do Not Remove This Comment */</script><script type="text/javascript">
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<body>
<span style="display: none;">v3.22.0.1</span><table class="report" border="0" cellspacing="2" id="idm139691008666808">
<tr>
<th class="tl" colspan="1" rowspan="2"><div style="width: 200px;"><strong>Organization and Significant Accounting Policies, Contracts Receivable (Details) - Partner<br></strong></div></th>
<th class="th" colspan="2">12 Months Ended</th>
</tr>
<tr>
<th class="th"><div>Dec. 31, 2021</div></th>
<th class="th"><div>Dec. 31, 2020</div></th>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ContractReceivablesAbstract', window );"><strong>Contracts Receivable [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_PeriodAfterBillingWhenPaymentIsReceived', window );">Period of time after billing when payment is received</a></td>
<td class="text">3 months<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_SignificantPartnersAbstract', window );"><strong>Significant Partners [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_NumberOfSignificantCustomers', window );">Number of significant customers</a></td>
<td class="nump">2<span></span>
</td>
<td class="nump">2<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ConcentrationRiskByBenchmarkAxis=us-gaap_AccountsReceivableMember', window );">Contracts Receivables [Member] | Credit Concentration [Member] | Two Significant Customers [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_SignificantPartnersAbstract', window );"><strong>Significant Partners [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ConcentrationRiskPercentage1', window );">Concentration percentage</a></td>
<td class="nump">93.80%<span></span>
</td>
<td class="nump">99.50%<span></span>
</td>
</tr>
</table>
<div style="display: none;">
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_NumberOfSignificantCustomers">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The number of significant customers with which the Company does business.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_NumberOfSignificantCustomers</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:integerItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_PeriodAfterBillingWhenPaymentIsReceived">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The time period between billing a collaboration partner for goods delivered or services performed that are due unconditionally and payment is received from the collaboration partner, in 'PnYnMnDTnHnMnS' format, for example, 'P1Y5M13D' represents the reported fact of one year, five months, and thirteen days.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_PeriodAfterBillingWhenPaymentIsReceived</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:durationItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_SignificantPartnersAbstract">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_SignificantPartnersAbstract</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:stringItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_ConcentrationRiskPercentage1">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>For an entity that discloses a concentration risk in relation to quantitative amount, which serves as the "benchmark" (or denominator) in the equation, this concept represents the concentration percentage derived from the division.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 280<br> -SubTopic 10<br> -Section 50<br> -Paragraph 42<br> -URI http://asc.fasb.org/extlink&amp;oid=123359005&amp;loc=d3e9054-108599<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 275<br> -SubTopic 10<br> -Section 50<br> -Paragraph 18<br> -URI http://asc.fasb.org/extlink&amp;oid=99393423&amp;loc=d3e6351-108592<br><br>Reference 3: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 825<br> -SubTopic 10<br> -Section 50<br> -Paragraph 20<br> -URI http://asc.fasb.org/extlink&amp;oid=123594938&amp;loc=d3e13531-108611<br><br>Reference 4: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 825<br> -SubTopic 10<br> -Section 50<br> -Paragraph 21<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=123594938&amp;loc=d3e13537-108611<br><br>Reference 5: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 275<br> -SubTopic 10<br> -Section 50<br> -Paragraph 20<br> -URI http://asc.fasb.org/extlink&amp;oid=99393423&amp;loc=d3e6404-108592<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ConcentrationRiskPercentage1</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>dtr-types:percentItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_ContractReceivablesAbstract">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ContractReceivablesAbstract</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:stringItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_ConcentrationRiskByBenchmarkAxis=us-gaap_AccountsReceivableMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ConcentrationRiskByBenchmarkAxis=us-gaap_AccountsReceivableMember</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td></td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_ConcentrationRiskByTypeAxis=us-gaap_CreditConcentrationRiskMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ConcentrationRiskByTypeAxis=us-gaap_CreditConcentrationRiskMember</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td></td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_srt_MajorCustomersAxis=ions_TwoSignificantCustomersMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">srt_MajorCustomersAxis=ions_TwoSignificantCustomersMember</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td></td>
</tr>
</table></div>
</div></td></tr>
</table>
</div>
</body>
</html>
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</DOCUMENT>
<DOCUMENT>
<TYPE>XML
<SEQUENCE>65
<FILENAME>R35.htm
<DESCRIPTION>IDEA: XBRL DOCUMENT
<TEXT>
<html>
<head>
<title></title>
<link rel="stylesheet" type="text/css" href="report.css">
<script type="text/javascript" src="Show.js">/* Do Not Remove This Comment */</script><script type="text/javascript">
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</head>
<body>
<span style="display: none;">v3.22.0.1</span><table class="report" border="0" cellspacing="2" id="idm139691014673320">
<tr>
<th class="tl" colspan="1" rowspan="2"><div style="width: 200px;"><strong>Organization and Significant Accounting Policies, Deferred Revenue (Details) - USD ($)<br> $ in Millions</strong></div></th>
<th class="th" colspan="2">12 Months Ended</th>
</tr>
<tr>
<th class="th"><div>Dec. 31, 2021</div></th>
<th class="th"><div>Dec. 31, 2020</div></th>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ContractWithCustomerLiabilityAbstract', window );"><strong>Deferred Revenue [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ContractWithCustomerLiabilityRevenueRecognized', window );">Revenue recognized from amounts in beginning deferred revenue balance</a></td>
<td class="nump">$ 98.1<span></span>
</td>
<td class="nump">$ 100.4<span></span>
</td>
</tr>
</table>
<div style="display: none;">
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_ContractWithCustomerLiabilityAbstract">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ContractWithCustomerLiabilityAbstract</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
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<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:stringItemType</td>
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<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
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<td><strong> Period Type:</strong></td>
<td>duration</td>
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<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_ContractWithCustomerLiabilityRevenueRecognized">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of revenue recognized that was previously included in balance of obligation to transfer good or service to customer for which consideration from customer has been received or is due.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 606<br> -SubTopic 10<br> -Section 50<br> -Paragraph 8<br> -Subparagraph (b)<br> -URI http://asc.fasb.org/extlink&amp;oid=123351226&amp;loc=SL49130549-203045<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ContractWithCustomerLiabilityRevenueRecognized</td>
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<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
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<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
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<td><strong> Balance Type:</strong></td>
<td>credit</td>
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<td>duration</td>
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<span style="display: none;">v3.22.0.1</span><table class="report" border="0" cellspacing="2" id="idm139691007619704">
<tr>
<th class="tl" colspan="1" rowspan="2"><div style="width: 200px;"><strong>Organization and Significant Accounting Policies, Research, Development and Patent Expenses (Details) - USD ($)<br> $ in Thousands</strong></div></th>
<th class="th" colspan="3">12 Months Ended</th>
</tr>
<tr>
<th class="th"><div>Dec. 31, 2021</div></th>
<th class="th"><div>Dec. 31, 2020</div></th>
<th class="th"><div>Dec. 31, 2019</div></th>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ResearchAndDevelopmentExpenseAbstract', window );"><strong>Research, Development and Patent Expenses [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ResearchAndDevelopmentExpense', window );">Research and development expenses</a></td>
<td class="nump">$ 638,200<span></span>
</td>
<td class="nump">$ 531,000<span></span>
</td>
<td class="nump">$ 461,500<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_FiniteLivedIntangibleAssetsFutureAmortizationExpenseAbstract', window );"><strong>Estimated Amortization Expense [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ImpairmentOfIntangibleAssetsFinitelived', window );">Non-cash charges related to write-down</a></td>
<td class="nump">2,707<span></span>
</td>
<td class="nump">1,948<span></span>
</td>
<td class="nump">2,226<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_FiniteLivedIntangibleAssetsByMajorClassAxis=us-gaap_PatentsMember', window );">Patents [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ResearchAndDevelopmentExpenseAbstract', window );"><strong>Research, Development and Patent Expenses [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ResearchAndDevelopmentExpense', window );">Research and development expenses</a></td>
<td class="nump">$ 5,300<span></span>
</td>
<td class="nump">4,100<span></span>
</td>
<td class="nump">4,200<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_FiniteLivedIntangibleAssetUsefulLife', window );">Estimated useful life</a></td>
<td class="text">10 years 2 months 12 days<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_FiniteLivedIntangibleAssetsGross', window );">Cost</a></td>
<td class="nump">$ 38,400<span></span>
</td>
<td class="nump">37,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_FiniteLivedIntangibleAssetsAccumulatedAmortization', window );">Accumulated amortization</a></td>
<td class="nump">9,400<span></span>
</td>
<td class="nump">9,100<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_FiniteLivedIntangibleAssetsFutureAmortizationExpenseAbstract', window );"><strong>Estimated Amortization Expense [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_FiniteLivedIntangibleAssetsAmortizationExpenseNextTwelveMonths', window );">2022</a></td>
<td class="nump">2,200<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_FiniteLivedIntangibleAssetsAmortizationExpenseYearTwo', window );">2023</a></td>
<td class="nump">2,100<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_FiniteLivedIntangibleAssetsAmortizationExpenseYearThree', window );">2024</a></td>
<td class="nump">1,900<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_FiniteLivedIntangibleAssetsAmortizationExpenseYearFour', window );">2025</a></td>
<td class="nump">1,800<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_FiniteLivedIntangibleAssetsAmortizationExpenseYearFive', window );">2026</a></td>
<td class="nump">1,800<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ImpairmentOfIntangibleAssetsFinitelived', window );">Non-cash charges related to write-down</a></td>
<td class="nump">$ 2,700<span></span>
</td>
<td class="nump">$ 1,900<span></span>
</td>
<td class="nump">$ 2,200<span></span>
</td>
</tr>
</table>
<div style="display: none;">
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_FiniteLivedIntangibleAssetUsefulLife">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Useful life of finite-lived intangible assets, in 'PnYnMnDTnHnMnS' format, for example, 'P1Y5M13D' represents the reported fact of one year, five months, and thirteen days.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_FiniteLivedIntangibleAssetUsefulLife</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:durationItemType</td>
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<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
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<td><strong> Period Type:</strong></td>
<td>duration</td>
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<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_FiniteLivedIntangibleAssetsAccumulatedAmortization">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Accumulated amount of amortization of assets, excluding financial assets and goodwill, lacking physical substance with a finite life.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 350<br> -SubTopic 30<br> -Section 50<br> -Paragraph 2<br> -Subparagraph (a)(1)<br> -URI http://asc.fasb.org/extlink&amp;oid=66006027&amp;loc=d3e16323-109275<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_FiniteLivedIntangibleAssetsAccumulatedAmortization</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
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<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of amortization for assets, excluding financial assets and goodwill, lacking physical substance with finite life expected to be recognized in next fiscal year following current fiscal year. Excludes interim and annual periods when interim periods are reported from current statement of financial position date (rolling approach).</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 350<br> -SubTopic 30<br> -Section 50<br> -Paragraph 2<br> -Subparagraph (a)(3)<br> -URI http://asc.fasb.org/extlink&amp;oid=66006027&amp;loc=d3e16323-109275<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_FiniteLivedIntangibleAssetsAmortizationExpenseNextTwelveMonths</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
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<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_FiniteLivedIntangibleAssetsAmortizationExpenseYearFive">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of amortization for assets, excluding financial assets and goodwill, lacking physical substance with finite life expected to be recognized in fifth fiscal year following current fiscal year. Excludes interim and annual periods when interim periods are reported from current statement of financial position date (rolling approach).</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 350<br> -SubTopic 30<br> -Section 50<br> -Paragraph 2<br> -Subparagraph (a)(3)<br> -URI http://asc.fasb.org/extlink&amp;oid=66006027&amp;loc=d3e16323-109275<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_FiniteLivedIntangibleAssetsAmortizationExpenseYearFive</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
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<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_FiniteLivedIntangibleAssetsAmortizationExpenseYearFour">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of amortization for assets, excluding financial assets and goodwill, lacking physical substance with finite life expected to be recognized in fourth fiscal year following current fiscal year. Excludes interim and annual periods when interim periods are reported from current statement of financial position date (rolling approach).</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 350<br> -SubTopic 30<br> -Section 50<br> -Paragraph 2<br> -Subparagraph (a)(3)<br> -URI http://asc.fasb.org/extlink&amp;oid=66006027&amp;loc=d3e16323-109275<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_FiniteLivedIntangibleAssetsAmortizationExpenseYearFour</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
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<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_FiniteLivedIntangibleAssetsAmortizationExpenseYearThree">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of amortization for assets, excluding financial assets and goodwill, lacking physical substance with finite life expected to be recognized in third fiscal year following current fiscal year. Excludes interim and annual periods when interim periods are reported from current statement of financial position date (rolling approach).</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 350<br> -SubTopic 30<br> -Section 50<br> -Paragraph 2<br> -Subparagraph (a)(3)<br> -URI http://asc.fasb.org/extlink&amp;oid=66006027&amp;loc=d3e16323-109275<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_FiniteLivedIntangibleAssetsAmortizationExpenseYearThree</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
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<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of amortization for assets, excluding financial assets and goodwill, lacking physical substance with finite life expected to be recognized in second fiscal year following current fiscal year. Excludes interim and annual periods when interim periods are reported from current statement of financial position date (rolling approach).</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 350<br> -SubTopic 30<br> -Section 50<br> -Paragraph 2<br> -Subparagraph (a)(3)<br> -URI http://asc.fasb.org/extlink&amp;oid=66006027&amp;loc=d3e16323-109275<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_FiniteLivedIntangibleAssetsAmortizationExpenseYearTwo</td>
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<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
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<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
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<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
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<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
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<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_FiniteLivedIntangibleAssetsFutureAmortizationExpenseAbstract">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_FiniteLivedIntangibleAssetsFutureAmortizationExpenseAbstract</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
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<td>xbrli:stringItemType</td>
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<td>na</td>
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<td><strong> Period Type:</strong></td>
<td>duration</td>
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</div></td></tr>
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<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_FiniteLivedIntangibleAssetsGross">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount before amortization of assets, excluding financial assets and goodwill, lacking physical substance with a finite life.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 928<br> -SubTopic 340<br> -Section 50<br> -Paragraph 1<br> -URI http://asc.fasb.org/extlink&amp;oid=6473545&amp;loc=d3e61844-108004<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 350<br> -SubTopic 30<br> -Section 50<br> -Paragraph 2<br> -Subparagraph (a)(1)<br> -URI http://asc.fasb.org/extlink&amp;oid=66006027&amp;loc=d3e16323-109275<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_FiniteLivedIntangibleAssetsGross</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
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<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
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</div></td></tr>
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<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_ImpairmentOfIntangibleAssetsFinitelived">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The amount of impairment loss recognized in the period resulting from the write-down of the carrying amount of a finite-lived intangible asset to fair value.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2009/role/commonPracticeRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 230<br> -SubTopic 10<br> -Section 45<br> -Paragraph 28<br> -Subparagraph (b)<br> -URI http://asc.fasb.org/extlink&amp;oid=123570139&amp;loc=d3e3602-108585<br><br>Reference 2: http://www.xbrl.org/2009/role/commonPracticeRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 350<br> -SubTopic 30<br> -Section 50<br> -Paragraph 3<br> -Subparagraph (b)<br> -URI http://asc.fasb.org/extlink&amp;oid=66006027&amp;loc=d3e16373-109275<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ImpairmentOfIntangibleAssetsFinitelived</td>
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<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
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<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The aggregate costs incurred (1) in a planned search or critical investigation aimed at discovery of new knowledge with the hope that such knowledge will be useful in developing a new product or service, a new process or technique, or in bringing about a significant improvement to an existing product or process; or (2) to translate research findings or other knowledge into a plan or design for a new product or process or for a significant improvement to an existing product or process whether intended for sale or the entity's use, during the reporting period charged to research and development projects, including the costs of developing computer software up to the point in time of achieving technological feasibility, and costs allocated in accounting for a business combination to in-process projects deemed to have no alternative future use.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2009/role/commonPracticeRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 912<br> -SubTopic 730<br> -Section 25<br> -Paragraph 1<br> -URI http://asc.fasb.org/extlink&amp;oid=6472174&amp;loc=d3e58812-109433<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 985<br> -SubTopic 20<br> -Section 50<br> -Paragraph 1<br> -URI http://asc.fasb.org/extlink&amp;oid=6501960&amp;loc=d3e128462-111756<br><br>Reference 3: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 730<br> -SubTopic 10<br> -Section 50<br> -Paragraph 1<br> -URI http://asc.fasb.org/extlink&amp;oid=6420194&amp;loc=d3e21568-108373<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ResearchAndDevelopmentExpense</td>
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<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
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<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_ResearchAndDevelopmentExpenseAbstract">
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<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ResearchAndDevelopmentExpenseAbstract</td>
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<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
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<td>xbrli:stringItemType</td>
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<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_FiniteLivedIntangibleAssetsByMajorClassAxis=us-gaap_PatentsMember</td>
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<span style="display: none;">v3.22.0.1</span><table class="report" border="0" cellspacing="2" id="idm139691008684024">
<tr>
<th class="tl" colspan="1" rowspan="1"><div style="width: 200px;"><strong>Organization and Significant Accounting Policies, Accrued Liabilities (Details) - USD ($)<br> $ in Thousands</strong></div></th>
<th class="th"><div>Dec. 31, 2021</div></th>
<th class="th"><div>Dec. 31, 2020</div></th>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AccruedLiabilitiesCurrentAbstract', window );"><strong>Accrued Liabilities [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_AccruedClinicalExpenses', window );">Clincial expenses</a></td>
<td class="nump">$ 65,730<span></span>
</td>
<td class="nump">$ 39,477<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_AccruedInLicensingFeesCurrent', window );">In-licensing expenses</a></td>
<td class="nump">8,044<span></span>
</td>
<td class="nump">8,264<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_AccruedCommercialExpensesCurrent', window );">Commercial expenses</a></td>
<td class="nump">2,471<span></span>
</td>
<td class="nump">11,559<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_OtherAccruedLiabilitiesCurrent', window );">Other miscellaneous expenses</a></td>
<td class="nump">12,315<span></span>
</td>
<td class="nump">30,861<span></span>
</td>
</tr>
<tr class="rou">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AccruedLiabilitiesCurrent', window );">Total accrued liabilities</a></td>
<td class="nump">$ 88,560<span></span>
</td>
<td class="nump">$ 90,161<span></span>
</td>
</tr>
</table>
<div style="display: none;">
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_AccruedClinicalExpenses">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Carrying value as of the balance sheet date of obligations incurred through that date and payable for clinical expenses. Used to reflect the current portion of the liabilities (due within one year or within the normal operating cycle if longer).</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_AccruedClinicalExpenses</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
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<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
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<td><strong> Balance Type:</strong></td>
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<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
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<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Carrying value as of the balance sheet date of obligations incurred through that date and payable for commercial expenses. Used to reflect the current portion of the liabilities (due within one year or within the normal operating cycle if longer).</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_AccruedCommercialExpensesCurrent</td>
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<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
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<td>credit</td>
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<td><strong> Period Type:</strong></td>
<td>instant</td>
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<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Carrying value as of the balance sheet date of obligations incurred through that date and payable for in-licensing fees under collaboration agreements. Used to reflect the current portion of the liabilities (due within one year or within the normal operating cycle if longer).</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_AccruedInLicensingFeesCurrent</td>
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<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
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<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Carrying value as of the balance sheet date of obligations incurred and payable, pertaining to costs that are statutory in nature, are incurred on contractual obligations, or accumulate over time and for which invoices have not yet been received or will not be rendered. Examples include taxes, interest, rent and utilities. Used to reflect the current portion of the liabilities (due within one year or within the normal operating cycle if longer).</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 210<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.5-02.20)<br> -URI http://asc.fasb.org/extlink&amp;oid=120391452&amp;loc=d3e13212-122682<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_AccruedLiabilitiesCurrent</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
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<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
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<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_AccruedLiabilitiesCurrentAbstract</td>
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<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
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<td><strong> Data Type:</strong></td>
<td>xbrli:stringItemType</td>
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<td><strong> Balance Type:</strong></td>
<td>na</td>
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<td><strong> Period Type:</strong></td>
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<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of expenses incurred but not yet paid classified as other, due within one year or the normal operating cycle, if longer.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 210<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.5-02.20)<br> -URI http://asc.fasb.org/extlink&amp;oid=120391452&amp;loc=d3e13212-122682<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 210<br> -SubTopic 10<br> -Section 45<br> -Paragraph 6<br> -URI http://asc.fasb.org/extlink&amp;oid=124098289&amp;loc=d3e6911-107765<br><br>Reference 3: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 210<br> -SubTopic 10<br> -Section 45<br> -Paragraph 9<br> -URI http://asc.fasb.org/extlink&amp;oid=124098289&amp;loc=d3e7018-107765<br><br>Reference 4: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 210<br> -SubTopic 10<br> -Section 45<br> -Paragraph 8<br> -URI http://asc.fasb.org/extlink&amp;oid=124098289&amp;loc=d3e6935-107765<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
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<span style="display: none;">v3.22.0.1</span><table class="report" border="0" cellspacing="2" id="idm139691001103304">
<tr>
<th class="tl" colspan="1" rowspan="1"><div style="width: 200px;"><strong>Organization and Significant Accounting Policies, Noncontrolling Interest in Akcea Therapeutics, Inc. (Details) - Akcea [Member]<br></strong></div></th>
<th class="th"><div>Dec. 31, 2021</div></th>
<th class="th"><div>Oct. 31, 2020</div></th>
<th class="th"><div>Sep. 30, 2020</div></th>
<th class="th"><div>Jun. 30, 2017</div></th>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ProceedsFromIssuanceOrSaleOfEquityAbstract', window );"><strong>Noncontrolling Interest in Akcea Therapeutics, Inc. [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
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<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_MinorityInterestOwnershipPercentageByParent', window );">Percentage ownership</a></td>
<td class="nump">100.00%<span></span>
</td>
<td class="nump">100.00%<span></span>
</td>
<td class="nump">76.00%<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_srt_OwnershipAxis=ions_AkceaTherapeuticsIncMember', window );">Minimum [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ProceedsFromIssuanceOrSaleOfEquityAbstract', window );"><strong>Noncontrolling Interest in Akcea Therapeutics, Inc. [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_MinorityInterestOwnershipPercentageByParent', window );">Percentage ownership</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">68.00%<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
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<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_srt_OwnershipAxis=ions_AkceaTherapeuticsIncMember', window );">Maximum [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ProceedsFromIssuanceOrSaleOfEquityAbstract', window );"><strong>Noncontrolling Interest in Akcea Therapeutics, Inc. [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
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<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_MinorityInterestOwnershipPercentageByParent', window );">Percentage ownership</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">77.00%<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">100.00%<span></span>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The parent entity's interest in net assets of the subsidiary, expressed as a percentage.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ProceedsFromIssuanceOrSaleOfEquityAbstract</td>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
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<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">srt_RangeAxis=srt_MinimumMember</td>
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<html>
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<link rel="stylesheet" type="text/css" href="report.css">
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<span style="display: none;">v3.22.0.1</span><table class="report" border="0" cellspacing="2" id="idm139691008049048">
<tr>
<th class="tl" colspan="1" rowspan="2"><div style="width: 200px;"><strong>Organization and Significant Accounting Policies, Cash, Cash Equivalents and Investments (Details)<br> $ in Thousands</strong></div></th>
<th class="th" colspan="3">12 Months Ended</th>
</tr>
<tr>
<th class="th">
<div>Dec. 31, 2021 </div>
<div>USD ($) </div>
<div>Company</div>
</th>
<th class="th">
<div>Dec. 31, 2020 </div>
<div>USD ($) </div>
<div>Investment</div>
</th>
<th class="th">
<div>Dec. 31, 2019 </div>
<div>USD ($)</div>
</th>
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<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_CashCashEquivalentsAndShortTermInvestmentsAbstract', window );"><strong>Cash, Cash Equivalents and Investments [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
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<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_NumberOfPubliclyHeldCompaniesInWhichEntityHasEquityInvestment', window );">Number of publicly held companies in which there is an equity ownership interest of less than 20% | Company</a></td>
<td class="nump">3<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
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<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_NumberOfPrivatelyHeldCompaniesInWhichEntityHasEquityInvestment', window );">Number of privately held companies in which there is an equity ownership interest of less than 20% | Company</a></td>
<td class="nump">7<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_NumberOfInvestmentsInPrivatelyHeldCompaniesThatWereRevalued', window );">Number of investments in privately held companies that were revalued | Investment</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">3<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_GainLossOnInvestments', window );">Gain on investment</a></td>
<td class="nump">$ 10,103<span></span>
</td>
<td class="nump">$ 16,540<span></span>
</td>
<td class="nump">$ 192<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_FinancialInstrumentAxis=ions_DynacureSasMember', window );">Dynacure [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_CashCashEquivalentsAndShortTermInvestmentsAbstract', window );"><strong>Cash, Cash Equivalents and Investments [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_GainLossOnInvestments', window );">Gain on investment</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">6,300<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_FinancialInstrumentAxis=ions_SuzhouRiboLifeScienceCoLtdMember', window );">Suzhou-Ribo [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_CashCashEquivalentsAndShortTermInvestmentsAbstract', window );"><strong>Cash, Cash Equivalents and Investments [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_GainLossOnInvestments', window );">Gain on investment</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">3,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_FinancialInstrumentAxis=ions_AroBiotherapeuticsMember', window );">Aro Biotherapeutics [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_CashCashEquivalentsAndShortTermInvestmentsAbstract', window );"><strong>Cash, Cash Equivalents and Investments [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_GainLossOnInvestments', window );">Gain on investment</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 5,500<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
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<div style="display: none;">
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_NumberOfInvestmentsInPrivatelyHeldCompaniesThatWereRevalued">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Number of investments in privately-held companies that were revalued since the companies sold additional equity securities.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_NumberOfInvestmentsInPrivatelyHeldCompaniesThatWereRevalued</td>
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<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Number of privately-held companies, in which the entity has an equity ownership interest of less than 20%, with which it conducts business. These are accounted for under the cost method.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Number of publicly-held companies, in which the entity has an equity ownership interest of less than 20%, with which it conducts business. These are accounted for at fair value.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
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<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_CashCashEquivalentsAndShortTermInvestmentsAbstract</td>
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<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of realized and unrealized gain (loss) on investment.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 320<br> -SubTopic 10<br> -Section 50<br> -Paragraph 10<br> -Subparagraph (c)<br> -URI http://asc.fasb.org/extlink&amp;oid=123581744&amp;loc=d3e27405-111563<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 220<br> -SubTopic 10<br> -Section S99<br> -Paragraph 2<br> -Subparagraph (SX 210.5-03.7(c),9(a))<br> -URI http://asc.fasb.org/extlink&amp;oid=123367319&amp;loc=SL114868664-224227<br><br>Reference 3: http://www.xbrl.org/2003/role/recommendedDisclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 230<br> -SubTopic 10<br> -Section 45<br> -Paragraph 28<br> -Subparagraph (b)<br> -URI http://asc.fasb.org/extlink&amp;oid=123570139&amp;loc=d3e3602-108585<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_GainLossOnInvestments</td>
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<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
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<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
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<td><strong> Name:</strong></td>
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<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
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<td><strong> Data Type:</strong></td>
<td>na</td>
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<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
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<td><strong> Data Type:</strong></td>
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<span style="display: none;">v3.22.0.1</span><table class="report" border="0" cellspacing="2" id="idm139691017358968">
<tr>
<th class="tl" colspan="1" rowspan="2"><div style="width: 200px;"><strong>Organization and Significant Accounting Policies, Inventory Valuation (Details) - USD ($)<br> $ in Thousands</strong></div></th>
<th class="th" colspan="2">12 Months Ended</th>
</tr>
<tr>
<th class="th"><div>Dec. 31, 2021</div></th>
<th class="th"><div>Dec. 31, 2020</div></th>
</tr>
<tr class="re">
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<td class="text">&#160;<span></span>
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<td class="text">&#160;<span></span>
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<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_InventoryWriteDown', window );">Inventory write-off</a></td>
<td class="text"> <span></span>
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<td class="text"> <span></span>
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<td class="nump">18,646<span></span>
</td>
<td class="nump">16,708<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_InventoryWorkInProcess', window );">Work in process</a></td>
<td class="nump">5,770<span></span>
</td>
<td class="nump">2,252<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_InventoryFinishedGoods', window );">Finished goods</a></td>
<td class="nump">390<span></span>
</td>
<td class="nump">3,005<span></span>
</td>
</tr>
<tr class="rou">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_InventoryNet', window );">Total inventory</a></td>
<td class="nump">24,806<span></span>
</td>
<td class="nump">21,965<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_PublicUtilitiesInventoryAxis=ions_ClinicalRawMaterialsMember', window );">Clinical [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_InventoryNetAbstract', window );"><strong>Inventory Valuation [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
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<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_InventoryRawMaterials', window );">Raw materials</a></td>
<td class="nump">14,507<span></span>
</td>
<td class="nump">9,206<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_PublicUtilitiesInventoryAxis=ions_CommercialRawMaterialsMember', window );">Commercial [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
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<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_InventoryNetAbstract', window );"><strong>Inventory Valuation [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
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<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_InventoryRawMaterials', window );">Raw materials</a></td>
<td class="nump">$ 4,139<span></span>
</td>
<td class="nump">$ 7,502<span></span>
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<div style="display: none;">
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_InventoryFinishedGoods">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount before valuation and LIFO reserves of completed merchandise or goods expected to be sold within one year or operating cycle, if longer.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 210<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.5-02.6(a)(1))<br> -URI http://asc.fasb.org/extlink&amp;oid=120391452&amp;loc=d3e13212-122682<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_InventoryFinishedGoods</td>
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<td>instant</td>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount after valuation and LIFO reserves of inventory expected to be sold, or consumed within one year or operating cycle, if longer.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 210<br> -SubTopic 10<br> -Section 45<br> -Paragraph 1<br> -Subparagraph (b)<br> -URI http://asc.fasb.org/extlink&amp;oid=124098289&amp;loc=d3e6676-107765<br><br>Reference 2: http://www.xbrl.org/2003/role/exampleRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 852<br> -SubTopic 10<br> -Section 55<br> -Paragraph 10<br> -URI http://asc.fasb.org/extlink&amp;oid=84165509&amp;loc=d3e56426-112766<br><br>Reference 3: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 210<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.5-02.6(a))<br> -URI http://asc.fasb.org/extlink&amp;oid=120391452&amp;loc=d3e13212-122682<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
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<td>xbrli:monetaryItemType</td>
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<td><strong> Balance Type:</strong></td>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount before valuation and LIFO reserves of raw materials expected to be sold, or consumed within one year or operating cycle, if longer.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 210<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.5-02.6(a)(4))<br> -URI http://asc.fasb.org/extlink&amp;oid=120391452&amp;loc=d3e13212-122682<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
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<td>debit</td>
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<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_InventoryWorkInProcess">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount before valuation and LIFO reserves of merchandise or goods in the production process expected to be completed within one year or operating cycle, if longer.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 210<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.5-02.6(a)(3))<br> -URI http://asc.fasb.org/extlink&amp;oid=120391452&amp;loc=d3e13212-122682<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_InventoryWorkInProcess</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_InventoryWriteDown">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of loss from reductions in inventory due to subsequent measurement adjustments, including, but not limited to, physical deterioration, obsolescence, or changes in price levels.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 330<br> -SubTopic 10<br> -Section 50<br> -Paragraph 2<br> -URI http://asc.fasb.org/extlink&amp;oid=116847112&amp;loc=d3e4542-108314<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_InventoryWriteDown</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_PublicUtilitiesInventoryAxis=ions_ClinicalRawMaterialsMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_PublicUtilitiesInventoryAxis=ions_ClinicalRawMaterialsMember</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td></td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_PublicUtilitiesInventoryAxis=ions_CommercialRawMaterialsMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_PublicUtilitiesInventoryAxis=ions_CommercialRawMaterialsMember</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td></td>
</tr>
</table></div>
</div></td></tr>
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<head>
<title></title>
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<span style="display: none;">v3.22.0.1</span><table class="report" border="0" cellspacing="2" id="idm139691002854280">
<tr>
<th class="tl" colspan="1" rowspan="2"><div style="width: 200px;"><strong>Organization and Significant Accounting Policies, Property, Plant and Equipment (Details) - USD ($)<br> $ in Thousands</strong></div></th>
<th class="th" colspan="1">12 Months Ended</th>
<th class="th" colspan="1"></th>
</tr>
<tr>
<th class="th"><div>Dec. 31, 2021</div></th>
<th class="th"><div>Dec. 31, 2020</div></th>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_PropertyPlantAndEquipmentAbstract', window );"><strong>Property, Plant and Equipment [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AccumulatedDepreciationDepletionAndAmortizationPropertyPlantAndEquipment', window );">Less accumulated depreciation</a></td>
<td class="num">$ (102,653)<span></span>
</td>
<td class="num">$ (87,379)<span></span>
</td>
</tr>
<tr class="reu">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_PropertyPlantAndEquipmentNet', window );">Property, plant and equipment, net</a></td>
<td class="nump">178,069<span></span>
</td>
<td class="nump">181,077<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_PropertyPlantAndEquipmentByTypeAxis=ions_PropertyPlantAndEquipmentExcludingLandMember', window );">Property, Plant and Equipment, Excluding Land [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_PropertyPlantAndEquipmentAbstract', window );"><strong>Property, Plant and Equipment [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_PropertyPlantAndEquipmentGross', window );">Property, plant and equipment</a></td>
<td class="nump">257,660<span></span>
</td>
<td class="nump">245,394<span></span>
</td>
</tr>
<tr class="reu">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_PropertyPlantAndEquipmentNet', window );">Property, plant and equipment, net</a></td>
<td class="nump">155,007<span></span>
</td>
<td class="nump">158,015<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_PropertyPlantAndEquipmentByTypeAxis=ions_EquipmentAndComputerSoftwareMember', window );">Computer Software, Laboratory, Manufacturing and Other Equipment [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_PropertyPlantAndEquipmentAbstract', window );"><strong>Property, Plant and Equipment [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_PropertyPlantAndEquipmentGross', window );">Property, plant and equipment</a></td>
<td class="nump">$ 72,802<span></span>
</td>
<td class="nump">68,990<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_PropertyPlantAndEquipmentByTypeAxis=ions_EquipmentAndComputerSoftwareMember', window );">Computer Software, Laboratory, Manufacturing and Other Equipment [Member] | Minimum [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_PropertyPlantAndEquipmentAbstract', window );"><strong>Property, Plant and Equipment [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_PropertyPlantAndEquipmentUsefulLife', window );">Estimated useful lives</a></td>
<td class="text">3 years<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_PropertyPlantAndEquipmentByTypeAxis=ions_EquipmentAndComputerSoftwareMember', window );">Computer Software, Laboratory, Manufacturing and Other Equipment [Member] | Maximum [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_PropertyPlantAndEquipmentAbstract', window );"><strong>Property, Plant and Equipment [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_PropertyPlantAndEquipmentUsefulLife', window );">Estimated useful lives</a></td>
<td class="text">10 years<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_PropertyPlantAndEquipmentByTypeAxis=us-gaap_BuildingAndBuildingImprovementsMember', window );">Building, Building Improvements and Building Systems [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_PropertyPlantAndEquipmentAbstract', window );"><strong>Property, Plant and Equipment [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_PropertyPlantAndEquipmentGross', window );">Property, plant and equipment</a></td>
<td class="nump">$ 144,046<span></span>
</td>
<td class="nump">137,879<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_PropertyPlantAndEquipmentByTypeAxis=us-gaap_BuildingAndBuildingImprovementsMember', window );">Building, Building Improvements and Building Systems [Member] | Minimum [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_PropertyPlantAndEquipmentAbstract', window );"><strong>Property, Plant and Equipment [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_PropertyPlantAndEquipmentUsefulLife', window );">Estimated useful lives</a></td>
<td class="text">15 years<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_PropertyPlantAndEquipmentByTypeAxis=us-gaap_BuildingAndBuildingImprovementsMember', window );">Building, Building Improvements and Building Systems [Member] | Maximum [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_PropertyPlantAndEquipmentAbstract', window );"><strong>Property, Plant and Equipment [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_PropertyPlantAndEquipmentUsefulLife', window );">Estimated useful lives</a></td>
<td class="text">40 years<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_PropertyPlantAndEquipmentByTypeAxis=us-gaap_LandImprovementsMember', window );">Land Improvements [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_PropertyPlantAndEquipmentAbstract', window );"><strong>Property, Plant and Equipment [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_PropertyPlantAndEquipmentGross', window );">Property, plant and equipment</a></td>
<td class="nump">$ 10,077<span></span>
</td>
<td class="nump">8,391<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_PropertyPlantAndEquipmentUsefulLife', window );">Estimated useful lives</a></td>
<td class="text">20 years<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_PropertyPlantAndEquipmentByTypeAxis=us-gaap_LeaseholdImprovementsMember', window );">Leasehold Improvements [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_PropertyPlantAndEquipmentAbstract', window );"><strong>Property, Plant and Equipment [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_PropertyPlantAndEquipmentGross', window );">Property, plant and equipment</a></td>
<td class="nump">$ 20,144<span></span>
</td>
<td class="nump">17,263<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_PropertyPlantAndEquipmentByTypeAxis=us-gaap_LeaseholdImprovementsMember', window );">Leasehold Improvements [Member] | Minimum [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_PropertyPlantAndEquipmentAbstract', window );"><strong>Property, Plant and Equipment [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_PropertyPlantAndEquipmentUsefulLife', window );">Estimated useful lives</a></td>
<td class="text">5 years<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_PropertyPlantAndEquipmentByTypeAxis=us-gaap_LeaseholdImprovementsMember', window );">Leasehold Improvements [Member] | Maximum [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_PropertyPlantAndEquipmentAbstract', window );"><strong>Property, Plant and Equipment [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_PropertyPlantAndEquipmentUsefulLife', window );">Estimated useful lives</a></td>
<td class="text">15 years<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_PropertyPlantAndEquipmentByTypeAxis=us-gaap_FurnitureAndFixturesMember', window );">Furniture and Fixtures [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_PropertyPlantAndEquipmentAbstract', window );"><strong>Property, Plant and Equipment [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_PropertyPlantAndEquipmentGross', window );">Property, plant and equipment</a></td>
<td class="nump">$ 10,591<span></span>
</td>
<td class="nump">12,871<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_PropertyPlantAndEquipmentByTypeAxis=us-gaap_FurnitureAndFixturesMember', window );">Furniture and Fixtures [Member] | Minimum [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_PropertyPlantAndEquipmentAbstract', window );"><strong>Property, Plant and Equipment [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_PropertyPlantAndEquipmentUsefulLife', window );">Estimated useful lives</a></td>
<td class="text">5 years<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_PropertyPlantAndEquipmentByTypeAxis=us-gaap_FurnitureAndFixturesMember', window );">Furniture and Fixtures [Member] | Maximum [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_PropertyPlantAndEquipmentAbstract', window );"><strong>Property, Plant and Equipment [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_PropertyPlantAndEquipmentUsefulLife', window );">Estimated useful lives</a></td>
<td class="text">10 years<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_PropertyPlantAndEquipmentByTypeAxis=us-gaap_LandMember', window );">Land [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_PropertyPlantAndEquipmentAbstract', window );"><strong>Property, Plant and Equipment [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_PropertyPlantAndEquipmentGross', window );">Property, plant and equipment</a></td>
<td class="nump">$ 23,062<span></span>
</td>
<td class="nump">$ 23,062<span></span>
</td>
</tr>
</table>
<div style="display: none;">
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_AccumulatedDepreciationDepletionAndAmortizationPropertyPlantAndEquipment">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of accumulated depreciation, depletion and amortization for physical assets used in the normal conduct of business to produce goods and services.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 360<br> -SubTopic 10<br> -Section 50<br> -Paragraph 1<br> -Subparagraph (c)<br> -URI http://asc.fasb.org/extlink&amp;oid=6391035&amp;loc=d3e2868-110229<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 210<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.5-02.14)<br> -URI http://asc.fasb.org/extlink&amp;oid=120391452&amp;loc=d3e13212-122682<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_AccumulatedDepreciationDepletionAndAmortizationPropertyPlantAndEquipment</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_PropertyPlantAndEquipmentAbstract">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_PropertyPlantAndEquipmentAbstract</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:stringItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_PropertyPlantAndEquipmentGross">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount before accumulated depreciation, depletion and amortization of physical assets used in the normal conduct of business and not intended for resale. Examples include, but are not limited to, land, buildings, machinery and equipment, office equipment, and furniture and fixtures.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 360<br> -SubTopic 10<br> -Section 50<br> -Paragraph 1<br> -Subparagraph (b)<br> -URI http://asc.fasb.org/extlink&amp;oid=6391035&amp;loc=d3e2868-110229<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 210<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.5-02.13)<br> -URI http://asc.fasb.org/extlink&amp;oid=120391452&amp;loc=d3e13212-122682<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_PropertyPlantAndEquipmentGross</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_PropertyPlantAndEquipmentNet">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount after accumulated depreciation, depletion and amortization of physical assets used in the normal conduct of business to produce goods and services and not intended for resale. Examples include, but are not limited to, land, buildings, machinery and equipment, office equipment, and furniture and fixtures.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 210<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.5-02(14))<br> -URI http://asc.fasb.org/extlink&amp;oid=120391452&amp;loc=d3e13212-122682<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 360<br> -SubTopic 10<br> -Section 50<br> -Paragraph 1<br> -URI http://asc.fasb.org/extlink&amp;oid=6391035&amp;loc=d3e2868-110229<br><br>Reference 3: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 944<br> -SubTopic 210<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.7-03(a)(8))<br> -URI http://asc.fasb.org/extlink&amp;oid=120400017&amp;loc=d3e572229-122910<br><br>Reference 4: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 942<br> -SubTopic 360<br> -Section 50<br> -Paragraph 1<br> -URI http://asc.fasb.org/extlink&amp;oid=124429447&amp;loc=SL124453093-239630<br><br>Reference 5: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 210<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.5-02(13))<br> -URI http://asc.fasb.org/extlink&amp;oid=120391452&amp;loc=d3e13212-122682<br><br>Reference 6: http://www.xbrl.org/2003/role/exampleRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 852<br> -SubTopic 10<br> -Section 55<br> -Paragraph 10<br> -URI http://asc.fasb.org/extlink&amp;oid=84165509&amp;loc=d3e56426-112766<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_PropertyPlantAndEquipmentNet</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_PropertyPlantAndEquipmentUsefulLife">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Useful life of long lived, physical assets used in the normal conduct of business and not intended for resale, in 'PnYnMnDTnHnMnS' format, for example, 'P1Y5M13D' represents the reported fact of one year, five months, and thirteen days. Examples include, but not limited to, land, buildings, machinery and equipment, office equipment, furniture and fixtures, and computer equipment.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_PropertyPlantAndEquipmentUsefulLife</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:durationItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_PropertyPlantAndEquipmentByTypeAxis=ions_PropertyPlantAndEquipmentExcludingLandMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_PropertyPlantAndEquipmentByTypeAxis=ions_PropertyPlantAndEquipmentExcludingLandMember</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td></td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_PropertyPlantAndEquipmentByTypeAxis=ions_EquipmentAndComputerSoftwareMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_PropertyPlantAndEquipmentByTypeAxis=ions_EquipmentAndComputerSoftwareMember</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td></td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_srt_RangeAxis=srt_MinimumMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">srt_RangeAxis=srt_MinimumMember</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td></td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_srt_RangeAxis=srt_MaximumMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">srt_RangeAxis=srt_MaximumMember</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td></td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_PropertyPlantAndEquipmentByTypeAxis=us-gaap_BuildingAndBuildingImprovementsMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_PropertyPlantAndEquipmentByTypeAxis=us-gaap_BuildingAndBuildingImprovementsMember</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td></td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_PropertyPlantAndEquipmentByTypeAxis=us-gaap_LandImprovementsMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_PropertyPlantAndEquipmentByTypeAxis=us-gaap_LandImprovementsMember</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td></td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_PropertyPlantAndEquipmentByTypeAxis=us-gaap_LeaseholdImprovementsMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_PropertyPlantAndEquipmentByTypeAxis=us-gaap_LeaseholdImprovementsMember</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td></td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_PropertyPlantAndEquipmentByTypeAxis=us-gaap_FurnitureAndFixturesMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_PropertyPlantAndEquipmentByTypeAxis=us-gaap_FurnitureAndFixturesMember</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td></td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_PropertyPlantAndEquipmentByTypeAxis=us-gaap_LandMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_PropertyPlantAndEquipmentByTypeAxis=us-gaap_LandMember</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td></td>
</tr>
</table></div>
</div></td></tr>
</table>
</div>
</body>
</html>
</TEXT>
</DOCUMENT>
<DOCUMENT>
<TYPE>XML
<SEQUENCE>72
<FILENAME>R42.htm
<DESCRIPTION>IDEA: XBRL DOCUMENT
<TEXT>
<html>
<head>
<title></title>
<link rel="stylesheet" type="text/css" href="report.css">
<script type="text/javascript" src="Show.js">/* Do Not Remove This Comment */</script><script type="text/javascript">
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<span style="display: none;">v3.22.0.1</span><table class="report" border="0" cellspacing="2" id="idm139691015190312">
<tr>
<th class="tl" colspan="1" rowspan="2"><div style="width: 200px;"><strong>Organization and Significant Accounting Policies, Long-Lived Assets (Details) - USD ($)<br> $ in Thousands</strong></div></th>
<th class="th" colspan="3">12 Months Ended</th>
</tr>
<tr>
<th class="th"><div>Dec. 31, 2021</div></th>
<th class="th"><div>Dec. 31, 2020</div></th>
<th class="th"><div>Dec. 31, 2019</div></th>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AssetImpairmentChargesAbstract', window );"><strong>Long-Lived Assets [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ImpairmentOfIntangibleAssetsFinitelived', window );">Charges related to write-down of patents</a></td>
<td class="nump">$ 2,707<span></span>
</td>
<td class="nump">$ 1,948<span></span>
</td>
<td class="nump">$ 2,226<span></span>
</td>
</tr>
</table>
<div style="display: none;">
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_AssetImpairmentChargesAbstract">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_AssetImpairmentChargesAbstract</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:stringItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_ImpairmentOfIntangibleAssetsFinitelived">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The amount of impairment loss recognized in the period resulting from the write-down of the carrying amount of a finite-lived intangible asset to fair value.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2009/role/commonPracticeRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 230<br> -SubTopic 10<br> -Section 45<br> -Paragraph 28<br> -Subparagraph (b)<br> -URI http://asc.fasb.org/extlink&amp;oid=123570139&amp;loc=d3e3602-108585<br><br>Reference 2: http://www.xbrl.org/2009/role/commonPracticeRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 350<br> -SubTopic 30<br> -Section 50<br> -Paragraph 3<br> -Subparagraph (b)<br> -URI http://asc.fasb.org/extlink&amp;oid=66006027&amp;loc=d3e16373-109275<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ImpairmentOfIntangibleAssetsFinitelived</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
</div>
</body>
</html>
</TEXT>
</DOCUMENT>
<DOCUMENT>
<TYPE>XML
<SEQUENCE>73
<FILENAME>R43.htm
<DESCRIPTION>IDEA: XBRL DOCUMENT
<TEXT>
<html>
<head>
<title></title>
<link rel="stylesheet" type="text/css" href="report.css">
<script type="text/javascript" src="Show.js">/* Do Not Remove This Comment */</script><script type="text/javascript">
							function toggleNextSibling (e) {
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</head>
<body>
<span style="display: none;">v3.22.0.1</span><table class="report" border="0" cellspacing="2" id="idm139691017401400">
<tr>
<th class="tl" colspan="1" rowspan="2"><div style="width: 200px;"><strong>Organization and Significant Accounting Policies, Stock-Based Compensation Expense (Details)<br></strong></div></th>
<th class="th" colspan="2">12 Months Ended</th>
</tr>
<tr>
<th class="th">
<div>Dec. 31, 2021 </div>
<div>Period </div>
<div>$ / shares </div>
<div>shares</div>
</th>
<th class="th">
<div>Dec. 31, 2020 </div>
<div>$ / shares</div>
</th>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AwardTypeAxis=us-gaap_RestrictedStockUnitsRSUMember', window );">RSUs [Member] | Employees [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationAbstract', window );"><strong>Stock-Based Compensation Expense [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardAwardVestingPeriod1', window );">Vesting period</a></td>
<td class="text">4 years<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AwardTypeAxis=us-gaap_RestrictedStockUnitsRSUMember', window );">RSUs [Member] | Board of Directors [Member] | Granted Prior to June 2020 [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationAbstract', window );"><strong>Stock-Based Compensation Expense [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardAwardVestingPeriod1', window );">Vesting period</a></td>
<td class="text">4 years<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AwardTypeAxis=us-gaap_RestrictedStockUnitsRSUMember', window );">RSUs [Member] | Board of Directors [Member] | Granted After June 2020 [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationAbstract', window );"><strong>Stock-Based Compensation Expense [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardAwardVestingPeriod1', window );">Vesting period</a></td>
<td class="text">1 year<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AwardTypeAxis=us-gaap_PerformanceSharesMember', window );">PRSUs [Member] | Chief Executive Officer, Dr. Brett Monia [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationAbstract', window );"><strong>Stock-Based Compensation Expense [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_ShareBasedCompensationArrangementByShareBasedPaymentAwardNumberOfPerformancePeriods', window );">Number of performance periods | Period</a></td>
<td class="nump">3<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardAwardVestingPeriod1', window );">Vesting period</a></td>
<td class="text">3 years<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_ShareBasedCompensationArrangementByShareBasedPaymentAwardNumberOfUnitsGuaranteedToVest', window );">Number of units guaranteed to vest | shares</a></td>
<td class="nump">0<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsGrantsInPeriodWeightedAverageGrantDateFairValue', window );">Weighted-average grant date fair value (in dollars per share) | $ / shares</a></td>
<td class="nump">$ 77.17<span></span>
</td>
<td class="nump">$ 93.09<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AwardTypeAxis=us-gaap_PerformanceSharesMember', window );">PRSUs [Member] | Chief Executive Officer, Dr. Brett Monia [Member] | Minimum [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationAbstract', window );"><strong>Stock-Based Compensation Expense [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_ShareBasedCompensationArrangementByShareBasedPaymentAwardPercentageOfUnitsGuaranteedToVest', window );">Percentage of units guaranteed to vest</a></td>
<td class="nump">0.00%<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AwardTypeAxis=us-gaap_PerformanceSharesMember', window );">PRSUs [Member] | Chief Executive Officer, Dr. Brett Monia [Member] | Maximum [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationAbstract', window );"><strong>Stock-Based Compensation Expense [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_ShareBasedCompensationArrangementByShareBasedPaymentAwardPercentageOfUnitsGuaranteedToVest', window );">Percentage of units guaranteed to vest</a></td>
<td class="nump">150.00%<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AwardTypeAxis=us-gaap_PerformanceSharesMember', window );">PRSUs [Member] | Chief Executive Officer, Dr. Brett Monia [Member] | One-Year Period [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationAbstract', window );"><strong>Stock-Based Compensation Expense [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_SharebasedCompensationArrangementBySharebasedPaymentAwardAwardVestingRightsPercentage', window );">Vesting percentage</a></td>
<td class="nump">33.30%<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardAwardVestingPeriod1', window );">Vesting period</a></td>
<td class="text">1 year<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AwardTypeAxis=us-gaap_PerformanceSharesMember', window );">PRSUs [Member] | Chief Executive Officer, Dr. Brett Monia [Member] | Two-Year Period [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationAbstract', window );"><strong>Stock-Based Compensation Expense [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_SharebasedCompensationArrangementBySharebasedPaymentAwardAwardVestingRightsPercentage', window );">Vesting percentage</a></td>
<td class="nump">33.30%<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardAwardVestingPeriod1', window );">Vesting period</a></td>
<td class="text">2 years<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AwardTypeAxis=us-gaap_PerformanceSharesMember', window );">PRSUs [Member] | Chief Executive Officer, Dr. Brett Monia [Member] | Three-Year Period [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationAbstract', window );"><strong>Stock-Based Compensation Expense [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_SharebasedCompensationArrangementBySharebasedPaymentAwardAwardVestingRightsPercentage', window );">Vesting percentage</a></td>
<td class="nump">33.30%<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardAwardVestingPeriod1', window );">Vesting period</a></td>
<td class="text">3 years<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
</table>
<div style="display: none;">
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_ShareBasedCompensationArrangementByShareBasedPaymentAwardNumberOfPerformancePeriods">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Number of separate performance periods under share-based payment arrangement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_ShareBasedCompensationArrangementByShareBasedPaymentAwardNumberOfPerformancePeriods</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:integerItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_ShareBasedCompensationArrangementByShareBasedPaymentAwardNumberOfUnitsGuaranteedToVest">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Number of units guaranteed to vest under share-based payment arrangement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_ShareBasedCompensationArrangementByShareBasedPaymentAwardNumberOfUnitsGuaranteedToVest</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:sharesItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_ShareBasedCompensationArrangementByShareBasedPaymentAwardPercentageOfUnitsGuaranteedToVest">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Percentage of units guaranteed to vest under share-based payment arrangement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_ShareBasedCompensationArrangementByShareBasedPaymentAwardPercentageOfUnitsGuaranteedToVest</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>dtr-types:percentItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_ShareBasedCompensationAbstract">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ShareBasedCompensationAbstract</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:stringItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardAwardVestingPeriod1">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Period over which grantee's right to exercise award under share-based payment arrangement is no longer contingent on satisfaction of service or performance condition, in 'PnYnMnDTnHnMnS' format, for example, 'P1Y5M13D' represents reported fact of one year, five months, and thirteen days. Includes, but is not limited to, combination of market, performance or service condition.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 718<br> -SubTopic 10<br> -Section 50<br> -Paragraph 2<br> -Subparagraph (a)(1)<br> -URI http://asc.fasb.org/extlink&amp;oid=120381028&amp;loc=d3e5070-113901<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardAwardVestingPeriod1</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:durationItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsGrantsInPeriodWeightedAverageGrantDateFairValue">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The weighted average grant-date fair value of options granted during the reporting period as calculated by applying the disclosed option pricing methodology.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 718<br> -SubTopic 10<br> -Section 50<br> -Paragraph 2<br> -Subparagraph (d)(1)<br> -URI http://asc.fasb.org/extlink&amp;oid=120381028&amp;loc=d3e5070-113901<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsGrantsInPeriodWeightedAverageGrantDateFairValue</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>dtr-types:perShareItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_SharebasedCompensationArrangementBySharebasedPaymentAwardAwardVestingRightsPercentage">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Percentage of vesting of award under share-based payment arrangement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 718<br> -SubTopic 10<br> -Section 50<br> -Paragraph 2<br> -Subparagraph (a)(1)<br> -URI http://asc.fasb.org/extlink&amp;oid=120381028&amp;loc=d3e5070-113901<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_SharebasedCompensationArrangementBySharebasedPaymentAwardAwardVestingRightsPercentage</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>dtr-types:percentItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_AwardTypeAxis=us-gaap_RestrictedStockUnitsRSUMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_AwardTypeAxis=us-gaap_RestrictedStockUnitsRSUMember</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td></td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_GranteeStatusAxis=us-gaap_ShareBasedPaymentArrangementEmployeeMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_GranteeStatusAxis=us-gaap_ShareBasedPaymentArrangementEmployeeMember</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td></td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_GranteeStatusAxis=ions_ShareBasedPaymentArrangementBoardOfDirectorMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_GranteeStatusAxis=ions_ShareBasedPaymentArrangementBoardOfDirectorMember</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td></td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_AwardDateAxis=ions_GrantedPriorToJune2020Member">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_AwardDateAxis=ions_GrantedPriorToJune2020Member</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td></td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_AwardDateAxis=ions_GrantedAfterJune2020Member">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_AwardDateAxis=ions_GrantedAfterJune2020Member</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td></td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_AwardTypeAxis=us-gaap_PerformanceSharesMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_AwardTypeAxis=us-gaap_PerformanceSharesMember</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td></td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_GranteeStatusAxis=srt_ChiefExecutiveOfficerMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_GranteeStatusAxis=srt_ChiefExecutiveOfficerMember</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td></td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_srt_RangeAxis=srt_MinimumMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">srt_RangeAxis=srt_MinimumMember</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td></td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_srt_RangeAxis=srt_MaximumMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">srt_RangeAxis=srt_MaximumMember</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td></td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_VestingAxis=us-gaap_ShareBasedCompensationAwardTrancheOneMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_VestingAxis=us-gaap_ShareBasedCompensationAwardTrancheOneMember</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td></td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_VestingAxis=us-gaap_ShareBasedCompensationAwardTrancheTwoMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_VestingAxis=us-gaap_ShareBasedCompensationAwardTrancheTwoMember</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td></td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_VestingAxis=us-gaap_ShareBasedCompensationAwardTrancheThreeMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_VestingAxis=us-gaap_ShareBasedCompensationAwardTrancheThreeMember</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
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<span style="display: none;">v3.22.0.1</span><table class="report" border="0" cellspacing="2" id="idm139691007899352">
<tr>
<th class="tl" colspan="2" rowspan="2"><div style="width: 200px;"><strong>Organization and Significant Accounting Policies, Accumulated Other Comprehensive Loss (Details) - USD ($)<br> $ in Thousands</strong></div></th>
<th class="th" colspan="3">12 Months Ended</th>
</tr>
<tr>
<th class="th"><div>Dec. 31, 2021</div></th>
<th class="th"><div>Dec. 31, 2020</div></th>
<th class="th"><div>Dec. 31, 2019</div></th>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ReclassificationFromAccumulatedOtherComprehensiveIncomeCurrentPeriodNetOfTaxAbstract', window );"><strong>Accumulated Other Comprehensive Loss [Roll Forward]</strong></a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_StockholdersEquityIncludingPortionAttributableToNoncontrollingInterest', window );">Balance</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">$ 743,282<span></span>
</td>
<td class="nump">$ 1,577,459<span></span>
</td>
<td class="nump">$ 1,100,623<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_OtherComprehensiveIncomeLossAdjustmentsFromPurchaseOfNoncontrollingInterestOfSubsidiary', window );">Adjustments to other comprehensive loss from purchase of noncontrolling interest of Akcea Therapeutics, Inc.</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">0<span></span>
</td>
<td class="num">(127)<span></span>
</td>
<td class="nump">0<span></span>
</td>
</tr>
<tr class="rou">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_OtherComprehensiveIncomeLossNetOfTax', window );">Net other comprehensive loss for the period</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="num">(11,597)<span></span>
</td>
<td class="nump">4,219<span></span>
</td>
<td class="nump">6,726<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_StockholdersEquityIncludingPortionAttributableToNoncontrollingInterest', window );">Balance</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">771,737<span></span>
</td>
<td class="nump">743,282<span></span>
</td>
<td class="nump">1,577,459<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_OtherComprehensiveIncomeLossTax', window );">Income tax expense (benefit) included in other comprehensive loss</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">0<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="num">(1,400)<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_StatementEquityComponentsAxis=us-gaap_AociIncludingPortionAttributableToNoncontrollingInterestMember', window );">Accumulated Other Comprehensive Loss [Member]</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ReclassificationFromAccumulatedOtherComprehensiveIncomeCurrentPeriodNetOfTaxAbstract', window );"><strong>Accumulated Other Comprehensive Loss [Roll Forward]</strong></a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_StockholdersEquityIncludingPortionAttributableToNoncontrollingInterest', window );">Balance</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="num">(21,071)<span></span>
</td>
<td class="num">(25,290)<span></span>
</td>
<td class="num">(32,016)<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_StockholdersEquityIncludingPortionAttributableToNoncontrollingInterest', window );">Balance</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="num">(32,668)<span></span>
</td>
<td class="num">(21,071)<span></span>
</td>
<td class="num">(25,290)<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_StatementEquityComponentsAxis=us-gaap_AccumulatedNetInvestmentGainLossIncludingPortionAttributableToNoncontrollingInterestMember', window );">Unrealized Gains (Losses) on Securities [Member]</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ReclassificationFromAccumulatedOtherComprehensiveIncomeCurrentPeriodNetOfTaxAbstract', window );"><strong>Accumulated Other Comprehensive Loss [Roll Forward]</strong></a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_OtherComprehensiveIncomeLossBeforeReclassificationsNetOfTax', window );">Other comprehensive loss before reclassifications, net of tax</a></td>
<td class="th" style="border-bottom: 0px;"><sup>[1]</sup></td>
<td class="num">(11,486)<span></span>
</td>
<td class="nump">3,729<span></span>
</td>
<td class="nump">6,633<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_StatementEquityComponentsAxis=us-gaap_AccumulatedForeignCurrencyAdjustmentIncludingPortionAttributableToNoncontrollingInterestMember', window );">Currency Translation Adjustment [Member]</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ReclassificationFromAccumulatedOtherComprehensiveIncomeCurrentPeriodNetOfTaxAbstract', window );"><strong>Accumulated Other Comprehensive Loss [Roll Forward]</strong></a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_OtherComprehensiveIncomeLossBeforeReclassificationsNetOfTax', window );">Other comprehensive loss before reclassifications, net of tax</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="num">$ (111)<span></span>
</td>
<td class="nump">$ 617<span></span>
</td>
<td class="nump">$ 93<span></span>
</td>
</tr>
<tr><td colspan="4"></td></tr>
<tr><td colspan="4"><table class="outerFootnotes" width="100%"><tr class="outerFootnote">
<td style="vertical-align: top; width: 12pt;" valign="top">[1]</td>
<td style="vertical-align: top;" valign="top">We did not have tax expense included in our other comprehensive loss for the years ended December 31, 2021 and 2020. For the year ended December 31,
              2019, we had a tax benefit of $1.4
              million included in other comprehensive loss.</td>
</tr></table></td></tr>
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<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Adjustments to other comprehensive income (loss) from purchase of noncontrolling interest of subsidiary.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount after tax, before reclassification adjustments of other comprehensive income (loss).</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 220<br> -SubTopic 10<br> -Section 50<br> -Paragraph 5<br> -URI http://asc.fasb.org/extlink&amp;oid=124431353&amp;loc=SL124442411-227067<br><br>Reference 2: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 830<br> -SubTopic 30<br> -Section 45<br> -Paragraph 17<br> -URI http://asc.fasb.org/extlink&amp;oid=118261656&amp;loc=d3e32136-110900<br><br>Reference 3: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 830<br> -SubTopic 30<br> -Section 50<br> -Paragraph 1<br> -URI http://asc.fasb.org/extlink&amp;oid=6450520&amp;loc=d3e32583-110901<br><br>Reference 4: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 220<br> -SubTopic 10<br> -Section 45<br> -Paragraph 14A<br> -URI http://asc.fasb.org/extlink&amp;oid=124509347&amp;loc=SL7669686-108580<br><br>Reference 5: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 220<br> -SubTopic 10<br> -Section 55<br> -Paragraph 15<br> -URI http://asc.fasb.org/extlink&amp;oid=124507222&amp;loc=d3e1436-108581<br><br>Reference 6: http://www.xbrl.org/2009/role/commonPracticeRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 220<br> -SubTopic 10<br> -Section 50<br> -Paragraph 4<br> -URI http://asc.fasb.org/extlink&amp;oid=124431353&amp;loc=SL124442407-227067<br><br>Reference 7: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 830<br> -SubTopic 30<br> -Section 45<br> -Paragraph 20<br> -Subparagraph (b)<br> -URI http://asc.fasb.org/extlink&amp;oid=118261656&amp;loc=d3e32211-110900<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_OtherComprehensiveIncomeLossBeforeReclassificationsNetOfTax</td>
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<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
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<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount after tax and reclassification adjustments of other comprehensive income (loss).</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 220<br> -SubTopic 10<br> -Section 45<br> -Paragraph 1A<br> -Subparagraph (b)<br> -URI http://asc.fasb.org/extlink&amp;oid=124509347&amp;loc=SL7669619-108580<br><br>Reference 2: http://www.xbrl.org/2009/role/commonPracticeRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 220<br> -SubTopic 10<br> -Section 50<br> -Paragraph 4<br> -URI http://asc.fasb.org/extlink&amp;oid=124431353&amp;loc=SL124442407-227067<br><br>Reference 3: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 505<br> -SubTopic 10<br> -Section 50<br> -Paragraph 2<br> -URI http://asc.fasb.org/extlink&amp;oid=123467817&amp;loc=d3e21463-112644<br><br>Reference 4: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 830<br> -SubTopic 30<br> -Section 45<br> -Paragraph 17<br> -URI http://asc.fasb.org/extlink&amp;oid=118261656&amp;loc=d3e32136-110900<br><br>Reference 5: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 220<br> -SubTopic 10<br> -Section S99<br> -Paragraph 2<br> -Subparagraph (SX 210.5-03(21))<br> -URI http://asc.fasb.org/extlink&amp;oid=123367319&amp;loc=SL114868664-224227<br><br>Reference 6: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 220<br> -SubTopic 10<br> -Section 55<br> -Paragraph 15<br> -URI http://asc.fasb.org/extlink&amp;oid=124507222&amp;loc=d3e1436-108581<br><br>Reference 7: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 830<br> -SubTopic 30<br> -Section 45<br> -Paragraph 20<br> -URI http://asc.fasb.org/extlink&amp;oid=118261656&amp;loc=d3e32211-110900<br><br>Reference 8: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 830<br> -SubTopic 30<br> -Section 50<br> -Paragraph 1<br> -URI http://asc.fasb.org/extlink&amp;oid=6450520&amp;loc=d3e32583-110901<br><br>Reference 9: http://www.xbrl.org/2009/role/commonPracticeRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 220<br> -SubTopic 10<br> -Section 50<br> -Paragraph 5<br> -URI http://asc.fasb.org/extlink&amp;oid=124431353&amp;loc=SL124442411-227067<br><br>Reference 10: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 220<br> -SubTopic 10<br> -Section 45<br> -Paragraph 1B<br> -Subparagraph (b)<br> -URI http://asc.fasb.org/extlink&amp;oid=124509347&amp;loc=SL7669625-108580<br><br>Reference 11: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 942<br> -SubTopic 220<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.9-04(23))<br> -URI http://asc.fasb.org/extlink&amp;oid=120399700&amp;loc=SL114874048-224260<br><br>Reference 12: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 944<br> -SubTopic 220<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.7-04(19))<br> -URI http://asc.fasb.org/extlink&amp;oid=120400993&amp;loc=SL114874131-224263<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_OtherComprehensiveIncomeLossNetOfTax</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
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<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
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<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
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<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
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<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_OtherComprehensiveIncomeLossTax">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of tax expense (benefit) allocated to other comprehensive income (loss).</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 20<br> -Section 45<br> -Paragraph 11<br> -Subparagraph (b)<br> -URI http://asc.fasb.org/extlink&amp;oid=123586238&amp;loc=d3e39076-109324<br><br>Reference 2: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 830<br> -SubTopic 30<br> -Section 45<br> -Paragraph 17<br> -URI http://asc.fasb.org/extlink&amp;oid=118261656&amp;loc=d3e32136-110900<br><br>Reference 3: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 830<br> -SubTopic 30<br> -Section 45<br> -Paragraph 20<br> -Subparagraph (c)<br> -URI http://asc.fasb.org/extlink&amp;oid=118261656&amp;loc=d3e32211-110900<br><br>Reference 4: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 20<br> -Section 45<br> -Paragraph 2<br> -Subparagraph (d)<br> -URI http://asc.fasb.org/extlink&amp;oid=123586238&amp;loc=d3e38679-109324<br><br>Reference 5: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 220<br> -SubTopic 10<br> -Section 50<br> -Paragraph 4<br> -URI http://asc.fasb.org/extlink&amp;oid=124431353&amp;loc=SL124442407-227067<br><br>Reference 6: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 942<br> -SubTopic 220<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.9-04(23))<br> -URI http://asc.fasb.org/extlink&amp;oid=120399700&amp;loc=SL114874048-224260<br><br>Reference 7: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 220<br> -SubTopic 10<br> -Section S99<br> -Paragraph 2<br> -Subparagraph (SX 210.5-03(21))<br> -URI http://asc.fasb.org/extlink&amp;oid=123367319&amp;loc=SL114868664-224227<br><br>Reference 8: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section 50<br> -Paragraph 10<br> -URI http://asc.fasb.org/extlink&amp;oid=121826272&amp;loc=d3e32672-109319<br><br>Reference 9: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 830<br> -SubTopic 30<br> -Section 50<br> -Paragraph 1<br> -URI http://asc.fasb.org/extlink&amp;oid=6450520&amp;loc=d3e32583-110901<br><br>Reference 10: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 220<br> -SubTopic 10<br> -Section 45<br> -Paragraph 12<br> -URI http://asc.fasb.org/extlink&amp;oid=124509347&amp;loc=d3e640-108580<br><br>Reference 11: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 944<br> -SubTopic 220<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.7-04(19))<br> -URI http://asc.fasb.org/extlink&amp;oid=120400993&amp;loc=SL114874131-224263<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_OtherComprehensiveIncomeLossTax</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
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<tr>
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<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
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<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_ReclassificationFromAccumulatedOtherComprehensiveIncomeCurrentPeriodNetOfTaxAbstract">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>A roll forward is a reconciliation of a concept from the beginning of a period to the end of a period.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ReclassificationFromAccumulatedOtherComprehensiveIncomeCurrentPeriodNetOfTaxAbstract</td>
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<td>xbrli:stringItemType</td>
</tr>
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<td><strong> Balance Type:</strong></td>
<td>na</td>
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<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
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<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_StockholdersEquityIncludingPortionAttributableToNoncontrollingInterest">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of stockholders' equity (deficit), net of receivables from officers, directors, owners, and affiliates of the entity, attributable to both the parent and noncontrolling interests. Amount excludes temporary equity. Alternate caption for the concept is permanent equity.</p></div>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_StockholdersEquityIncludingPortionAttributableToNoncontrollingInterest</td>
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<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
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<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
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<td><strong> Balance Type:</strong></td>
<td>credit</td>
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<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
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<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
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<span style="display: none;">v3.22.0.1</span><table class="report" border="0" cellspacing="2" id="idm139690999529608">
<tr>
<th class="tl" colspan="1" rowspan="2"><div style="width: 200px;"><strong>Organization and Significant Accounting Policies, Convertible Debt (Details)<br> $ / shares in Units, $ in Thousands</strong></div></th>
<th class="th" colspan="2">1 Months Ended</th>
<th class="th" colspan="4">3 Months Ended</th>
<th class="th" colspan="3">12 Months Ended</th>
<th class="th" colspan="1"></th>
<th class="th" colspan="1"></th>
<th class="th" colspan="1"></th>
<th class="th" colspan="1"></th>
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<tr>
<th class="th">
<div>Apr. 30, 2021 </div>
<div>USD ($)</div>
</th>
<th class="th">
<div>Dec. 31, 2019 </div>
<div>USD ($)</div>
</th>
<th class="th" colspan="2">
<div>Dec. 31, 2021 </div>
<div>USD ($) </div>
<div>$ / shares</div>
</th>
<th class="th" colspan="2">
<div>Dec. 31, 2020 </div>
<div>USD ($) </div>
<div>Note </div>
<div>$ / shares</div>
</th>
<th class="th">
<div>Dec. 31, 2021 </div>
<div>USD ($) </div>
<div>$ / shares</div>
</th>
<th class="th">
<div>Dec. 31, 2020 </div>
<div>USD ($) </div>
<div>Note </div>
<div>$ / shares</div>
</th>
<th class="th">
<div>Dec. 31, 2019 </div>
<div>USD ($) </div>
<div>$ / shares</div>
</th>
<th class="th"><div>Nov. 30, 2021</div></th>
<th class="th">
<div>Dec. 31, 2018 </div>
<div>USD ($)</div>
</th>
<th class="th">
<div>Dec. 31, 2016 </div>
<div>USD ($)</div>
</th>
<th class="th">
<div>Nov. 30, 2014 </div>
<div>USD ($)</div>
</th>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_LongTermDebtByComponentsCurrentAndNoncurrentAlternativeAbstract', window );"><strong>Convertible Debt [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_DebtInstrumentNumberOfConvertibleNotes', window );">Number of outstanding convertible notes | Note</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">2<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">2<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_StatementOfFinancialPositionAbstract', window );"><strong>Consolidated Balance Sheet [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ConvertibleDebtCurrent', window );">1 percent convertible senior notes, net</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 0<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">$ 308,809<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">$ 0<span></span>
</td>
<td class="nump">$ 308,809<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AdditionalPaidInCapitalCommonStock', window );">Additional paid-in capital</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">1,964,167<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">1,895,519<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">1,964,167<span></span>
</td>
<td class="nump">1,895,519<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RetainedEarningsAccumulatedDeficit', window );">Accumulated deficit</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="num">(1,159,903)<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="num">(1,131,306)<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="num">(1,159,903)<span></span>
</td>
<td class="num">(1,131,306)<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_IncomeStatementAbstract', window );"><strong>Consolidated Statement of Operations [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_InterestExpense', window );">Interest expense</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="num">(9,349)<span></span>
</td>
<td class="num">(9,510)<span></span>
</td>
<td class="num">$ (12,440)<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_GainsLossesOnExtinguishmentOfDebt', window );">Loss on early retirement of debt</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="num">(8,627)<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="num">(66,196)<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_IncomeLossFromContinuingOperationsBeforeIncomeTaxesExtraordinaryItemsNoncontrollingInterest', window );">Income (loss) before income tax benefit (expense)</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="num">(29,148)<span></span>
</td>
<td class="num">(134,552)<span></span>
</td>
<td class="nump">338,766<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_IncomeTaxExpenseBenefit', window );">Income tax expense</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">551<span></span>
</td>
<td class="num">(345,191)<span></span>
</td>
<td class="num">(51,507)<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ProfitLoss', window );">Net income (loss)</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">224,613<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="num">(355,687)<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="num">(28,597)<span></span>
</td>
<td class="num">(479,743)<span></span>
</td>
<td class="nump">287,259<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_NetIncomeLoss', window );">Net income (loss) attributable to Ionis Pharmaceuticals, Inc. common stockholders</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 224,613<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="num">$ (354,532)<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="num">$ (28,597)<span></span>
</td>
<td class="num">$ (444,263)<span></span>
</td>
<td class="nump">$ 278,143<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_EarningsPerShareBasic', window );">Basic net loss per share (in dollars per share) | $ / shares</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 1.59<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"><sup>[1],[2]</sup></td>
<td class="num">$ (2.54)<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"><sup>[1],[2]</sup></td>
<td class="num">$ (0.20)<span></span>
</td>
<td class="num">$ (3.18)<span></span>
</td>
<td class="nump">$ 2.00<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_EarningsPerShareDiluted', window );">Diluted net loss per share (in dollars per share) | $ / shares</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 1.41<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"><sup>[1],[3]</sup></td>
<td class="num">$ (2.54)<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"><sup>[1]</sup></td>
<td class="num">$ (0.20)<span></span>
</td>
<td class="num">$ (3.18)<span></span>
</td>
<td class="nump">$ 1.90<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_StatementOfStockholdersEquityAbstract', window );"><strong>Consolidated Statements of Stockholders' Equity [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_StockholdersEquityIncludingPortionAttributableToNoncontrollingInterest', window );">Balance</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 1,577,459<span></span>
</td>
<td class="nump">$ 771,737<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">$ 743,282<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">$ 771,737<span></span>
</td>
<td class="nump">$ 743,282<span></span>
</td>
<td class="nump">$ 1,577,459<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 1,100,623<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_StatementEquityComponentsAxis=us-gaap_AdditionalPaidInCapitalMember', window );">Additional Paid In Capital [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_IncomeStatementAbstract', window );"><strong>Consolidated Statement of Operations [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_NetIncomeLoss', window );">Net income (loss) attributable to Ionis Pharmaceuticals, Inc. common stockholders</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">0<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_StatementOfStockholdersEquityAbstract', window );"><strong>Consolidated Statements of Stockholders' Equity [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_StockholdersEquityIncludingPortionAttributableToNoncontrollingInterest', window );">Balance</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">1,985,650<span></span>
</td>
<td class="nump">1,964,167<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">1,895,519<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">1,964,167<span></span>
</td>
<td class="nump">1,895,519<span></span>
</td>
<td class="nump">1,985,650<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">1,833,668<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_StatementEquityComponentsAxis=us-gaap_RetainedEarningsMember', window );">Accumulated Deficit [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_IncomeStatementAbstract', window );"><strong>Consolidated Statement of Operations [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_NetIncomeLoss', window );">Net income (loss) attributable to Ionis Pharmaceuticals, Inc. common stockholders</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="num">(28,597)<span></span>
</td>
<td class="num">(444,263)<span></span>
</td>
<td class="nump">278,143<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_StatementOfStockholdersEquityAbstract', window );"><strong>Consolidated Statements of Stockholders' Equity [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_StockholdersEquityIncludingPortionAttributableToNoncontrollingInterest', window );">Balance</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="num">(596,495)<span></span>
</td>
<td class="num">(1,159,903)<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="num">(1,131,306)<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="num">(1,159,903)<span></span>
</td>
<td class="num">(1,131,306)<span></span>
</td>
<td class="num">(596,495)<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="num">(840,251)<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_StatementEquityComponentsAxis=us-gaap_ParentMember', window );">Total Ionis Stockholders' Equity [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_IncomeStatementAbstract', window );"><strong>Consolidated Statement of Operations [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_NetIncomeLoss', window );">Net income (loss) attributable to Ionis Pharmaceuticals, Inc. common stockholders</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="num">(28,597)<span></span>
</td>
<td class="num">(444,263)<span></span>
</td>
<td class="nump">278,143<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_StatementOfStockholdersEquityAbstract', window );"><strong>Consolidated Statements of Stockholders' Equity [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_StockholdersEquityIncludingPortionAttributableToNoncontrollingInterest', window );">Balance</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 1,364,005<span></span>
</td>
<td class="nump">$ 771,737<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">$ 743,282<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">$ 771,737<span></span>
</td>
<td class="nump">$ 743,282<span></span>
</td>
<td class="nump">$ 1,364,005<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 961,539<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DebtInstrumentAxis=ions_ConvertibleSeniorNotes0125PercentMember', window );">0.125 Percent Convertible Senior Notes [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_LongTermDebtByComponentsCurrentAndNoncurrentAlternativeAbstract', window );"><strong>Convertible Debt [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DebtInstrumentInterestRateStatedPercentage', window );">Interest rate on convertible senior notes</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">0.125%<span></span>
</td>
<td class="nump">0.125%<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">0.125%<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">0.125%<span></span>
</td>
<td class="nump">0.125%<span></span>
</td>
<td class="nump">0.125%<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_StatementOfFinancialPositionAbstract', window );"><strong>Consolidated Balance Sheet [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ConvertibleDebtNoncurrent', window );">Convertible senior notes</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 542,314<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">$ 540,136<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">$ 542,314<span></span>
</td>
<td class="nump">$ 540,136<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_IncomeStatementAbstract', window );"><strong>Consolidated Statement of Operations [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DebtInstrumentInterestRateEffectivePercentage', window );">Effective interest rate</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">0.50%<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">0.50%<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DebtInstrumentAxis=ions_ConvertibleSeniorNotes1PercentMember', window );">1 Percent Convertible Senior Notes [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_LongTermDebtByComponentsCurrentAndNoncurrentAlternativeAbstract', window );"><strong>Convertible Debt [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DebtInstrumentInterestRateStatedPercentage', window );">Interest rate on convertible senior notes</a></td>
<td class="nump">1.00%<span></span>
</td>
<td class="nump">1.00%<span></span>
</td>
<td class="nump">1.00%<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">1.00%<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">1.00%<span></span>
</td>
<td class="nump">1.00%<span></span>
</td>
<td class="nump">1.00%<span></span>
</td>
<td class="nump">1.00%<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">1.00%<span></span>
</td>
<td class="nump">1.00%<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DebtInstrumentFaceAmount', window );">Face amount of offering</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 185,500<span></span>
</td>
<td class="nump">$ 500,000<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_IncomeStatementAbstract', window );"><strong>Consolidated Statement of Operations [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_GainsLossesOnExtinguishmentOfDebt', window );">Loss on early retirement of debt</a></td>
<td class="nump">$ 8,600<span></span>
</td>
<td class="num">$ (66,200)<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DebtInstrumentInterestRateEffectivePercentage', window );">Effective interest rate</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">1.40%<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">1.40%<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DebtInstrumentAxis=ions_ConvertibleSeniorNotes0PercentMember', window );">0 Percent Convertible Senior Notes [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_LongTermDebtByComponentsCurrentAndNoncurrentAlternativeAbstract', window );"><strong>Convertible Debt [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DebtInstrumentInterestRateStatedPercentage', window );">Interest rate on convertible senior notes</a></td>
<td class="nump">0.00%<span></span>
</td>
<td class="nump">0.00%<span></span>
</td>
<td class="nump">0.00%<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">0.00%<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">0.00%<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DebtInstrumentFaceAmount', window );">Face amount of offering</a></td>
<td class="nump">$ 632,500<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_StatementOfFinancialPositionAbstract', window );"><strong>Consolidated Balance Sheet [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ConvertibleDebtNoncurrent', window );">Convertible senior notes</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 619,119<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">$ 0<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">$ 619,119<span></span>
</td>
<td class="nump">$ 0<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_IncomeStatementAbstract', window );"><strong>Consolidated Statement of Operations [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DebtInstrumentInterestRateEffectivePercentage', window );">Effective interest rate</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">0.50%<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">0.50%<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_srt_RestatementAxis=srt_ScenarioPreviouslyReportedMember', window );">As Previously Reported [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_StatementOfFinancialPositionAbstract', window );"><strong>Consolidated Balance Sheet [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ConvertibleDebtCurrent', window );">1 percent convertible senior notes, net</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">293,161<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">293,161<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AdditionalPaidInCapitalCommonStock', window );">Additional paid-in capital</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">2,113,646<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">2,113,646<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RetainedEarningsAccumulatedDeficit', window );">Accumulated deficit</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="num">(1,249,368)<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="num">(1,249,368)<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_IncomeStatementAbstract', window );"><strong>Consolidated Statement of Operations [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_InterestExpense', window );">Interest expense</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="num">(44,990)<span></span>
</td>
<td class="num">$ (48,768)<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_GainsLossesOnExtinguishmentOfDebt', window );">Loss on early retirement of debt</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="num">(21,865)<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_IncomeLossFromContinuingOperationsBeforeIncomeTaxesExtraordinaryItemsNoncontrollingInterest', window );">Income (loss) before income tax benefit (expense)</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="num">(170,032)<span></span>
</td>
<td class="nump">346,769<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_IncomeTaxExpenseBenefit', window );">Income tax expense</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="num">(316,734)<span></span>
</td>
<td class="num">(43,507)<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ProfitLoss', window );">Net income (loss)</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="num">(486,766)<span></span>
</td>
<td class="nump">303,262<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_NetIncomeLoss', window );">Net income (loss) attributable to Ionis Pharmaceuticals, Inc. common stockholders</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="num">$ (451,286)<span></span>
</td>
<td class="nump">$ 294,146<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_EarningsPerShareBasic', window );">Basic net loss per share (in dollars per share) | $ / shares</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="num">$ (3.23)<span></span>
</td>
<td class="nump">$ 2.12<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_EarningsPerShareDiluted', window );">Diluted net loss per share (in dollars per share) | $ / shares</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="num">$ (3.23)<span></span>
</td>
<td class="nump">$ 2.08<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_StatementOfStockholdersEquityAbstract', window );"><strong>Consolidated Statements of Stockholders' Equity [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_StockholdersEquityIncludingPortionAttributableToNoncontrollingInterest', window );">Balance</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 1,684,547<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">843,347<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 843,347<span></span>
</td>
<td class="nump">$ 1,684,547<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_srt_RestatementAxis=srt_ScenarioPreviouslyReportedMember', window );">As Previously Reported [Member] | Additional Paid In Capital [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_StatementOfStockholdersEquityAbstract', window );"><strong>Consolidated Statements of Stockholders' Equity [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_StockholdersEquityIncludingPortionAttributableToNoncontrollingInterest', window );">Balance</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">2,203,778<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">2,113,646<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">2,113,646<span></span>
</td>
<td class="nump">2,203,778<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_srt_RestatementAxis=srt_ScenarioPreviouslyReportedMember', window );">As Previously Reported [Member] | Accumulated Deficit [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_StatementOfStockholdersEquityAbstract', window );"><strong>Consolidated Statements of Stockholders' Equity [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_StockholdersEquityIncludingPortionAttributableToNoncontrollingInterest', window );">Balance</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="num">(707,534)<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="num">(1,249,368)<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="num">(1,249,368)<span></span>
</td>
<td class="num">(707,534)<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_srt_RestatementAxis=srt_ScenarioPreviouslyReportedMember', window );">As Previously Reported [Member] | 0.125 Percent Convertible Senior Notes [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_StatementOfFinancialPositionAbstract', window );"><strong>Consolidated Balance Sheet [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ConvertibleDebtNoncurrent', window );">Convertible senior notes</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">455,719<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">455,719<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_srt_RestatementAxis=srt_RevisionOfPriorPeriodAccountingStandardsUpdateAdjustmentMember', window );">Adjustment [Member] | ASU 2020-06 [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_StatementOfFinancialPositionAbstract', window );"><strong>Consolidated Balance Sheet [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ConvertibleDebtCurrent', window );">1 percent convertible senior notes, net</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">15,648<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">15,648<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AdditionalPaidInCapitalCommonStock', window );">Additional paid-in capital</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="num">(218,127)<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="num">(218,127)<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RetainedEarningsAccumulatedDeficit', window );">Accumulated deficit</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">118,062<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">118,062<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DeferredIncomeTaxAssetsNet', window );">Net deferred tax assets</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">0<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_IncomeStatementAbstract', window );"><strong>Consolidated Statement of Operations [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_InterestExpense', window );">Interest expense</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">35,480<span></span>
</td>
<td class="nump">36,328<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_GainsLossesOnExtinguishmentOfDebt', window );">Loss on early retirement of debt</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="num">(44,331)<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_IncomeLossFromContinuingOperationsBeforeIncomeTaxesExtraordinaryItemsNoncontrollingInterest', window );">Income (loss) before income tax benefit (expense)</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">35,480<span></span>
</td>
<td class="num">(8,003)<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_IncomeTaxExpenseBenefit', window );">Income tax expense</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="num">(28,457)<span></span>
</td>
<td class="num">(8,000)<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ProfitLoss', window );">Net income (loss)</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">7,023<span></span>
</td>
<td class="num">(16,003)<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_NetIncomeLoss', window );">Net income (loss) attributable to Ionis Pharmaceuticals, Inc. common stockholders</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 7,023<span></span>
</td>
<td class="num">$ (16,003)<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_EarningsPerShareBasic', window );">Basic net loss per share (in dollars per share) | $ / shares</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 0.05<span></span>
</td>
<td class="num">$ (0.12)<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_EarningsPerShareDiluted', window );">Diluted net loss per share (in dollars per share) | $ / shares</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 0.05<span></span>
</td>
<td class="num">$ (0.18)<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_StatementOfStockholdersEquityAbstract', window );"><strong>Consolidated Statements of Stockholders' Equity [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_StockholdersEquityIncludingPortionAttributableToNoncontrollingInterest', window );">Balance</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="num">(107,088)<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="num">(100,065)<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="num">$ (100,065)<span></span>
</td>
<td class="num">$ (107,088)<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_srt_RestatementAxis=srt_RevisionOfPriorPeriodAccountingStandardsUpdateAdjustmentMember', window );">Adjustment [Member] | ASU 2020-06 [Member] | Additional Paid In Capital [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_StatementOfStockholdersEquityAbstract', window );"><strong>Consolidated Statements of Stockholders' Equity [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_StockholdersEquityIncludingPortionAttributableToNoncontrollingInterest', window );">Balance</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="num">(218,128)<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="num">(218,127)<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="num">(218,127)<span></span>
</td>
<td class="num">(218,128)<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_srt_RestatementAxis=srt_RevisionOfPriorPeriodAccountingStandardsUpdateAdjustmentMember', window );">Adjustment [Member] | ASU 2020-06 [Member] | Accumulated Deficit [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_StatementOfStockholdersEquityAbstract', window );"><strong>Consolidated Statements of Stockholders' Equity [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_StockholdersEquityIncludingPortionAttributableToNoncontrollingInterest', window );">Balance</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 111,039<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">118,062<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">118,062<span></span>
</td>
<td class="nump">$ 111,039<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_srt_RestatementAxis=srt_RevisionOfPriorPeriodAccountingStandardsUpdateAdjustmentMember', window );">Adjustment [Member] | ASU 2020-06 [Member] | 0.125 Percent Convertible Senior Notes [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_StatementOfFinancialPositionAbstract', window );"><strong>Consolidated Balance Sheet [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ConvertibleDebtNoncurrent', window );">Convertible senior notes</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">$ 84,417<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 84,417<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr><td colspan="14"></td></tr>
<tr><td colspan="14"><table class="outerFootnotes" width="100%">
<tr class="outerFootnote">
<td style="vertical-align: top; width: 12pt;" valign="top">[1]</td>
<td style="vertical-align: top;" valign="top"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">We </span>compute net income (loss) per share independently for each quarter during <span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">the year.</span></td>
</tr>
<tr class="outerFootnote">
<td style="vertical-align: top; width: 12pt;" valign="top">[2]</td>
<td style="vertical-align: top;" valign="top">As discussed in Note 1, Organization and Significant Accounting Policies, we compute basic net income (loss) per share by dividing the total net income (loss)
            attributable to our common stockholders by our weighted-average number of common shares outstanding during the period. Our basic net income per share for the fourth quarter of 2021 was $1.59.Our basic net loss per share calculation for the fourth quarter of 2020 considered our net loss for Ionis on a stand-alone
    basis plus our share of Akcea&#8217;s net loss for the period. To calculate the portion of Akcea&#8217;s net loss attributable to our ownership, we multiplied Akcea&#8217;s loss per share by the weighted average shares we owned in Akcea during the period. As a result of
    this calculation, our total net loss available to Ionis common stockholders for the calculation of net loss per share is different than net loss attributable to Ionis Pharmaceuticals, Inc. common stockholders in the consolidated statements of
    operations.</td>
</tr>
<tr class="outerFootnote">
<td style="vertical-align: top; width: 12pt;" valign="top">[3]</td>
<td style="vertical-align: top;" valign="top">We had net income available
            to Ionis common stockholders for the fourth quarter of 2021. As a result, we computed diluted net income per share using the weighted-average number of common shares and dilutive common equivalent shares outstanding during the period</td>
</tr>
</table></td></tr>
</table>
<div style="display: none;">
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<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Number of outstanding convertible notes.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_DebtInstrumentNumberOfConvertibleNotes</td>
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<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
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<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Value received from shareholders in common stock-related transactions that are in excess of par value or stated value and amounts received from other stock-related transactions. Includes only common stock transactions (excludes preferred stock transactions). May be called contributed capital, capital in excess of par, capital surplus, or paid-in capital.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 210<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.5-02(30)(a)(1))<br> -URI http://asc.fasb.org/extlink&amp;oid=120391452&amp;loc=d3e13212-122682<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_AdditionalPaidInCapitalCommonStock</td>
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<td><strong> Data Type:</strong></td>
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<td><strong> Balance Type:</strong></td>
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<td><strong> Period Type:</strong></td>
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<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_ConvertibleDebtCurrent">
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<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The portion of the carrying value of long-term convertible debt as of the balance sheet date that is scheduled to be repaid within one year or in the normal operating cycle if longer. Convertible debt is a financial instrument which can be exchanged for a specified amount of another security, typically the entity's common stock, at the option of the issuer or the holder.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 210<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.5-02(19))<br> -URI http://asc.fasb.org/extlink&amp;oid=120391452&amp;loc=d3e13212-122682<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ConvertibleDebtCurrent</td>
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<td><strong> Data Type:</strong></td>
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<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Carrying amount of long-term convertible debt as of the balance sheet date, net of the amount due in the next twelve months or greater than the normal operating cycle, if longer. The debt is convertible into another form of financial instrument, typically the entity's common stock.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 210<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.5-02.22)<br> -URI http://asc.fasb.org/extlink&amp;oid=120391452&amp;loc=d3e13212-122682<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ConvertibleDebtNoncurrent</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_DebtInstrumentFaceAmount">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Face (par) amount of debt instrument at time of issuance.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 470<br> -SubTopic 20<br> -Section 50<br> -Paragraph 1B<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=123466505&amp;loc=SL123495323-112611<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 835<br> -SubTopic 30<br> -Section 45<br> -Paragraph 2<br> -URI http://asc.fasb.org/extlink&amp;oid=124435984&amp;loc=d3e28551-108399<br><br>Reference 3: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 835<br> -SubTopic 30<br> -Section 55<br> -Paragraph 8<br> -URI http://asc.fasb.org/extlink&amp;oid=114775985&amp;loc=d3e28878-108400<br><br>Reference 4: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 835<br> -SubTopic 30<br> -Section 50<br> -Paragraph 1<br> -URI http://asc.fasb.org/extlink&amp;oid=124429444&amp;loc=SL124452920-239629<br><br>Reference 5: http://www.xbrl.org/2003/role/exampleRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 470<br> -SubTopic 20<br> -Section 55<br> -Paragraph 69C<br> -URI http://asc.fasb.org/extlink&amp;oid=123466577&amp;loc=SL123495737-112612<br><br>Reference 6: http://www.xbrl.org/2003/role/exampleRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 470<br> -SubTopic 20<br> -Section 55<br> -Paragraph 69B<br> -URI http://asc.fasb.org/extlink&amp;oid=123466577&amp;loc=SL123495735-112612<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_DebtInstrumentFaceAmount</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_DebtInstrumentInterestRateEffectivePercentage">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Effective interest rate for the funds borrowed under the debt agreement considering interest compounding and original issue discount or premium.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 470<br> -SubTopic 20<br> -Section 50<br> -Paragraph 6<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=123466204&amp;loc=SL6036836-161870<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 835<br> -SubTopic 30<br> -Section 45<br> -Paragraph 2<br> -URI http://asc.fasb.org/extlink&amp;oid=124435984&amp;loc=d3e28551-108399<br><br>Reference 3: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 835<br> -SubTopic 30<br> -Section 50<br> -Paragraph 1<br> -URI http://asc.fasb.org/extlink&amp;oid=124429444&amp;loc=SL124452920-239629<br><br>Reference 4: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 210<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.5-02.22(a)(1))<br> -URI http://asc.fasb.org/extlink&amp;oid=120391452&amp;loc=d3e13212-122682<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_DebtInstrumentInterestRateEffectivePercentage</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>dtr-types:percentItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_DebtInstrumentInterestRateStatedPercentage">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Contractual interest rate for funds borrowed, under the debt agreement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 470<br> -SubTopic 20<br> -Section 50<br> -Paragraph 1B<br> -Subparagraph (b)<br> -URI http://asc.fasb.org/extlink&amp;oid=123466505&amp;loc=SL123495323-112611<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 210<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.5-02.22(a)(1))<br> -URI http://asc.fasb.org/extlink&amp;oid=120391452&amp;loc=d3e13212-122682<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_DebtInstrumentInterestRateStatedPercentage</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>dtr-types:percentItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_DeferredIncomeTaxAssetsNet">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount, after allocation of valuation allowances and deferred tax liability, of deferred tax asset attributable to deductible differences and carryforwards, with jurisdictional netting.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section 45<br> -Paragraph 6<br> -URI http://asc.fasb.org/extlink&amp;oid=123427490&amp;loc=d3e31931-109318<br><br>Reference 2: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section 45<br> -Paragraph 4<br> -URI http://asc.fasb.org/extlink&amp;oid=123427490&amp;loc=d3e31917-109318<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_DeferredIncomeTaxAssetsNet</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_EarningsPerShareBasic">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The amount of net income (loss) for the period per each share of common stock or unit outstanding during the reporting period.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 815<br> -SubTopic 40<br> -Section 65<br> -Paragraph 1<br> -Subparagraph (e)(4)<br> -URI http://asc.fasb.org/extlink&amp;oid=123482062&amp;loc=SL123482106-238011<br><br>Reference 2: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 250<br> -SubTopic 10<br> -Section 50<br> -Paragraph 3<br> -URI http://asc.fasb.org/extlink&amp;oid=124431687&amp;loc=d3e22583-107794<br><br>Reference 3: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 250<br> -SubTopic 10<br> -Section 50<br> -Paragraph 11<br> -Subparagraph (b)<br> -URI http://asc.fasb.org/extlink&amp;oid=124431687&amp;loc=d3e22694-107794<br><br>Reference 4: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 260<br> -SubTopic 10<br> -Section 45<br> -Paragraph 10<br> -URI http://asc.fasb.org/extlink&amp;oid=125511455&amp;loc=d3e1448-109256<br><br>Reference 5: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 250<br> -SubTopic 10<br> -Section 50<br> -Paragraph 4<br> -URI http://asc.fasb.org/extlink&amp;oid=124431687&amp;loc=d3e22595-107794<br><br>Reference 6: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 250<br> -SubTopic 10<br> -Section 50<br> -Paragraph 11<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=124431687&amp;loc=d3e22694-107794<br><br>Reference 7: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 260<br> -SubTopic 10<br> -Section 45<br> -Paragraph 7<br> -URI http://asc.fasb.org/extlink&amp;oid=125511455&amp;loc=d3e1337-109256<br><br>Reference 8: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 815<br> -SubTopic 40<br> -Section 65<br> -Paragraph 1<br> -Subparagraph (f)<br> -URI http://asc.fasb.org/extlink&amp;oid=123482062&amp;loc=SL123482106-238011<br><br>Reference 9: http://www.xbrl.org/2003/role/exampleRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 260<br> -SubTopic 10<br> -Section 55<br> -Paragraph 52<br> -URI http://asc.fasb.org/extlink&amp;oid=125512782&amp;loc=d3e4984-109258<br><br>Reference 10: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 944<br> -SubTopic 220<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.7-04(23))<br> -URI http://asc.fasb.org/extlink&amp;oid=120400993&amp;loc=SL114874131-224263<br><br>Reference 11: 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10<br> -Section S99<br> -Paragraph 2<br> -Subparagraph (SX 210.5-03(25))<br> -URI http://asc.fasb.org/extlink&amp;oid=123367319&amp;loc=SL114868664-224227<br><br>Reference 15: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 260<br> -SubTopic 10<br> -Section 45<br> -Paragraph 2<br> -URI http://asc.fasb.org/extlink&amp;oid=125511455&amp;loc=d3e1252-109256<br><br>Reference 16: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 260<br> -SubTopic 10<br> -Section 45<br> -Paragraph 60B<br> -Subparagraph (d)<br> -URI http://asc.fasb.org/extlink&amp;oid=125511455&amp;loc=SL5780133-109256<br><br>Reference 17: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 942<br> -SubTopic 220<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.9-04(27))<br> -URI http://asc.fasb.org/extlink&amp;oid=120399700&amp;loc=SL114874048-224260<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_EarningsPerShareBasic</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>dtr-types:perShareItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_EarningsPerShareDiluted">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The amount of net income (loss) for the period available to each share of common stock or common unit outstanding during the reporting period and to each share or unit that would have been outstanding assuming the issuance of common shares or units for all dilutive potential common shares or units outstanding during the reporting period.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/exampleRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 260<br> -SubTopic 10<br> -Section 55<br> -Paragraph 52<br> -URI http://asc.fasb.org/extlink&amp;oid=125512782&amp;loc=d3e4984-109258<br><br>Reference 2: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 250<br> -SubTopic 10<br> -Section 50<br> -Paragraph 7<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=124431687&amp;loc=d3e22644-107794<br><br>Reference 3: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 260<br> -SubTopic 10<br> -Section 55<br> -Paragraph 15<br> -URI http://asc.fasb.org/extlink&amp;oid=125512782&amp;loc=d3e3842-109258<br><br>Reference 4: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 260<br> -SubTopic 10<br> -Section 45<br> -Paragraph 2<br> -URI http://asc.fasb.org/extlink&amp;oid=125511455&amp;loc=d3e1252-109256<br><br>Reference 5: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 250<br> -SubTopic 10<br> -Section 50<br> -Paragraph 11<br> -Subparagraph (b)<br> -URI http://asc.fasb.org/extlink&amp;oid=124431687&amp;loc=d3e22694-107794<br><br>Reference 6: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 250<br> -SubTopic 10<br> -Section 50<br> -Paragraph 4<br> -URI http://asc.fasb.org/extlink&amp;oid=124431687&amp;loc=d3e22595-107794<br><br>Reference 7: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 250<br> -SubTopic 10<br> -Section 50<br> -Paragraph 3<br> -URI http://asc.fasb.org/extlink&amp;oid=124431687&amp;loc=d3e22583-107794<br><br>Reference 8: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 260<br> -SubTopic 10<br> -Section 45<br> -Paragraph 60B<br> -Subparagraph (d)<br> -URI http://asc.fasb.org/extlink&amp;oid=125511455&amp;loc=SL5780133-109256<br><br>Reference 9: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 815<br> -SubTopic 40<br> -Section 65<br> -Paragraph 1<br> -Subparagraph (f)<br> -URI http://asc.fasb.org/extlink&amp;oid=123482062&amp;loc=SL123482106-238011<br><br>Reference 10: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 942<br> -SubTopic 220<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.9-04(27))<br> -URI http://asc.fasb.org/extlink&amp;oid=120399700&amp;loc=SL114874048-224260<br><br>Reference 11: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 260<br> -SubTopic 10<br> -Section 50<br> -Paragraph 1<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=124432515&amp;loc=d3e3550-109257<br><br>Reference 12: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 944<br> -SubTopic 220<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.7-04(23))<br> -URI http://asc.fasb.org/extlink&amp;oid=120400993&amp;loc=SL114874131-224263<br><br>Reference 13: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 250<br> -SubTopic 10<br> -Section 50<br> -Paragraph 11<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=124431687&amp;loc=d3e22694-107794<br><br>Reference 14: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 260<br> -SubTopic 10<br> -Section 45<br> -Paragraph 7<br> -URI http://asc.fasb.org/extlink&amp;oid=125511455&amp;loc=d3e1337-109256<br><br>Reference 15: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 815<br> -SubTopic 40<br> -Section 65<br> -Paragraph 1<br> -Subparagraph (e)(4)<br> -URI http://asc.fasb.org/extlink&amp;oid=123482062&amp;loc=SL123482106-238011<br><br>Reference 16: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 220<br> -SubTopic 10<br> -Section S99<br> -Paragraph 2<br> -Subparagraph (SX 210.5-03(25))<br> -URI http://asc.fasb.org/extlink&amp;oid=123367319&amp;loc=SL114868664-224227<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_EarningsPerShareDiluted</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>dtr-types:perShareItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_GainsLossesOnExtinguishmentOfDebt">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Difference between the fair value of payments made and the carrying amount of debt which is extinguished prior to maturity.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 470<br> -SubTopic 50<br> -Section 40<br> -Paragraph 4<br> -URI http://asc.fasb.org/extlink&amp;oid=123467658&amp;loc=d3e12355-112629<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 470<br> -SubTopic 50<br> -Section 40<br> -Paragraph 2<br> -URI http://asc.fasb.org/extlink&amp;oid=123467658&amp;loc=d3e12317-112629<br><br>Reference 3: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 230<br> -SubTopic 10<br> -Section 45<br> -Paragraph 28<br> -Subparagraph (b)<br> -URI http://asc.fasb.org/extlink&amp;oid=123570139&amp;loc=d3e3602-108585<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_GainsLossesOnExtinguishmentOfDebt</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_IncomeLossFromContinuingOperationsBeforeIncomeTaxesExtraordinaryItemsNoncontrollingInterest">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of income (loss) from continuing operations, including income (loss) from equity method investments, before deduction of income tax expense (benefit), and income (loss) attributable to noncontrolling interest.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 280<br> -SubTopic 10<br> -Section 50<br> -Paragraph 32<br> -Subparagraph (c)<br> -URI http://asc.fasb.org/extlink&amp;oid=123359005&amp;loc=d3e8933-108599<br><br>Reference 2: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 280<br> -SubTopic 10<br> -Section 50<br> -Paragraph 30<br> -Subparagraph (b)<br> -URI http://asc.fasb.org/extlink&amp;oid=123359005&amp;loc=d3e8906-108599<br><br>Reference 3: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 280<br> -SubTopic 10<br> -Section 50<br> -Paragraph 32<br> -Subparagraph (f)<br> -URI http://asc.fasb.org/extlink&amp;oid=123359005&amp;loc=d3e8933-108599<br><br>Reference 4: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 940<br> -SubTopic 20<br> -Section 25<br> -Paragraph 1<br> -URI http://asc.fasb.org/extlink&amp;oid=123384075&amp;loc=d3e41242-110953<br><br>Reference 5: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 280<br> -SubTopic 10<br> -Section 50<br> -Paragraph 22<br> -URI http://asc.fasb.org/extlink&amp;oid=123359005&amp;loc=d3e8736-108599<br><br>Reference 6: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 220<br> -SubTopic 10<br> -Section S99<br> -Paragraph 2<br> -Subparagraph (SX 210.5-03(10))<br> -URI http://asc.fasb.org/extlink&amp;oid=123367319&amp;loc=SL114868664-224227<br><br>Reference 7: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 944<br> -SubTopic 220<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.7-04(8))<br> -URI http://asc.fasb.org/extlink&amp;oid=120400993&amp;loc=SL114874131-224263<br><br>Reference 8: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 942<br> -SubTopic 235<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.9-05(b)(2))<br> -URI http://asc.fasb.org/extlink&amp;oid=120399901&amp;loc=d3e537907-122884<br><br>Reference 9: http://www.xbrl.org/2003/role/exampleRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 280<br> -SubTopic 10<br> -Section 50<br> -Paragraph 31<br> -URI http://asc.fasb.org/extlink&amp;oid=123359005&amp;loc=d3e8924-108599<br><br>Reference 10: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 942<br> -SubTopic 220<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.9-04(15))<br> -URI http://asc.fasb.org/extlink&amp;oid=120399700&amp;loc=SL114874048-224260<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_IncomeLossFromContinuingOperationsBeforeIncomeTaxesExtraordinaryItemsNoncontrollingInterest</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_IncomeStatementAbstract">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_IncomeStatementAbstract</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:stringItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_IncomeTaxExpenseBenefit">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of current income tax expense (benefit) and deferred income tax expense (benefit) pertaining to continuing operations.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SAB TOPIC 6.I.7)<br> -URI http://asc.fasb.org/extlink&amp;oid=122134291&amp;loc=d3e330036-122817<br><br>Reference 2: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section 50<br> -Paragraph 10<br> -URI http://asc.fasb.org/extlink&amp;oid=121826272&amp;loc=d3e32672-109319<br><br>Reference 3: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 280<br> -SubTopic 10<br> -Section 50<br> -Paragraph 22<br> -Subparagraph (h)<br> -URI http://asc.fasb.org/extlink&amp;oid=123359005&amp;loc=d3e8736-108599<br><br>Reference 4: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 235<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.4-08(h))<br> -URI http://asc.fasb.org/extlink&amp;oid=120395691&amp;loc=d3e23780-122690<br><br>Reference 5: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 250<br> -SubTopic 10<br> -Section 50<br> -Paragraph 9<br> -URI http://asc.fasb.org/extlink&amp;oid=124431687&amp;loc=d3e22663-107794<br><br>Reference 6: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 20<br> -Section 45<br> -Paragraph 2<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=123586238&amp;loc=d3e38679-109324<br><br>Reference 7: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 944<br> -SubTopic 220<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.7-04(9))<br> -URI http://asc.fasb.org/extlink&amp;oid=120400993&amp;loc=SL114874131-224263<br><br>Reference 8: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 250<br> -SubTopic 10<br> -Section 50<br> -Paragraph 8<br> -URI http://asc.fasb.org/extlink&amp;oid=124431687&amp;loc=d3e22658-107794<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_IncomeTaxExpenseBenefit</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_InterestExpense">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of the cost of borrowed funds accounted for as interest expense.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 835<br> -SubTopic 20<br> -Section 50<br> -Paragraph 1<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=6450988&amp;loc=d3e26243-108391<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 835<br> -SubTopic 30<br> -Section 45<br> -Paragraph 3<br> -URI http://asc.fasb.org/extlink&amp;oid=124435984&amp;loc=d3e28555-108399<br><br>Reference 3: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 280<br> -SubTopic 10<br> -Section 50<br> -Paragraph 22<br> -Subparagraph (d)<br> -URI http://asc.fasb.org/extlink&amp;oid=123359005&amp;loc=d3e8736-108599<br><br>Reference 4: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 220<br> -SubTopic 10<br> -Section S99<br> -Paragraph 2<br> -Subparagraph (210.5-03(11))<br> -URI http://asc.fasb.org/extlink&amp;oid=123367319&amp;loc=SL114868664-224227<br><br>Reference 5: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 942<br> -SubTopic 220<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.9-04.9)<br> -URI http://asc.fasb.org/extlink&amp;oid=120399700&amp;loc=SL114874048-224260<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_InterestExpense</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_LongTermDebtByComponentsCurrentAndNoncurrentAlternativeAbstract">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_LongTermDebtByComponentsCurrentAndNoncurrentAlternativeAbstract</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:stringItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_NetIncomeLoss">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The portion of profit or loss for the period, net of income taxes, which is attributable to the parent.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 942<br> -SubTopic 220<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.9-04(22))<br> -URI http://asc.fasb.org/extlink&amp;oid=120399700&amp;loc=SL114874048-224260<br><br>Reference 2: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 280<br> -SubTopic 10<br> -Section 50<br> -Paragraph 32<br> -Subparagraph (f)<br> -URI http://asc.fasb.org/extlink&amp;oid=123359005&amp;loc=d3e8933-108599<br><br>Reference 3: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 250<br> -SubTopic 10<br> -Section 50<br> -Paragraph 4<br> -URI 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-Section S99<br> -Paragraph 1B<br> -Subparagraph (SX 210.13-02(a)(4)(i))<br> -URI http://asc.fasb.org/extlink&amp;oid=124359900&amp;loc=SL124442552-122756<br><br>Reference 14: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 470<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1A<br> -Subparagraph (SX 210.13-01(a)(4)(i))<br> -URI http://asc.fasb.org/extlink&amp;oid=124359900&amp;loc=SL124442526-122756<br><br>Reference 15: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 250<br> -SubTopic 10<br> -Section 50<br> -Paragraph 9<br> -URI http://asc.fasb.org/extlink&amp;oid=124431687&amp;loc=d3e22663-107794<br><br>Reference 16: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 470<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1B<br> -Subparagraph (SX 210.13-02(a)(4)(iv))<br> -URI 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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_NetIncomeLoss</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_ProfitLoss">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The consolidated profit or loss for the period, net of income taxes, including the portion attributable to the noncontrolling interest.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 235<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.4-08(g)(1)(ii))<br> -URI http://asc.fasb.org/extlink&amp;oid=120395691&amp;loc=d3e23780-122690<br><br>Reference 2: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 220<br> -SubTopic 10<br> -Section 45<br> -Paragraph 1A<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=124509347&amp;loc=SL7669619-108580<br><br>Reference 3: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 810<br> -SubTopic 10<br> -Section 50<br> -Paragraph 1A<br> -Subparagraph (a)(1)<br> -URI 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FASB<br> -Name Accounting Standards Codification<br> -Topic 250<br> -SubTopic 10<br> -Section 50<br> -Paragraph 8<br> -URI http://asc.fasb.org/extlink&amp;oid=124431687&amp;loc=d3e22658-107794<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ProfitLoss</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
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</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_RetainedEarningsAccumulatedDeficit">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The cumulative amount of the reporting entity's undistributed earnings or deficit.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 210<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.5-02(30)(a)(3))<br> -URI http://asc.fasb.org/extlink&amp;oid=120391452&amp;loc=d3e13212-122682<br><br>Reference 2: http://www.xbrl.org/2003/role/exampleRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 852<br> -SubTopic 10<br> -Section 55<br> -Paragraph 10<br> -URI http://asc.fasb.org/extlink&amp;oid=84165509&amp;loc=d3e56426-112766<br><br>Reference 3: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 718<br> -SubTopic 10<br> -Section 65<br> -Paragraph 15<br> -Subparagraph (g)(2)<br> -URI http://asc.fasb.org/extlink&amp;oid=121322162&amp;loc=SL121327923-165333<br><br>Reference 4: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 944<br> -SubTopic 210<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.7-03(a)(23)(a)(4))<br> -URI http://asc.fasb.org/extlink&amp;oid=120400017&amp;loc=d3e572229-122910<br><br>Reference 5: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 944<br> -SubTopic 40<br> -Section 65<br> -Paragraph 2<br> -Subparagraph (h)(2)<br> -URI http://asc.fasb.org/extlink&amp;oid=124501264&amp;loc=SL117420844-207641<br><br>Reference 6: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 505<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.3-04)<br> -URI http://asc.fasb.org/extlink&amp;oid=120397183&amp;loc=d3e187085-122770<br><br>Reference 7: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 944<br> -SubTopic 40<br> -Section 65<br> -Paragraph 2<br> -Subparagraph (g)(2)(i)<br> -URI http://asc.fasb.org/extlink&amp;oid=124501264&amp;loc=SL117420844-207641<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_RetainedEarningsAccumulatedDeficit</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
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<tr>
<td><strong> Balance Type:</strong></td>
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</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
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<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_StatementOfFinancialPositionAbstract</td>
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<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
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<td><strong> Data Type:</strong></td>
<td>xbrli:stringItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
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<tr>
<td><strong> Period Type:</strong></td>
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</div></td></tr>
</table>
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<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_StatementOfStockholdersEquityAbstract</td>
</tr>
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<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
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<td><strong> Data Type:</strong></td>
<td>xbrli:stringItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_StockholdersEquityIncludingPortionAttributableToNoncontrollingInterest">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of stockholders' equity (deficit), net of receivables from officers, directors, owners, and affiliates of the entity, attributable to both the parent and noncontrolling interests. Amount excludes temporary equity. Alternate caption for the concept is permanent equity.</p></div>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_StockholdersEquityIncludingPortionAttributableToNoncontrollingInterest</td>
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<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
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<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
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<tr>
<td><strong> Period Type:</strong></td>
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</tr>
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</div></td></tr>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
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<tr>
<td><strong> Balance Type:</strong></td>
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<tr>
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<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_StatementEquityComponentsAxis=us-gaap_RetainedEarningsMember</td>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
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<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_StatementEquityComponentsAxis=us-gaap_ParentMember</td>
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<td><strong> Name:</strong></td>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_DebtInstrumentAxis=ions_ConvertibleSeniorNotes1PercentMember</td>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_DebtInstrumentAxis=ions_ConvertibleSeniorNotes0PercentMember</td>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
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<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">srt_RestatementAxis=srt_ScenarioPreviouslyReportedMember</td>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_AdjustmentsForNewAccountingPronouncementsAxis=us-gaap_AccountingStandardsUpdate202006Member</td>
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<DOCUMENT>
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<head>
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<span style="display: none;">v3.22.0.1</span><table class="report" border="0" cellspacing="2" id="idm139691017365128">
<tr>
<th class="tl" colspan="1" rowspan="1"><div style="width: 200px;"><strong>Organization and Significant Accounting Policies, Call Spread (Details)<br></strong></div></th>
<th class="th"><div>Dec. 31, 2021</div></th>
<th class="th"><div>Apr. 30, 2021</div></th>
<th class="th"><div>Dec. 31, 2020</div></th>
<th class="th"><div>Dec. 31, 2019</div></th>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DebtInstrumentAxis=ions_ConvertibleSeniorNotes0PercentMember', window );">0 Percent Convertible Senior Notes [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_GeneralDiscussionOfDerivativeInstrumentsAndHedgingActivitiesAbstract', window );"><strong>Call Spread [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DebtInstrumentInterestRateStatedPercentage', window );">Interest rate on convertible senior notes</a></td>
<td class="nump">0.00%<span></span>
</td>
<td class="nump">0.00%<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">0.00%<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DebtInstrumentAxis=ions_ConvertibleSeniorNotes0125PercentMember', window );">0.125 Percent Convertible Senior Notes [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_GeneralDiscussionOfDerivativeInstrumentsAndHedgingActivitiesAbstract', window );"><strong>Call Spread [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DebtInstrumentInterestRateStatedPercentage', window );">Interest rate on convertible senior notes</a></td>
<td class="nump">0.125%<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">0.125%<span></span>
</td>
<td class="nump">0.125%<span></span>
</td>
</tr>
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<div style="display: none;">
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_DebtInstrumentInterestRateStatedPercentage">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Contractual interest rate for funds borrowed, under the debt agreement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 470<br> -SubTopic 20<br> -Section 50<br> -Paragraph 1B<br> -Subparagraph (b)<br> -URI http://asc.fasb.org/extlink&amp;oid=123466505&amp;loc=SL123495323-112611<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 210<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.5-02.22(a)(1))<br> -URI http://asc.fasb.org/extlink&amp;oid=120391452&amp;loc=d3e13212-122682<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
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<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
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<td style="white-space:nowrap;">us-gaap_GeneralDiscussionOfDerivativeInstrumentsAndHedgingActivitiesAbstract</td>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
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<td><strong> Name:</strong></td>
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<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_DebtInstrumentAxis=ions_ConvertibleSeniorNotes0125PercentMember</td>
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<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
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<td><strong> Data Type:</strong></td>
<td>na</td>
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<tr>
<td><strong> Balance Type:</strong></td>
<td></td>
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<tr>
<td><strong> Period Type:</strong></td>
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<DOCUMENT>
<TYPE>XML
<SEQUENCE>77
<FILENAME>R47.htm
<DESCRIPTION>IDEA: XBRL DOCUMENT
<TEXT>
<html>
<head>
<title></title>
<link rel="stylesheet" type="text/css" href="report.css">
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<span style="display: none;">v3.22.0.1</span><table class="report" border="0" cellspacing="2" id="idm139691017272696">
<tr>
<th class="tl" colspan="1" rowspan="2"><div style="width: 200px;"><strong>Organization and Significant Accounting Policies, Segment Information (Details) - Segment<br></strong></div></th>
<th class="th" colspan="2">12 Months Ended</th>
</tr>
<tr>
<th class="th"><div>Dec. 31, 2021</div></th>
<th class="th"><div>Dec. 31, 2020</div></th>
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<td class="text">&#160;<span></span>
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<td class="text">&#160;<span></span>
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<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_NumberOfOperatingSegments', window );">Number of operating segments</a></td>
<td class="nump">1<span></span>
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<td class="nump">2<span></span>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Number of operating segments. An operating segment is a component of an enterprise: (a) that engages in business activities from which it may earn revenues and incur expenses (including revenues and expenses relating to transactions with other components of the same enterprise), (b) whose operating results are regularly reviewed by the enterprise's chief operating decision maker to make decisions about resources to be allocated to the segment and assess its performance, and (c) for which discrete financial information is available. An operating segment may engage in business activities for which it has yet to earn revenues, for example, start-up operations may be operating segments before earning revenues.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2009/role/commonPracticeRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 280<br> -SubTopic 10<br> -Section 50<br> -Paragraph 18<br> -URI http://asc.fasb.org/extlink&amp;oid=123359005&amp;loc=d3e8672-108599<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
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<td><strong> Period Type:</strong></td>
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<DOCUMENT>
<TYPE>XML
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<DESCRIPTION>IDEA: XBRL DOCUMENT
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<span style="display: none;">v3.22.0.1</span><table class="report" border="0" cellspacing="2" id="idm139690998706952">
<tr>
<th class="tl" colspan="2" rowspan="1"><div style="width: 200px;"><strong>Organization and Significant Accounting Policies, Fair Value Measurements (Details) - USD ($)<br> $ in Thousands</strong></div></th>
<th class="th" colspan="2"><div>Dec. 31, 2021</div></th>
<th class="th"><div>Apr. 30, 2021</div></th>
<th class="th" colspan="2"><div>Dec. 31, 2020</div></th>
<th class="th"><div>Dec. 31, 2019</div></th>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DebtInstrumentAxis=ions_ConvertibleSeniorNotes0125PercentMember', window );">0.125% Notes [Member]</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_FairValueNetAssetLiabilityAbstract', window );"><strong>Fair Value Measurements [Abstract]</strong></a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DebtInstrumentInterestRateStatedPercentage', window );">Interest rate on convertible senior notes</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">0.125%<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">0.125%<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">0.125%<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DebtInstrumentAxis=ions_ConvertibleSeniorNotes0PercentMember', window );">0% Notes [Member]</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_FairValueNetAssetLiabilityAbstract', window );"><strong>Fair Value Measurements [Abstract]</strong></a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DebtInstrumentInterestRateStatedPercentage', window );">Interest rate on convertible senior notes</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">0.00%<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">0.00%<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">0.00%<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_FairValueByMeasurementFrequencyAxis=us-gaap_FairValueMeasurementsRecurringMember', window );">Recurring Basis [Member]</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_FairValueNetAssetLiabilityAbstract', window );"><strong>Fair Value Measurements [Abstract]</strong></a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_CashAndCashEquivalentsFairValueDisclosure', window );">Cash equivalents</a></td>
<td class="th" style="border-bottom: 0px;"><sup>[1]</sup></td>
<td class="nump">$ 541,199<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 221,125<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rou">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AssetsFairValueDisclosure', window );">Total</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">1,807,528<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">1,745,363<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_FairValueByMeasurementFrequencyAxis=us-gaap_FairValueMeasurementsRecurringMember', window );">Recurring Basis [Member] | Bicycle Therapeutics plc [Member]</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_FairValueNetAssetLiabilityAbstract', window );"><strong>Fair Value Measurements [Abstract]</strong></a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_EquitySecuritiesFvNi', window );">Investment</a></td>
<td class="th" style="border-bottom: 0px;"><sup>[2]</sup></td>
<td class="nump">14,330<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_FairValueByMeasurementFrequencyAxis=us-gaap_FairValueMeasurementsRecurringMember', window );">Recurring Basis [Member] | ProQR Therapeutics N.V. [Member]</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_FairValueNetAssetLiabilityAbstract', window );"><strong>Fair Value Measurements [Abstract]</strong></a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_EquitySecuritiesFvNi', window );">Investment</a></td>
<td class="th" style="border-bottom: 0px;"><sup>[2]</sup></td>
<td class="nump">3,875<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">2,031<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_FairValueByMeasurementFrequencyAxis=us-gaap_FairValueMeasurementsRecurringMember', window );">Recurring Basis [Member] | Corporate Debt Securities [Member]</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_FairValueNetAssetLiabilityAbstract', window );"><strong>Fair Value Measurements [Abstract]</strong></a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleSecuritiesDebtSecurities', window );">Available-for-sale securities</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">764,059<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"><sup>[3]</sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">846,315<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"><sup>[4]</sup></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_FairValueByMeasurementFrequencyAxis=us-gaap_FairValueMeasurementsRecurringMember', window );">Recurring Basis [Member] | Corporate Debt Securities [Member] | Cash and Cash Equivalents [Member]</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_FairValueNetAssetLiabilityAbstract', window );"><strong>Fair Value Measurements [Abstract]</strong></a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleSecuritiesDebtSecurities', window );">Available-for-sale securities</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">2,300<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">10,000<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_FairValueByMeasurementFrequencyAxis=us-gaap_FairValueMeasurementsRecurringMember', window );">Recurring Basis [Member] | Debt Securities Issued by U.S. Government Agencies [Member]</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_FairValueNetAssetLiabilityAbstract', window );"><strong>Fair Value Measurements [Abstract]</strong></a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleSecuritiesDebtSecurities', window );">Available-for-sale securities</a></td>
<td class="th" style="border-bottom: 0px;"><sup>[3]</sup></td>
<td class="nump">120,868<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">174,861<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_FairValueByMeasurementFrequencyAxis=us-gaap_FairValueMeasurementsRecurringMember', window );">Recurring Basis [Member] | Debt Securities Issued by U.S. Government Agencies [Member] | Cash and Cash Equivalents [Member]</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_FairValueNetAssetLiabilityAbstract', window );"><strong>Fair Value Measurements [Abstract]</strong></a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleSecuritiesDebtSecurities', window );">Available-for-sale securities</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">17,500<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_FairValueByMeasurementFrequencyAxis=us-gaap_FairValueMeasurementsRecurringMember', window );">Recurring Basis [Member] | Debt Securities Issued by the U.S. Treasury [Member]</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_FairValueNetAssetLiabilityAbstract', window );"><strong>Fair Value Measurements [Abstract]</strong></a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleSecuritiesDebtSecurities', window );">Available-for-sale securities</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">182,634<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"><sup>[3]</sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">358,497<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"><sup>[5]</sup></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_FairValueByMeasurementFrequencyAxis=us-gaap_FairValueMeasurementsRecurringMember', window );">Recurring Basis [Member] | Debt Securities Issued by States of the U.S. and Political Subdivisions of the States [Member]</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_FairValueNetAssetLiabilityAbstract', window );"><strong>Fair Value Measurements [Abstract]</strong></a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleSecuritiesDebtSecurities', window );">Available-for-sale securities</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">174,464<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"><sup>[6]</sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">136,309<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"><sup>[3]</sup></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_FairValueByMeasurementFrequencyAxis=us-gaap_FairValueMeasurementsRecurringMember', window );">Recurring Basis [Member] | Other Municipal Debt Securities [Member]</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_FairValueNetAssetLiabilityAbstract', window );"><strong>Fair Value Measurements [Abstract]</strong></a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleSecuritiesDebtSecurities', window );">Available-for-sale securities</a></td>
<td class="th" style="border-bottom: 0px;"><sup>[3]</sup></td>
<td class="nump">6,099<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">6,225<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_FairValueByMeasurementFrequencyAxis=us-gaap_FairValueMeasurementsRecurringMember', window );">Recurring Basis [Member] | Quoted Prices in Active Markets (Level 1) [Member]</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_FairValueNetAssetLiabilityAbstract', window );"><strong>Fair Value Measurements [Abstract]</strong></a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_CashAndCashEquivalentsFairValueDisclosure', window );">Cash equivalents</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">541,199<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">221,125<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="reu">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AssetsFairValueDisclosure', window );">Total</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">727,708<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">581,653<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_FairValueByMeasurementFrequencyAxis=us-gaap_FairValueMeasurementsRecurringMember', window );">Recurring Basis [Member] | Quoted Prices in Active Markets (Level 1) [Member] | Bicycle Therapeutics plc [Member]</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_FairValueNetAssetLiabilityAbstract', window );"><strong>Fair Value Measurements [Abstract]</strong></a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_EquitySecuritiesFvNi', window );">Investment</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">0<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_FairValueByMeasurementFrequencyAxis=us-gaap_FairValueMeasurementsRecurringMember', window );">Recurring Basis [Member] | Quoted Prices in Active Markets (Level 1) [Member] | ProQR Therapeutics N.V. [Member]</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_FairValueNetAssetLiabilityAbstract', window );"><strong>Fair Value Measurements [Abstract]</strong></a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_EquitySecuritiesFvNi', window );">Investment</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">3,875<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">2,031<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_FairValueByMeasurementFrequencyAxis=us-gaap_FairValueMeasurementsRecurringMember', window );">Recurring Basis [Member] | Quoted Prices in Active Markets (Level 1) [Member] | Corporate Debt Securities [Member]</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_FairValueNetAssetLiabilityAbstract', window );"><strong>Fair Value Measurements [Abstract]</strong></a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleSecuritiesDebtSecurities', window );">Available-for-sale securities</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">0<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_FairValueByMeasurementFrequencyAxis=us-gaap_FairValueMeasurementsRecurringMember', window );">Recurring Basis [Member] | Quoted Prices in Active Markets (Level 1) [Member] | Debt Securities Issued by U.S. Government Agencies [Member]</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_FairValueNetAssetLiabilityAbstract', window );"><strong>Fair Value Measurements [Abstract]</strong></a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleSecuritiesDebtSecurities', window );">Available-for-sale securities</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">0<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_FairValueByMeasurementFrequencyAxis=us-gaap_FairValueMeasurementsRecurringMember', window );">Recurring Basis [Member] | Quoted Prices in Active Markets (Level 1) [Member] | Debt Securities Issued by the U.S. Treasury [Member]</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_FairValueNetAssetLiabilityAbstract', window );"><strong>Fair Value Measurements [Abstract]</strong></a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleSecuritiesDebtSecurities', window );">Available-for-sale securities</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">182,634<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">358,497<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_FairValueByMeasurementFrequencyAxis=us-gaap_FairValueMeasurementsRecurringMember', window );">Recurring Basis [Member] | Quoted Prices in Active Markets (Level 1) [Member] | Debt Securities Issued by States of the U.S. and Political Subdivisions of the States [Member]</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_FairValueNetAssetLiabilityAbstract', window );"><strong>Fair Value Measurements [Abstract]</strong></a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleSecuritiesDebtSecurities', window );">Available-for-sale securities</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">0<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_FairValueByMeasurementFrequencyAxis=us-gaap_FairValueMeasurementsRecurringMember', window );">Recurring Basis [Member] | Quoted Prices in Active Markets (Level 1) [Member] | Other Municipal Debt Securities [Member]</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_FairValueNetAssetLiabilityAbstract', window );"><strong>Fair Value Measurements [Abstract]</strong></a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleSecuritiesDebtSecurities', window );">Available-for-sale securities</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">0<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_FairValueByMeasurementFrequencyAxis=us-gaap_FairValueMeasurementsRecurringMember', window );">Recurring Basis [Member] | Significant Other Observable Inputs (Level 2) [Member]</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_FairValueNetAssetLiabilityAbstract', window );"><strong>Fair Value Measurements [Abstract]</strong></a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_CashAndCashEquivalentsFairValueDisclosure', window );">Cash equivalents</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">0<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rou">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AssetsFairValueDisclosure', window );">Total</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">1,065,490<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">1,163,710<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_FairValueByMeasurementFrequencyAxis=us-gaap_FairValueMeasurementsRecurringMember', window );">Recurring Basis [Member] | Significant Other Observable Inputs (Level 2) [Member] | 0.125% Notes [Member]</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_FairValueNetAssetLiabilityAbstract', window );"><strong>Fair Value Measurements [Abstract]</strong></a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_NotesPayableFairValueDisclosure', window );">Fair value of convertible notes</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">495,400<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_FairValueByMeasurementFrequencyAxis=us-gaap_FairValueMeasurementsRecurringMember', window );">Recurring Basis [Member] | Significant Other Observable Inputs (Level 2) [Member] | 0% Notes [Member]</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_FairValueNetAssetLiabilityAbstract', window );"><strong>Fair Value Measurements [Abstract]</strong></a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_NotesPayableFairValueDisclosure', window );">Fair value of convertible notes</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">559,200<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_FairValueByMeasurementFrequencyAxis=us-gaap_FairValueMeasurementsRecurringMember', window );">Recurring Basis [Member] | Significant Other Observable Inputs (Level 2) [Member] | Bicycle Therapeutics plc [Member]</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_FairValueNetAssetLiabilityAbstract', window );"><strong>Fair Value Measurements [Abstract]</strong></a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_EquitySecuritiesFvNi', window );">Investment</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">0<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_FairValueByMeasurementFrequencyAxis=us-gaap_FairValueMeasurementsRecurringMember', window );">Recurring Basis [Member] | Significant Other Observable Inputs (Level 2) [Member] | ProQR Therapeutics N.V. [Member]</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_FairValueNetAssetLiabilityAbstract', window );"><strong>Fair Value Measurements [Abstract]</strong></a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_EquitySecuritiesFvNi', window );">Investment</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">0<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_FairValueByMeasurementFrequencyAxis=us-gaap_FairValueMeasurementsRecurringMember', window );">Recurring Basis [Member] | Significant Other Observable Inputs (Level 2) [Member] | Corporate Debt Securities [Member]</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_FairValueNetAssetLiabilityAbstract', window );"><strong>Fair Value Measurements [Abstract]</strong></a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleSecuritiesDebtSecurities', window );">Available-for-sale securities</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">764,059<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">846,315<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_FairValueByMeasurementFrequencyAxis=us-gaap_FairValueMeasurementsRecurringMember', window );">Recurring Basis [Member] | Significant Other Observable Inputs (Level 2) [Member] | Debt Securities Issued by U.S. Government Agencies [Member]</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_FairValueNetAssetLiabilityAbstract', window );"><strong>Fair Value Measurements [Abstract]</strong></a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleSecuritiesDebtSecurities', window );">Available-for-sale securities</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">120,868<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">174,861<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_FairValueByMeasurementFrequencyAxis=us-gaap_FairValueMeasurementsRecurringMember', window );">Recurring Basis [Member] | Significant Other Observable Inputs (Level 2) [Member] | Debt Securities Issued by the U.S. Treasury [Member]</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_FairValueNetAssetLiabilityAbstract', window );"><strong>Fair Value Measurements [Abstract]</strong></a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleSecuritiesDebtSecurities', window );">Available-for-sale securities</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">0<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_FairValueByMeasurementFrequencyAxis=us-gaap_FairValueMeasurementsRecurringMember', window );">Recurring Basis [Member] | Significant Other Observable Inputs (Level 2) [Member] | Debt Securities Issued by States of the U.S. and Political Subdivisions of the States [Member]</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_FairValueNetAssetLiabilityAbstract', window );"><strong>Fair Value Measurements [Abstract]</strong></a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleSecuritiesDebtSecurities', window );">Available-for-sale securities</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">174,464<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">136,309<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_FairValueByMeasurementFrequencyAxis=us-gaap_FairValueMeasurementsRecurringMember', window );">Recurring Basis [Member] | Significant Other Observable Inputs (Level 2) [Member] | Other Municipal Debt Securities [Member]</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_FairValueNetAssetLiabilityAbstract', window );"><strong>Fair Value Measurements [Abstract]</strong></a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleSecuritiesDebtSecurities', window );">Available-for-sale securities</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">6,099<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">6,225<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_FairValueByMeasurementFrequencyAxis=us-gaap_FairValueMeasurementsRecurringMember', window );">Recurring Basis [Member] | Significant Unobservable Inputs (Level 3) [Member]</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_FairValueNetAssetLiabilityAbstract', window );"><strong>Fair Value Measurements [Abstract]</strong></a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_CashAndCashEquivalentsFairValueDisclosure', window );">Cash equivalents</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">0<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="reu">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AssetsFairValueDisclosure', window );">Total</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">14,330<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 0<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_FairValueByMeasurementFrequencyAxis=us-gaap_FairValueMeasurementsRecurringMember', window );">Recurring Basis [Member] | Significant Unobservable Inputs (Level 3) [Member] | Bicycle Therapeutics plc [Member]</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_FairValueNetAssetLiabilityAbstract', window );"><strong>Fair Value Measurements [Abstract]</strong></a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_EquitySecuritiesFvNi', window );">Investment</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">14,330<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_FairValueByMeasurementFrequencyAxis=us-gaap_FairValueMeasurementsRecurringMember', window );">Recurring Basis [Member] | Significant Unobservable Inputs (Level 3) [Member] | ProQR Therapeutics N.V. [Member]</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_FairValueNetAssetLiabilityAbstract', window );"><strong>Fair Value Measurements [Abstract]</strong></a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_EquitySecuritiesFvNi', window );">Investment</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">0<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_FairValueByMeasurementFrequencyAxis=us-gaap_FairValueMeasurementsRecurringMember', window );">Recurring Basis [Member] | Significant Unobservable Inputs (Level 3) [Member] | Corporate Debt Securities [Member]</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_FairValueNetAssetLiabilityAbstract', window );"><strong>Fair Value Measurements [Abstract]</strong></a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleSecuritiesDebtSecurities', window );">Available-for-sale securities</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">0<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_FairValueByMeasurementFrequencyAxis=us-gaap_FairValueMeasurementsRecurringMember', window );">Recurring Basis [Member] | Significant Unobservable Inputs (Level 3) [Member] | Debt Securities Issued by U.S. Government Agencies [Member]</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_FairValueNetAssetLiabilityAbstract', window );"><strong>Fair Value Measurements [Abstract]</strong></a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleSecuritiesDebtSecurities', window );">Available-for-sale securities</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">0<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_FairValueByMeasurementFrequencyAxis=us-gaap_FairValueMeasurementsRecurringMember', window );">Recurring Basis [Member] | Significant Unobservable Inputs (Level 3) [Member] | Debt Securities Issued by the U.S. Treasury [Member]</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_FairValueNetAssetLiabilityAbstract', window );"><strong>Fair Value Measurements [Abstract]</strong></a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleSecuritiesDebtSecurities', window );">Available-for-sale securities</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">0<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_FairValueByMeasurementFrequencyAxis=us-gaap_FairValueMeasurementsRecurringMember', window );">Recurring Basis [Member] | Significant Unobservable Inputs (Level 3) [Member] | Debt Securities Issued by States of the U.S. and Political Subdivisions of the States [Member]</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_FairValueNetAssetLiabilityAbstract', window );"><strong>Fair Value Measurements [Abstract]</strong></a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleSecuritiesDebtSecurities', window );">Available-for-sale securities</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">0<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_FairValueByMeasurementFrequencyAxis=us-gaap_FairValueMeasurementsRecurringMember', window );">Recurring Basis [Member] | Significant Unobservable Inputs (Level 3) [Member] | Other Municipal Debt Securities [Member]</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_FairValueNetAssetLiabilityAbstract', window );"><strong>Fair Value Measurements [Abstract]</strong></a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleSecuritiesDebtSecurities', window );">Available-for-sale securities</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">$ 0<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr><td colspan="7"></td></tr>
<tr><td colspan="7"><table class="outerFootnotes" width="100%">
<tr class="outerFootnote">
<td style="vertical-align: top; width: 12pt;" valign="top">[1]</td>
<td style="vertical-align: top;" valign="top">Included in cash and cash
            equivalents on our consolidated balance sheet.</td>
</tr>
<tr class="outerFootnote">
<td style="vertical-align: top; width: 12pt;" valign="top">[2]</td>
<td style="vertical-align: top;" valign="top">Included in other current assets
            on our consolidated balance sheet.</td>
</tr>
<tr class="outerFootnote">
<td style="vertical-align: top; width: 12pt;" valign="top">[3]</td>
<td style="vertical-align: top;" valign="top">Included in short-term
            investments.</td>
</tr>
<tr class="outerFootnote">
<td style="vertical-align: top; width: 12pt;" valign="top">[4]</td>
<td style="vertical-align: top;" valign="top">$10.0 million included in cash and cash equivalents on our consolidated balance sheet, with the difference included in short-term investments on our
            consolidated balance sheet.</td>
</tr>
<tr class="outerFootnote">
<td style="vertical-align: top; width: 12pt;" valign="top">[5]</td>
<td style="vertical-align: top;" valign="top">$17.5 million included in cash and cash equivalents on our consolidated balance sheet, with the difference included in short-term investments on our
            consolidated balance sheet.</td>
</tr>
<tr class="outerFootnote">
<td style="vertical-align: top; width: 12pt;" valign="top">[6]</td>
<td style="vertical-align: top;" valign="top">$2.3 million included in cash and cash equivalents on our consolidated balance sheet, with the difference included in short-term investments on our
            consolidated balance sheet.</td>
</tr>
</table></td></tr>
</table>
<div style="display: none;">
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Fair value portion of probable future economic benefits obtained or controlled by an entity as a result of past transactions or events.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 820<br> -SubTopic 10<br> -Section 50<br> -Paragraph 2<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=123874694&amp;loc=d3e19207-110258<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of investment in debt security measured at fair value with change in fair value recognized in other comprehensive income (available-for-sale).</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 942<br> -SubTopic 210<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.9-03(6))<br> -URI http://asc.fasb.org/extlink&amp;oid=120398452&amp;loc=d3e534808-122878<br><br>Reference 2: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 326<br> -SubTopic 30<br> -Section 45<br> -Paragraph 1<br> -URI http://asc.fasb.org/extlink&amp;oid=124258926&amp;loc=SL82898722-210454<br><br>Reference 3: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 320<br> -SubTopic 10<br> -Section 45<br> -Paragraph 1<br> -Subparagraph (b)<br> -URI http://asc.fasb.org/extlink&amp;oid=124260329&amp;loc=d3e26610-111562<br><br>Reference 4: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 320<br> -SubTopic 10<br> -Section 50<br> -Paragraph 2<br> -Subparagraph (aa)<br> -URI http://asc.fasb.org/extlink&amp;oid=123581744&amp;loc=d3e27161-111563<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_AvailableForSaleSecuritiesDebtSecurities</td>
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<td><strong> Balance Type:</strong></td>
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<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_CashAndCashEquivalentsFairValueDisclosure">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Fair value portion of currency on hand as well as demand deposits with banks or financial institutions. Includes other kinds of accounts that have the general characteristics of demand deposits. Also includes short-term, highly liquid investments that are both readily convertible to known amounts of cash and so near their maturity that they present insignificant risk of changes in value because of changes in interest rates.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_CashAndCashEquivalentsFairValueDisclosure</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_DebtInstrumentInterestRateStatedPercentage">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Contractual interest rate for funds borrowed, under the debt agreement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 470<br> -SubTopic 20<br> -Section 50<br> -Paragraph 1B<br> -Subparagraph (b)<br> -URI http://asc.fasb.org/extlink&amp;oid=123466505&amp;loc=SL123495323-112611<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 210<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.5-02.22(a)(1))<br> -URI http://asc.fasb.org/extlink&amp;oid=120391452&amp;loc=d3e13212-122682<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_DebtInstrumentInterestRateStatedPercentage</td>
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<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
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<tr>
<td><strong> Data Type:</strong></td>
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<td><strong> Balance Type:</strong></td>
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<td><strong> Period Type:</strong></td>
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</table></div>
</div></td></tr>
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<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_EquitySecuritiesFvNi">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of investment in equity security measured at fair value with change in fair value recognized in net income (FV-NI), classified as current.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 825<br> -SubTopic 10<br> -Section 45<br> -Paragraph 1A<br> -URI http://asc.fasb.org/extlink&amp;oid=123594786&amp;loc=SL75136599-209740<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_EquitySecuritiesFvNi</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_FairValueNetAssetLiabilityAbstract">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_FairValueNetAssetLiabilityAbstract</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
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<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:stringItemType</td>
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<td><strong> Balance Type:</strong></td>
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</tr>
<tr>
<td><strong> Period Type:</strong></td>
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</tr>
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<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_NotesPayableFairValueDisclosure">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Fair value portion of notes payable.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 210<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.5-02.19,20,22)<br> -URI http://asc.fasb.org/extlink&amp;oid=120391452&amp;loc=d3e13212-122682<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_NotesPayableFairValueDisclosure</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
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<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_DebtInstrumentAxis=ions_ConvertibleSeniorNotes0125PercentMember</td>
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<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
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<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
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<tr>
<td><strong> Name:</strong></td>
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<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
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<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
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<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
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<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
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<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_BalanceSheetLocationAxis=us-gaap_CashAndCashEquivalentsMember</td>
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<td></td>
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<td></td>
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<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_FinancialInstrumentAxis=us-gaap_USGovernmentAgenciesDebtSecuritiesMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_FinancialInstrumentAxis=us-gaap_USGovernmentAgenciesDebtSecuritiesMember</td>
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<td><strong> Balance Type:</strong></td>
<td></td>
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<tr>
<td><strong> Period Type:</strong></td>
<td></td>
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<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_FinancialInstrumentAxis=us-gaap_USTreasurySecuritiesMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_FinancialInstrumentAxis=us-gaap_USTreasurySecuritiesMember</td>
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<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_FinancialInstrumentAxis=us-gaap_USStatesAndPoliticalSubdivisionsMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
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<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
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<tr>
<td><strong> Name:</strong></td>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_FairValueByFairValueHierarchyLevelAxis=us-gaap_FairValueInputsLevel3Member</td>
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<tr>
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<td><strong> Data Type:</strong></td>
<td>na</td>
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<tr>
<td><strong> Balance Type:</strong></td>
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<tr>
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<DOCUMENT>
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<DESCRIPTION>IDEA: XBRL DOCUMENT
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<html>
<head>
<title></title>
<link rel="stylesheet" type="text/css" href="report.css">
<script type="text/javascript" src="Show.js">/* Do Not Remove This Comment */</script><script type="text/javascript">
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<span style="display: none;">v3.22.0.1</span><table class="report" border="0" cellspacing="2" id="idm139691012822216">
<tr>
<th class="tl" colspan="1" rowspan="2"><div style="width: 200px;"><strong>Investments, Contract Maturity of Available-for-Sale Securities (Details)<br></strong></div></th>
<th class="th" colspan="1">12 Months Ended</th>
</tr>
<tr><th class="th">
<div>Dec. 31, 2021 </div>
<div>Company</div>
</th></tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleSecuritiesDebtMaturitiesAbstract', window );"><strong>Contract Maturity of Available-for-Sale Securities [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_AvailableForSaleSecuritiesDebtMaturitiesWithinOneYearPercentage', window );">One year or less</a></td>
<td class="nump">51.00%<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_AvailableForSaleSecuritiesDebtMaturitiesAfterOneThroughTwoYearsPercentage', window );">After one year but within two years</a></td>
<td class="nump">34.00%<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_AvailableForSaleSecuritiesDebtMaturitiesAfterTwoThroughThreeAndOneHalfYearsPercentage', window );">After two years but within three and a half years</a></td>
<td class="nump">15.00%<span></span>
</td>
</tr>
<tr class="reu">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_AvailableForSaleSecuritiesDebtMaturitiesTotalPercentage', window );">Total</a></td>
<td class="nump">100.00%<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_AvailableForSaleSecuritiesDebtMaturitiesWithinTwoYearsPercentage', window );">Percentage of available-for-sale securities with a maturity of less than two years</a></td>
<td class="nump">85.00%<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_MaximumContractMaturityPeriodRange1', window );">Maximum contract maturity period, range 1</a></td>
<td class="text">1 year<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_MaximumContractMaturityPeriodRange2', window );">Maximum contract maturity period, range 2</a></td>
<td class="text">2 years<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_MaximumContractMaturityPeriodRange3', window );">Maximum contract maturity period, range 3</a></td>
<td class="text">3 years 6 months<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_InvestmentsAllOtherInvestmentsAbstract', window );"><strong>Ownership Interests in Private and Public Companies [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_NumberOfPrivatelyHeldCompaniesInWhichEntityHasEquityInvestment', window );">Number of privately held companies in which there is an equity ownership interest of less than 20%</a></td>
<td class="nump">7<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_NumberOfPubliclyHeldCompaniesInWhichEntityHasEquityInvestment', window );">Number of publicly held companies in which there is an equity ownership interest of less than 20%</a></td>
<td class="nump">3<span></span>
</td>
</tr>
</table>
<div style="display: none;">
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_AvailableForSaleSecuritiesDebtMaturitiesAfterOneThroughTwoYearsPercentage">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The percentage of available-for-sale debt securities that mature beyond one year but within two years of the balance sheet date.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_AvailableForSaleSecuritiesDebtMaturitiesAfterOneThroughTwoYearsPercentage</td>
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<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
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<td>dtr-types:percentItemType</td>
</tr>
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<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
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<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_AvailableForSaleSecuritiesDebtMaturitiesAfterTwoThroughThreeAndOneHalfYearsPercentage">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The percentage of available-for-sale debt securities that mature beyond two years but within three and one-half years of the balance sheet date.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_AvailableForSaleSecuritiesDebtMaturitiesAfterTwoThroughThreeAndOneHalfYearsPercentage</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
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<td><strong> Balance Type:</strong></td>
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<td><strong> Period Type:</strong></td>
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<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The aggregate percentage of all available-for-sale debt securities, regardless of maturity.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_AvailableForSaleSecuritiesDebtMaturitiesTotalPercentage</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
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<tr>
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<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
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<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_AvailableForSaleSecuritiesDebtMaturitiesWithinOneYearPercentage">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The percentage of available-for-sale debt securities that mature within one year of the balance sheet date.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_AvailableForSaleSecuritiesDebtMaturitiesWithinOneYearPercentage</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
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<tr>
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<td><strong> Balance Type:</strong></td>
<td>na</td>
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<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
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<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_AvailableForSaleSecuritiesDebtMaturitiesWithinTwoYearsPercentage">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The percentage of available-for-sale debt securities that mature within two years of the balance sheet date.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_AvailableForSaleSecuritiesDebtMaturitiesWithinTwoYearsPercentage</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
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<td><strong> Data Type:</strong></td>
<td>dtr-types:percentItemType</td>
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<td><strong> Balance Type:</strong></td>
<td>na</td>
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<td><strong> Period Type:</strong></td>
<td>instant</td>
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</table></div>
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<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_MaximumContractMaturityPeriodRange1">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The maximum contract maturity period for the first range of available-for-sale securities, in 'PnYnMnDTnHnMnS' format, for example, 'P1Y5M13D' represents the reported fact of one year, five months, and thirteen days.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_MaximumContractMaturityPeriodRange1</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
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<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:durationItemType</td>
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<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
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<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
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<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_MaximumContractMaturityPeriodRange2">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The maximum contract maturity period for the second range of available-for-sale securities, in 'PnYnMnDTnHnMnS' format, for example, 'P1Y5M13D' represents the reported fact of one year, five months, and thirteen days.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_MaximumContractMaturityPeriodRange2</td>
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<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
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<td><strong> Data Type:</strong></td>
<td>xbrli:durationItemType</td>
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<td><strong> Balance Type:</strong></td>
<td>na</td>
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<td><strong> Period Type:</strong></td>
<td>duration</td>
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</table></div>
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<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_MaximumContractMaturityPeriodRange3">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The maximum contract maturity period for the third range of available-for-sale securities, in 'PnYnMnDTnHnMnS' format, for example, 'P1Y5M13D' represents the reported fact of one year, five months, and thirteen days.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_MaximumContractMaturityPeriodRange3</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
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<td><strong> Data Type:</strong></td>
<td>xbrli:durationItemType</td>
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<td><strong> Balance Type:</strong></td>
<td>na</td>
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<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_NumberOfPrivatelyHeldCompaniesInWhichEntityHasEquityInvestment">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Number of privately-held companies, in which the entity has an equity ownership interest of less than 20%, with which it conducts business. These are accounted for under the cost method.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_NumberOfPrivatelyHeldCompaniesInWhichEntityHasEquityInvestment</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:integerItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_NumberOfPubliclyHeldCompaniesInWhichEntityHasEquityInvestment">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Number of publicly-held companies, in which the entity has an equity ownership interest of less than 20%, with which it conducts business. These are accounted for at fair value.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_NumberOfPubliclyHeldCompaniesInWhichEntityHasEquityInvestment</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:integerItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_AvailableForSaleSecuritiesDebtMaturitiesAbstract">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_AvailableForSaleSecuritiesDebtMaturitiesAbstract</td>
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<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
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<td><strong> Data Type:</strong></td>
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<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_InvestmentsAllOtherInvestmentsAbstract">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_InvestmentsAllOtherInvestmentsAbstract</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
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<td><strong> Balance Type:</strong></td>
<td>na</td>
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<td>duration</td>
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<DOCUMENT>
<TYPE>XML
<SEQUENCE>80
<FILENAME>R50.htm
<DESCRIPTION>IDEA: XBRL DOCUMENT
<TEXT>
<html>
<head>
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<span style="display: none;">v3.22.0.1</span><table class="report" border="0" cellspacing="2" id="idm139691003708840">
<tr>
<th class="tl" colspan="2" rowspan="2"><div style="width: 200px;"><strong>Investments, Summary of Investments (Details) - USD ($)<br> $ in Thousands</strong></div></th>
<th class="th" colspan="2">12 Months Ended</th>
</tr>
<tr>
<th class="th"><div>Dec. 31, 2021</div></th>
<th class="th"><div>Dec. 31, 2020</div></th>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleSecuritiesFairValueToAmortizedCostBasisAbstract', window );"><strong>Summary of Investments [Abstract]</strong></a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rou">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_DebtSecuritiesAvailableForSaleAndEquitySecuritiesFvNiCost', window );">Amortized cost</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">$ 1,278,684<span></span>
</td>
<td class="nump">$ 1,533,544<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_DebtSecuritiesAvailableForSaleAndEquitySecuritiesFvNiGrossUnrealizedGain', window );">Gross unrealized gains</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">25,115<span></span>
</td>
<td class="nump">24,515<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_DebtSecuritiesAvailableForSaleAndEquitySecuritiesFvNiGrossUnrealizedLoss', window );">Gross unrealized losses</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="num">(5,148)<span></span>
</td>
<td class="num">(2,821)<span></span>
</td>
</tr>
<tr class="reu">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_DebtSecuritiesAvailableForSaleAndEquitySecuritiesFvNi', window );">Estimated fair value</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">1,298,651<span></span>
</td>
<td class="nump">1,555,238<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_FinancialInstrumentAxis=us-gaap_DebtSecuritiesMember', window );">Available-for-sale Securities [Member]</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleSecuritiesFairValueToAmortizedCostBasisAbstract', window );"><strong>Summary of Investments [Abstract]</strong></a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rou">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleDebtSecuritiesAmortizedCostBasis', window );">Amortized cost</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">1,251,172<span></span>
</td>
<td class="nump">1,513,770<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleDebtSecuritiesAccumulatedGrossUnrealizedGainBeforeTax', window );">Gross unrealized gains</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">1,263<span></span>
</td>
<td class="nump">8,577<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleDebtSecuritiesAccumulatedGrossUnrealizedLossBeforeTax', window );">Gross unrealized losses</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="num">(4,311)<span></span>
</td>
<td class="num">(140)<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleSecuritiesDebtSecurities', window );">Estimated fair value</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">1,248,124<span></span>
</td>
<td class="nump">1,522,207<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_FinancialInstrumentAxis=us-gaap_DebtSecuritiesMember', window );">Available-for-sale Securities [Member] | Securities with Maturity of One Year or Less [Member]</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleSecuritiesFairValueToAmortizedCostBasisAbstract', window );"><strong>Summary of Investments [Abstract]</strong></a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rou">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleDebtSecuritiesAmortizedCostBasis', window );">Amortized cost</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">612,557<span></span>
</td>
<td class="nump">1,025,454<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleDebtSecuritiesAccumulatedGrossUnrealizedGainBeforeTax', window );">Gross unrealized gains</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">792<span></span>
</td>
<td class="nump">2,977<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleDebtSecuritiesAccumulatedGrossUnrealizedLossBeforeTax', window );">Gross unrealized losses</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="num">(345)<span></span>
</td>
<td class="num">(71)<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleSecuritiesDebtSecurities', window );">Estimated fair value</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">613,004<span></span>
</td>
<td class="nump">1,028,360<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_FinancialInstrumentAxis=us-gaap_DebtSecuritiesMember', window );">Available-for-sale Securities [Member] | Securities with Maturity of More than One Year [Member]</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleSecuritiesFairValueToAmortizedCostBasisAbstract', window );"><strong>Summary of Investments [Abstract]</strong></a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rou">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleDebtSecuritiesAmortizedCostBasis', window );">Amortized cost</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">638,615<span></span>
</td>
<td class="nump">488,316<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleDebtSecuritiesAccumulatedGrossUnrealizedGainBeforeTax', window );">Gross unrealized gains</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">471<span></span>
</td>
<td class="nump">5,600<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleDebtSecuritiesAccumulatedGrossUnrealizedLossBeforeTax', window );">Gross unrealized losses</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="num">(3,966)<span></span>
</td>
<td class="num">(69)<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleSecuritiesDebtSecurities', window );">Estimated fair value</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">635,120<span></span>
</td>
<td class="nump">493,847<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_FinancialInstrumentAxis=us-gaap_CorporateDebtSecuritiesMember', window );">Corporate Debt Securities [Member] | Securities with Maturity of One Year or Less [Member]</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleSecuritiesFairValueToAmortizedCostBasisAbstract', window );"><strong>Summary of Investments [Abstract]</strong></a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rou">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleDebtSecuritiesAmortizedCostBasis', window );">Amortized cost</a></td>
<td class="th" style="border-bottom: 0px;"><sup>[1]</sup></td>
<td class="nump">383,870<span></span>
</td>
<td class="nump">514,182<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleDebtSecuritiesAccumulatedGrossUnrealizedGainBeforeTax', window );">Gross unrealized gains</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">728<span></span>
</td>
<td class="nump">2,194<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleDebtSecuritiesAccumulatedGrossUnrealizedLossBeforeTax', window );">Gross unrealized losses</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="num">(226)<span></span>
</td>
<td class="num">(41)<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleSecuritiesDebtSecurities', window );">Estimated fair value</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">384,372<span></span>
</td>
<td class="nump">516,335<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_FinancialInstrumentAxis=us-gaap_CorporateDebtSecuritiesMember', window );">Corporate Debt Securities [Member] | Securities with Maturity of More than One Year [Member]</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleSecuritiesFairValueToAmortizedCostBasisAbstract', window );"><strong>Summary of Investments [Abstract]</strong></a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rou">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleDebtSecuritiesAmortizedCostBasis', window );">Amortized cost</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">382,000<span></span>
</td>
<td class="nump">325,079<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleDebtSecuritiesAccumulatedGrossUnrealizedGainBeforeTax', window );">Gross unrealized gains</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">331<span></span>
</td>
<td class="nump">4,941<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleDebtSecuritiesAccumulatedGrossUnrealizedLossBeforeTax', window );">Gross unrealized losses</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="num">(2,644)<span></span>
</td>
<td class="num">(40)<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleSecuritiesDebtSecurities', window );">Estimated fair value</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">379,687<span></span>
</td>
<td class="nump">329,980<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_FinancialInstrumentAxis=us-gaap_USGovernmentAgenciesDebtSecuritiesMember', window );">Debt Securities Issued by U.S. Government Agencies [Member] | Securities with Maturity of One Year or Less [Member]</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleSecuritiesFairValueToAmortizedCostBasisAbstract', window );"><strong>Summary of Investments [Abstract]</strong></a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rou">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleDebtSecuritiesAmortizedCostBasis', window );">Amortized cost</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">48,493<span></span>
</td>
<td class="nump">94,234<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleDebtSecuritiesAccumulatedGrossUnrealizedGainBeforeTax', window );">Gross unrealized gains</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">19<span></span>
</td>
<td class="nump">354<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleDebtSecuritiesAccumulatedGrossUnrealizedLossBeforeTax', window );">Gross unrealized losses</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="num">(18)<span></span>
</td>
<td class="num">(2)<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleSecuritiesDebtSecurities', window );">Estimated fair value</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">48,494<span></span>
</td>
<td class="nump">94,586<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_FinancialInstrumentAxis=us-gaap_USGovernmentAgenciesDebtSecuritiesMember', window );">Debt Securities Issued by U.S. Government Agencies [Member] | Securities with Maturity of More than One Year [Member]</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleSecuritiesFairValueToAmortizedCostBasisAbstract', window );"><strong>Summary of Investments [Abstract]</strong></a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rou">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleDebtSecuritiesAmortizedCostBasis', window );">Amortized cost</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">72,935<span></span>
</td>
<td class="nump">80,099<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleDebtSecuritiesAccumulatedGrossUnrealizedGainBeforeTax', window );">Gross unrealized gains</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">0<span></span>
</td>
<td class="nump">185<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleDebtSecuritiesAccumulatedGrossUnrealizedLossBeforeTax', window );">Gross unrealized losses</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="num">(561)<span></span>
</td>
<td class="num">(9)<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleSecuritiesDebtSecurities', window );">Estimated fair value</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">72,374<span></span>
</td>
<td class="nump">80,275<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_FinancialInstrumentAxis=us-gaap_USTreasurySecuritiesMember', window );">Debt Securities Issued by the U.S. Treasury [Member] | Securities with Maturity of One Year or Less [Member]</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleSecuritiesFairValueToAmortizedCostBasisAbstract', window );"><strong>Summary of Investments [Abstract]</strong></a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rou">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleDebtSecuritiesAmortizedCostBasis', window );">Amortized cost</a></td>
<td class="th" style="border-bottom: 0px;"><sup>[1]</sup></td>
<td class="nump">45,424<span></span>
</td>
<td class="nump">307,576<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleDebtSecuritiesAccumulatedGrossUnrealizedGainBeforeTax', window );">Gross unrealized gains</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">0<span></span>
</td>
<td class="nump">233<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleDebtSecuritiesAccumulatedGrossUnrealizedLossBeforeTax', window );">Gross unrealized losses</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="num">(64)<span></span>
</td>
<td class="num">(9)<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleSecuritiesDebtSecurities', window );">Estimated fair value</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">45,360<span></span>
</td>
<td class="nump">307,800<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_FinancialInstrumentAxis=us-gaap_USTreasurySecuritiesMember', window );">Debt Securities Issued by the U.S. Treasury [Member] | Securities with Maturity of More than One Year [Member]</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleSecuritiesFairValueToAmortizedCostBasisAbstract', window );"><strong>Summary of Investments [Abstract]</strong></a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rou">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleDebtSecuritiesAmortizedCostBasis', window );">Amortized cost</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">137,635<span></span>
</td>
<td class="nump">50,318<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleDebtSecuritiesAccumulatedGrossUnrealizedGainBeforeTax', window );">Gross unrealized gains</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">139<span></span>
</td>
<td class="nump">383<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleDebtSecuritiesAccumulatedGrossUnrealizedLossBeforeTax', window );">Gross unrealized losses</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="num">(500)<span></span>
</td>
<td class="num">(4)<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleSecuritiesDebtSecurities', window );">Estimated fair value</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">137,274<span></span>
</td>
<td class="nump">50,697<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_FinancialInstrumentAxis=us-gaap_USStatesAndPoliticalSubdivisionsMember', window );">Debt Securities Issued by States of the U.S. and Political Subdivisions of the States [Member] | Securities with Maturity of One Year or Less [Member]</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleSecuritiesFairValueToAmortizedCostBasisAbstract', window );"><strong>Summary of Investments [Abstract]</strong></a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rou">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleDebtSecuritiesAmortizedCostBasis', window );">Amortized cost</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">134,770<span></span>
</td>
<td class="nump">104,271<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleDebtSecuritiesAccumulatedGrossUnrealizedGainBeforeTax', window );">Gross unrealized gains</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">45<span></span>
</td>
<td class="nump">196<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleDebtSecuritiesAccumulatedGrossUnrealizedLossBeforeTax', window );">Gross unrealized losses</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="num">(37)<span></span>
</td>
<td class="num">(12)<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleSecuritiesDebtSecurities', window );">Estimated fair value</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">134,778<span></span>
</td>
<td class="nump">104,455<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_FinancialInstrumentAxis=us-gaap_USStatesAndPoliticalSubdivisionsMember', window );">Debt Securities Issued by States of the U.S. and Political Subdivisions of the States [Member] | Securities with Maturity of More than One Year [Member]</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleSecuritiesFairValueToAmortizedCostBasisAbstract', window );"><strong>Summary of Investments [Abstract]</strong></a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rou">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleDebtSecuritiesAmortizedCostBasis', window );">Amortized cost</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">39,909<span></span>
</td>
<td class="nump">31,779<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleDebtSecuritiesAccumulatedGrossUnrealizedGainBeforeTax', window );">Gross unrealized gains</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">1<span></span>
</td>
<td class="nump">91<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleDebtSecuritiesAccumulatedGrossUnrealizedLossBeforeTax', window );">Gross unrealized losses</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="num">(224)<span></span>
</td>
<td class="num">(16)<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleSecuritiesDebtSecurities', window );">Estimated fair value</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">39,686<span></span>
</td>
<td class="nump">31,854<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_FinancialInstrumentAxis=us-gaap_OtherDebtSecuritiesMember', window );">Other Municipal Debt Securities [Member] | Securities with Maturity of One Year or Less [Member]</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleSecuritiesFairValueToAmortizedCostBasisAbstract', window );"><strong>Summary of Investments [Abstract]</strong></a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rou">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleDebtSecuritiesAmortizedCostBasis', window );">Amortized cost</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">5,191<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleDebtSecuritiesAccumulatedGrossUnrealizedGainBeforeTax', window );">Gross unrealized gains</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">0<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleDebtSecuritiesAccumulatedGrossUnrealizedLossBeforeTax', window );">Gross unrealized losses</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="num">(7)<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleSecuritiesDebtSecurities', window );">Estimated fair value</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">5,184<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_FinancialInstrumentAxis=us-gaap_OtherDebtSecuritiesMember', window );">Other Municipal Debt Securities [Member] | Securities with Maturity of More than One Year [Member]</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleSecuritiesFairValueToAmortizedCostBasisAbstract', window );"><strong>Summary of Investments [Abstract]</strong></a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rou">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleDebtSecuritiesAmortizedCostBasis', window );">Amortized cost</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">6,136<span></span>
</td>
<td class="nump">1,041<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleDebtSecuritiesAccumulatedGrossUnrealizedGainBeforeTax', window );">Gross unrealized gains</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">0<span></span>
</td>
<td class="nump">0<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleDebtSecuritiesAccumulatedGrossUnrealizedLossBeforeTax', window );">Gross unrealized losses</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="num">(37)<span></span>
</td>
<td class="nump">0<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleSecuritiesDebtSecurities', window );">Estimated fair value</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">6,099<span></span>
</td>
<td class="nump">1,041<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_FinancialInstrumentAxis=us-gaap_EquitySecuritiesMember', window );">Equity Securities [Member]</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleSecuritiesFairValueToAmortizedCostBasisAbstract', window );"><strong>Summary of Investments [Abstract]</strong></a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_EquitySecuritiesFvNiCost', window );">Amortized cost</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">27,512<span></span>
</td>
<td class="nump">19,774<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_EquitySecuritiesFvNiUnrealizedGain', window );">Gross unrealized gains</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">23,852<span></span>
</td>
<td class="nump">15,938<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_EquitySecuritiesFvNiUnrealizedLoss', window );">Gross unrealized losses</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="num">(837)<span></span>
</td>
<td class="num">(2,681)<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_EquitySecuritiesFvNi', window );">Estimated fair value</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">50,527<span></span>
</td>
<td class="nump">33,031<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_FinancialInstrumentAxis=ions_EquitySecuritiesPubliclyTradedCompaniesMember', window );">Equity Securities in Publicly Traded Company [Member]</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleSecuritiesFairValueToAmortizedCostBasisAbstract', window );"><strong>Summary of Investments [Abstract]</strong></a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_EquitySecuritiesFvNiCost', window );">Amortized cost</a></td>
<td class="th" style="border-bottom: 0px;"><sup>[2]</sup></td>
<td class="nump">11,897<span></span>
</td>
<td class="nump">4,712<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_EquitySecuritiesFvNiUnrealizedGain', window );">Gross unrealized gains</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">7,145<span></span>
</td>
<td class="nump">0<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_EquitySecuritiesFvNiUnrealizedLoss', window );">Gross unrealized losses</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="num">(837)<span></span>
</td>
<td class="num">(2,681)<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_EquitySecuritiesFvNi', window );">Estimated fair value</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">18,205<span></span>
</td>
<td class="nump">2,031<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_FinancialInstrumentAxis=ions_EquitySecuritiesPrivateCompaniesMember', window );">Equity Securities in Private Companies [Member]</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleSecuritiesFairValueToAmortizedCostBasisAbstract', window );"><strong>Summary of Investments [Abstract]</strong></a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_EquitySecuritiesFvNiCost', window );">Amortized cost</a></td>
<td class="th" style="border-bottom: 0px;"><sup>[3]</sup></td>
<td class="nump">15,615<span></span>
</td>
<td class="nump">15,062<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_EquitySecuritiesFvNiUnrealizedGain', window );">Gross unrealized gains</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">16,707<span></span>
</td>
<td class="nump">15,938<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_EquitySecuritiesFvNiUnrealizedLoss', window );">Gross unrealized losses</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">0<span></span>
</td>
<td class="nump">0<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_EquitySecuritiesFvNi', window );">Estimated fair value</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">$ 32,322<span></span>
</td>
<td class="nump">$ 31,000<span></span>
</td>
</tr>
<tr><td colspan="3"></td></tr>
<tr><td colspan="3"><table class="outerFootnotes" width="100%">
<tr class="outerFootnote">
<td style="vertical-align: top; width: 12pt;" valign="top">[1]</td>
<td style="vertical-align: top;" valign="top">Includes investments classified
            as cash equivalents on our consolidated balance sheet.</td>
</tr>
<tr class="outerFootnote">
<td style="vertical-align: top; width: 12pt;" valign="top">[2]</td>
<td style="vertical-align: top;" valign="top">Our equity securities included in other current
            assets consisted of our investments in publicly traded companies. We recognize publicly traded equity securities at fair value.</td>
</tr>
<tr class="outerFootnote">
<td style="vertical-align: top; width: 12pt;" valign="top">[3]</td>
<td style="vertical-align: top;" valign="top"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">Our equity securities included in deposits and other assets consisted of our investments in privately held companies. We recognize our private company equity securities at</span> cost minus
            impairments, plus or minus changes resulting from observable price changes in orderly transactions for the identical or similar investment of the same issuer<span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"> on our consolidated balance sheet.</span></td>
</tr>
</table></td></tr>
</table>
<div style="display: none;">
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_DebtSecuritiesAvailableForSaleAndEquitySecuritiesFvNi">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Total of (1) investment in debt security measured at fair value with change in fair value recognized in other comprehensive income (available-for-sale) and (2) amount of investment in equity security measured at fair value with change in fair value recognized in net income (FV-NI).</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_DebtSecuritiesAvailableForSaleAndEquitySecuritiesFvNi</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_DebtSecuritiesAvailableForSaleAndEquitySecuritiesFvNiCost">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Total of (1) amortized cost of investment in debt security measured at fair value with change in fair value recognized in other comprehensive income (available-for-sale) and (2) cost of investment in equity security measured at fair value with change in fair value recognized in net income (FV-NI).</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_DebtSecuritiesAvailableForSaleAndEquitySecuritiesFvNiCost</td>
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<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
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<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
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<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Total of (1) unrealized gain in accumulated other comprehensive income (AOCI) on investment in debt security measured at fair value with change in fair value recognized in other comprehensive income (available-for-sale) and (2) unrealized gain on investment in equity security measured at fair value with change in fair value recognized in net income (FV-NI).</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_DebtSecuritiesAvailableForSaleAndEquitySecuritiesFvNiGrossUnrealizedGain</td>
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<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
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<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_DebtSecuritiesAvailableForSaleAndEquitySecuritiesFvNiGrossUnrealizedLoss">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Total of (1) unrealized loss in accumulated other comprehensive income (AOCI) on investment in debt security measured at fair value with change in fair value recognized in other comprehensive income (available-for-sale) and (2) unrealized loss on investment in equity security measured at fair value with change in fair value recognized in net income (FV-NI).</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_DebtSecuritiesAvailableForSaleAndEquitySecuritiesFvNiGrossUnrealizedLoss</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_AvailableForSaleDebtSecuritiesAccumulatedGrossUnrealizedGainBeforeTax">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount, before tax, of unrealized gain in accumulated other comprehensive income (AOCI) on investment in debt security measured at fair value with change in fair value recognized in other comprehensive income (available-for-sale).</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 320<br> -SubTopic 10<br> -Section 50<br> -Paragraph 2<br> -Subparagraph (b)<br> -URI http://asc.fasb.org/extlink&amp;oid=123581744&amp;loc=d3e27161-111563<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_AvailableForSaleDebtSecuritiesAccumulatedGrossUnrealizedGainBeforeTax</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_AvailableForSaleDebtSecuritiesAccumulatedGrossUnrealizedLossBeforeTax">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount, before tax, of unrealized loss in accumulated other comprehensive income (AOCI) on investment in debt security measured at fair value with change in fair value recognized in other comprehensive income (available-for-sale).</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 320<br> -SubTopic 10<br> -Section 50<br> -Paragraph 2<br> -Subparagraph (c)<br> -URI http://asc.fasb.org/extlink&amp;oid=123581744&amp;loc=d3e27161-111563<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_AvailableForSaleDebtSecuritiesAccumulatedGrossUnrealizedLossBeforeTax</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_AvailableForSaleDebtSecuritiesAmortizedCostBasis">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amortized cost of investment in debt security measured at fair value with change in fair value recognized in other comprehensive income (available-for-sale).</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 320<br> -SubTopic 10<br> -Section 50<br> -Paragraph 2<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=123581744&amp;loc=d3e27161-111563<br><br>Reference 2: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 326<br> -SubTopic 30<br> -Section 45<br> -Paragraph 1<br> -URI http://asc.fasb.org/extlink&amp;oid=124258926&amp;loc=SL82898722-210454<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_AvailableForSaleDebtSecuritiesAmortizedCostBasis</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_AvailableForSaleSecuritiesDebtSecurities">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of investment in debt security measured at fair value with change in fair value recognized in other comprehensive income (available-for-sale).</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 942<br> -SubTopic 210<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.9-03(6))<br> -URI http://asc.fasb.org/extlink&amp;oid=120398452&amp;loc=d3e534808-122878<br><br>Reference 2: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 326<br> -SubTopic 30<br> -Section 45<br> -Paragraph 1<br> -URI http://asc.fasb.org/extlink&amp;oid=124258926&amp;loc=SL82898722-210454<br><br>Reference 3: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 320<br> -SubTopic 10<br> -Section 45<br> -Paragraph 1<br> -Subparagraph (b)<br> -URI http://asc.fasb.org/extlink&amp;oid=124260329&amp;loc=d3e26610-111562<br><br>Reference 4: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 320<br> -SubTopic 10<br> -Section 50<br> -Paragraph 2<br> -Subparagraph (aa)<br> -URI http://asc.fasb.org/extlink&amp;oid=123581744&amp;loc=d3e27161-111563<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_AvailableForSaleSecuritiesDebtSecurities</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
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<td><strong> Data Type:</strong></td>
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<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
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<td><strong> Period Type:</strong></td>
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</tr>
</table></div>
</div></td></tr>
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<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_AvailableForSaleSecuritiesFairValueToAmortizedCostBasisAbstract">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_AvailableForSaleSecuritiesFairValueToAmortizedCostBasisAbstract</td>
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<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
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<td><strong> Data Type:</strong></td>
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<td><strong> Balance Type:</strong></td>
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<td><strong> Period Type:</strong></td>
<td>duration</td>
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</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_EquitySecuritiesFvNi">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of investment in equity security measured at fair value with change in fair value recognized in net income (FV-NI), classified as current.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 825<br> -SubTopic 10<br> -Section 45<br> -Paragraph 1A<br> -URI http://asc.fasb.org/extlink&amp;oid=123594786&amp;loc=SL75136599-209740<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_EquitySecuritiesFvNi</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
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<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
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<td><strong> Balance Type:</strong></td>
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</table></div>
</div></td></tr>
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<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_EquitySecuritiesFvNiCost">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Cost of investment in equity security measured at fair value with change in fair value recognized in net income (FV-NI). Excludes equity method investment and investment in equity security without readily determinable fair value.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_EquitySecuritiesFvNiCost</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_EquitySecuritiesFvNiUnrealizedGain">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of unrealized gain on investment in equity security measured at fair value with change in fair value recognized in net income (FV-NI).</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 321<br> -SubTopic 10<br> -Section 50<br> -Paragraph 4<br> -URI http://asc.fasb.org/extlink&amp;oid=123583765&amp;loc=SL75117546-209714<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_EquitySecuritiesFvNiUnrealizedGain</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_EquitySecuritiesFvNiUnrealizedLoss">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of unrealized loss on investment in equity security measured at fair value with change in fair value recognized in net income (FV-NI).</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 321<br> -SubTopic 10<br> -Section 50<br> -Paragraph 4<br> -URI http://asc.fasb.org/extlink&amp;oid=123583765&amp;loc=SL75117546-209714<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_EquitySecuritiesFvNiUnrealizedLoss</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_FinancialInstrumentAxis=us-gaap_DebtSecuritiesMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_FinancialInstrumentAxis=us-gaap_DebtSecuritiesMember</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td></td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_InvestmentSecondaryCategorizationAxis=ions_SecuritiesWithMaturityOfOneYearOrLessMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_InvestmentSecondaryCategorizationAxis=ions_SecuritiesWithMaturityOfOneYearOrLessMember</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td></td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_InvestmentSecondaryCategorizationAxis=ions_SecuritiesWithMaturityOfMoreThanOneYearMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_InvestmentSecondaryCategorizationAxis=ions_SecuritiesWithMaturityOfMoreThanOneYearMember</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td></td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_FinancialInstrumentAxis=us-gaap_CorporateDebtSecuritiesMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_FinancialInstrumentAxis=us-gaap_CorporateDebtSecuritiesMember</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td></td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_FinancialInstrumentAxis=us-gaap_USGovernmentAgenciesDebtSecuritiesMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_FinancialInstrumentAxis=us-gaap_USGovernmentAgenciesDebtSecuritiesMember</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td></td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_FinancialInstrumentAxis=us-gaap_USTreasurySecuritiesMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_FinancialInstrumentAxis=us-gaap_USTreasurySecuritiesMember</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td></td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_FinancialInstrumentAxis=us-gaap_USStatesAndPoliticalSubdivisionsMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_FinancialInstrumentAxis=us-gaap_USStatesAndPoliticalSubdivisionsMember</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td></td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_FinancialInstrumentAxis=us-gaap_OtherDebtSecuritiesMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_FinancialInstrumentAxis=us-gaap_OtherDebtSecuritiesMember</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td></td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_FinancialInstrumentAxis=us-gaap_EquitySecuritiesMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_FinancialInstrumentAxis=us-gaap_EquitySecuritiesMember</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td></td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_FinancialInstrumentAxis=ions_EquitySecuritiesPubliclyTradedCompaniesMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_FinancialInstrumentAxis=ions_EquitySecuritiesPubliclyTradedCompaniesMember</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td></td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_FinancialInstrumentAxis=ions_EquitySecuritiesPrivateCompaniesMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_FinancialInstrumentAxis=ions_EquitySecuritiesPrivateCompaniesMember</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td></td>
</tr>
</table></div>
</div></td></tr>
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<html>
<head>
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<span style="display: none;">v3.22.0.1</span><table class="report" border="0" cellspacing="2" id="idm139691008655432">
<tr>
<th class="tl" colspan="1" rowspan="1"><div style="width: 200px;"><strong>Investments, Investments Temporarily Impaired (Details)<br> $ in Thousands</strong></div></th>
<th class="th">
<div>Dec. 31, 2021 </div>
<div>USD ($) </div>
<div>Investment</div>
</th>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleSecuritiesAbstract', window );"><strong>Temporarily Impaired Investments [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DebtSecuritiesAvailableForSaleContinuousUnrealizedLossPositionLessThan12MonthsNumberOfPositions', window );">Number of investments | Investment</a></td>
<td class="nump">727<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DebtSecuritiesAvailableForSaleContinuousUnrealizedLossPositionLessThan12Months', window );">Estimated fair value, less than 12 months of temporary impairment</a></td>
<td class="nump">$ 934,791<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DebtSecuritiesAvailableForSaleContinuousUnrealizedLossPositionLessThan12MonthsAccumulatedLoss', window );">Unrealized losses, less than 12 months of temporary impairment</a></td>
<td class="num">$ (4,311)<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_FinancialInstrumentAxis=us-gaap_CorporateDebtSecuritiesMember', window );">Corporate Debt Securities [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleSecuritiesAbstract', window );"><strong>Temporarily Impaired Investments [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DebtSecuritiesAvailableForSaleContinuousUnrealizedLossPositionLessThan12MonthsNumberOfPositions', window );">Number of investments | Investment</a></td>
<td class="nump">272<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DebtSecuritiesAvailableForSaleContinuousUnrealizedLossPositionLessThan12Months', window );">Estimated fair value, less than 12 months of temporary impairment</a></td>
<td class="nump">$ 552,966<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DebtSecuritiesAvailableForSaleContinuousUnrealizedLossPositionLessThan12MonthsAccumulatedLoss', window );">Unrealized losses, less than 12 months of temporary impairment</a></td>
<td class="num">$ (2,870)<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_FinancialInstrumentAxis=us-gaap_USGovernmentAgenciesDebtSecuritiesMember', window );">Debt Securities Issued by U.S. Government Agencies [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleSecuritiesAbstract', window );"><strong>Temporarily Impaired Investments [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DebtSecuritiesAvailableForSaleContinuousUnrealizedLossPositionLessThan12MonthsNumberOfPositions', window );">Number of investments | Investment</a></td>
<td class="nump">15<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DebtSecuritiesAvailableForSaleContinuousUnrealizedLossPositionLessThan12Months', window );">Estimated fair value, less than 12 months of temporary impairment</a></td>
<td class="nump">$ 114,338<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DebtSecuritiesAvailableForSaleContinuousUnrealizedLossPositionLessThan12MonthsAccumulatedLoss', window );">Unrealized losses, less than 12 months of temporary impairment</a></td>
<td class="num">$ (579)<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_FinancialInstrumentAxis=us-gaap_USTreasurySecuritiesMember', window );">Debt Securities Issued by the U.S. Treasury [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleSecuritiesAbstract', window );"><strong>Temporarily Impaired Investments [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DebtSecuritiesAvailableForSaleContinuousUnrealizedLossPositionLessThan12MonthsNumberOfPositions', window );">Number of investments | Investment</a></td>
<td class="nump">13<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DebtSecuritiesAvailableForSaleContinuousUnrealizedLossPositionLessThan12Months', window );">Estimated fair value, less than 12 months of temporary impairment</a></td>
<td class="nump">$ 134,987<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DebtSecuritiesAvailableForSaleContinuousUnrealizedLossPositionLessThan12MonthsAccumulatedLoss', window );">Unrealized losses, less than 12 months of temporary impairment</a></td>
<td class="num">$ (564)<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_FinancialInstrumentAxis=us-gaap_USStatesAndPoliticalSubdivisionsMember', window );">Debt Securities Issued by States of the U.S. and Political Subdivisions of the States [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleSecuritiesAbstract', window );"><strong>Temporarily Impaired Investments [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DebtSecuritiesAvailableForSaleContinuousUnrealizedLossPositionLessThan12MonthsNumberOfPositions', window );">Number of investments | Investment</a></td>
<td class="nump">425<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DebtSecuritiesAvailableForSaleContinuousUnrealizedLossPositionLessThan12Months', window );">Estimated fair value, less than 12 months of temporary impairment</a></td>
<td class="nump">$ 126,401<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DebtSecuritiesAvailableForSaleContinuousUnrealizedLossPositionLessThan12MonthsAccumulatedLoss', window );">Unrealized losses, less than 12 months of temporary impairment</a></td>
<td class="num">$ (261)<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_FinancialInstrumentAxis=us-gaap_OtherDebtSecuritiesMember', window );">Other Municipal Debt Securities [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleSecuritiesAbstract', window );"><strong>Temporarily Impaired Investments [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DebtSecuritiesAvailableForSaleContinuousUnrealizedLossPositionLessThan12MonthsNumberOfPositions', window );">Number of investments | Investment</a></td>
<td class="nump">2<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DebtSecuritiesAvailableForSaleContinuousUnrealizedLossPositionLessThan12Months', window );">Estimated fair value, less than 12 months of temporary impairment</a></td>
<td class="nump">$ 6,099<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DebtSecuritiesAvailableForSaleContinuousUnrealizedLossPositionLessThan12MonthsAccumulatedLoss', window );">Unrealized losses, less than 12 months of temporary impairment</a></td>
<td class="num">$ (37)<span></span>
</td>
</tr>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of investment in debt security measured at fair value with change in fair value recognized in other comprehensive income (available-for-sale), in continuous unrealized loss position for less than 12 months, without allowance for credit loss. Includes beneficial interest in securitized financial asset.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 320<br> -SubTopic 10<br> -Section 50<br> -Paragraph 7<br> -URI http://asc.fasb.org/extlink&amp;oid=123581744&amp;loc=d3e27337-111563<br><br>Reference 2: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 326<br> -SubTopic 30<br> -Section 50<br> -Paragraph 5<br> -URI http://asc.fasb.org/extlink&amp;oid=124269663&amp;loc=SL82922890-210455<br><br>Reference 3: http://www.xbrl.org/2003/role/exampleRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 326<br> -SubTopic 30<br> -Section 55<br> -Paragraph 8<br> -URI http://asc.fasb.org/extlink&amp;oid=121590138&amp;loc=SL82922954-210456<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_DebtSecuritiesAvailableForSaleContinuousUnrealizedLossPositionLessThan12Months</td>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of accumulated unrealized loss on investment in debt security measured at fair value with change in fair value recognized in other comprehensive income (available-for-sale), in continuous unrealized loss position for less than 12 months, without allowance for credit loss. Includes beneficial interest in securitized financial asset.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 326<br> -SubTopic 30<br> -Section 50<br> -Paragraph 5<br> -URI http://asc.fasb.org/extlink&amp;oid=124269663&amp;loc=SL82922890-210455<br><br>Reference 2: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 320<br> -SubTopic 10<br> -Section 50<br> -Paragraph 7<br> -URI http://asc.fasb.org/extlink&amp;oid=123581744&amp;loc=d3e27337-111563<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
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<td style="white-space:nowrap;">us-gaap_DebtSecuritiesAvailableForSaleContinuousUnrealizedLossPositionLessThan12MonthsAccumulatedLoss</td>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Number of investments in debt securities measured at fair value with change in fair value recognized in other comprehensive income (available-for-sale), in continuous unrealized loss position for less than 12 months, without an allowance for credit loss. Includes beneficial interest in securitized financial asset.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2009/role/commonPracticeRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 326<br> -SubTopic 30<br> -Section 50<br> -Paragraph 4<br> -Subparagraph (b)(3)<br> -URI http://asc.fasb.org/extlink&amp;oid=124269663&amp;loc=SL82922888-210455<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
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<span style="display: none;">v3.22.0.1</span><table class="report" border="0" cellspacing="2" id="idm139691003485128">
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<th class="tl" colspan="1" rowspan="1"><div style="width: 200px;"><strong>Long-Term Obligations and Commitments, Long-Term Obligations (Details) - USD ($)<br> $ in Thousands</strong></div></th>
<th class="th"><div>Dec. 31, 2021</div></th>
<th class="th"><div>Nov. 30, 2021</div></th>
<th class="th"><div>Apr. 30, 2021</div></th>
<th class="th" colspan="2"><div>Dec. 31, 2020</div></th>
<th class="th"><div>Dec. 31, 2019</div></th>
<th class="th"><div>Dec. 31, 2016</div></th>
<th class="th"><div>Nov. 30, 2014</div></th>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_LongtermDebtCurrentAndNoncurrentAbstract', window );"><strong>Long-Term Obligations [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_LoansPayableToBank', window );">Long-term mortgage debt</a></td>
<td class="nump">$ 59,713<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 59,984<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_LeasesAndOtherObligations', window );">Leases and other obligations</a></td>
<td class="nump">29,904<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">30,710<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rou">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_LongTermObligations', window );">Total</a></td>
<td class="nump">1,251,050<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">939,639<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_LongTermObligationsCurrent', window );">Less: current portion</a></td>
<td class="num">(3,526)<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="num">(316,110)<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"><sup>[1]</sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_LongTermObligationsNoncurrent', window );">Total Long-Term Obligations</a></td>
<td class="nump">1,247,524<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">623,529<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DebtInstrumentAxis=ions_ConvertibleSeniorNotes0125PercentMember', window );">0.125 Percent Convertible Senior Notes [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_LongtermDebtCurrentAndNoncurrentAbstract', window );"><strong>Long-Term Obligations [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ConvertibleDebt', window );">Convertible senior notes</a></td>
<td class="nump">$ 542,314<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 540,136<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DebtInstrumentInterestRateStatedPercentage', window );">Interest rate on convertible senior notes</a></td>
<td class="nump">0.125%<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">0.125%<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">0.125%<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DebtInstrumentAxis=ions_ConvertibleSeniorNotes1PercentMember', window );">1 Percent Convertible Senior Notes [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_LongtermDebtCurrentAndNoncurrentAbstract', window );"><strong>Long-Term Obligations [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ConvertibleDebt', window );">Convertible senior notes</a></td>
<td class="nump">$ 0<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 308,809<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"><sup>[1]</sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DebtInstrumentInterestRateStatedPercentage', window );">Interest rate on convertible senior notes</a></td>
<td class="nump">1.00%<span></span>
</td>
<td class="nump">1.00%<span></span>
</td>
<td class="nump">1.00%<span></span>
</td>
<td class="nump">1.00%<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">1.00%<span></span>
</td>
<td class="nump">1.00%<span></span>
</td>
<td class="nump">1.00%<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DebtInstrumentAxis=ions_ConvertibleSeniorNotes0PercentMember', window );">0 Percent Convertible Senior Notes [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_LongtermDebtCurrentAndNoncurrentAbstract', window );"><strong>Long-Term Obligations [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ConvertibleDebt', window );">Convertible senior notes</a></td>
<td class="nump">$ 619,119<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 0<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DebtInstrumentInterestRateStatedPercentage', window );">Interest rate on convertible senior notes</a></td>
<td class="nump">0.00%<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">0.00%<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">0.00%<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr><td colspan="9"></td></tr>
<tr><td colspan="9"><table class="outerFootnotes" width="100%"><tr class="outerFootnote">
<td style="vertical-align: top; width: 12pt;" valign="top">[1]</td>
<td style="vertical-align: top;" valign="top">We classified the carrying value of
            our 1% Notes as a current liability on our consolidated balance sheet at December 31, 2020 because it matured in November 2021.</td>
</tr></table></td></tr>
</table>
<div style="display: none;">
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_LeasesAndOtherObligations">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Present value of lessee's discounted obligation for lease payments and the aggregate of other miscellaneous borrowings owed.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_LeasesAndOtherObligations</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_LongTermObligations">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Including the current and noncurrent portions, amount of long-term debt and lease obligations.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_LongTermObligations</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_LongTermObligationsCurrent">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of long-term debt and lease obligations, classified as current.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_LongTermObligationsCurrent</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_LongTermObligationsNoncurrent">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of long-term debt and lease obligations, classified as noncurrent.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_LongTermObligationsNoncurrent</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_ConvertibleDebt">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Including the current and noncurrent portions, carrying amount of debt identified as being convertible into another form of financial instrument (typically the entity's common stock) as of the balance sheet date, which originally required full repayment more than twelve months after issuance or greater than the normal operating cycle of the company.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 944<br> -SubTopic 210<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.7-03(a)(16))<br> -URI http://asc.fasb.org/extlink&amp;oid=120400017&amp;loc=d3e572229-122910<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 210<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.5-02(22))<br> -URI http://asc.fasb.org/extlink&amp;oid=120391452&amp;loc=d3e13212-122682<br><br>Reference 3: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 942<br> -SubTopic 210<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.9-03(16))<br> -URI http://asc.fasb.org/extlink&amp;oid=120398452&amp;loc=d3e534808-122878<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ConvertibleDebt</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_DebtInstrumentInterestRateStatedPercentage">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Contractual interest rate for funds borrowed, under the debt agreement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 470<br> -SubTopic 20<br> -Section 50<br> -Paragraph 1B<br> -Subparagraph (b)<br> -URI http://asc.fasb.org/extlink&amp;oid=123466505&amp;loc=SL123495323-112611<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 210<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.5-02.22(a)(1))<br> -URI http://asc.fasb.org/extlink&amp;oid=120391452&amp;loc=d3e13212-122682<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_DebtInstrumentInterestRateStatedPercentage</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>dtr-types:percentItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_LoansPayableToBank">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Including the current and noncurrent portions, carrying value as of the balance sheet date of loans from a bank with maturities initially due after one year or beyond the normal operating cycle if longer.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 210<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.5-02(22))<br> -URI http://asc.fasb.org/extlink&amp;oid=120391452&amp;loc=d3e13212-122682<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 944<br> -SubTopic 210<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.7-03(16)(a))<br> -URI http://asc.fasb.org/extlink&amp;oid=120400017&amp;loc=d3e572229-122910<br><br>Reference 3: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 942<br> -SubTopic 210<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.9-03(16))<br> -URI http://asc.fasb.org/extlink&amp;oid=120398452&amp;loc=d3e534808-122878<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_LoansPayableToBank</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
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<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
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<td><strong> Balance Type:</strong></td>
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<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_LongtermDebtCurrentAndNoncurrentAbstract">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_LongtermDebtCurrentAndNoncurrentAbstract</td>
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<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_DebtInstrumentAxis=ions_ConvertibleSeniorNotes0125PercentMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_DebtInstrumentAxis=ions_ConvertibleSeniorNotes0125PercentMember</td>
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<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
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<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_DebtInstrumentAxis=ions_ConvertibleSeniorNotes1PercentMember</td>
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<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
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<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_DebtInstrumentAxis=ions_ConvertibleSeniorNotes0PercentMember</td>
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<DOCUMENT>
<TYPE>XML
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<DESCRIPTION>IDEA: XBRL DOCUMENT
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<html>
<head>
<title></title>
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<span style="display: none;">v3.22.0.1</span><table class="report" border="0" cellspacing="2" id="idm139691003013000">
<tr>
<th class="tl" colspan="1" rowspan="2"><div style="width: 200px;"><strong>Long-Term Obligations and Commitments, Convertible Debt and Call Spread (Details) - USD ($)<br> $ / shares in Units, $ in Thousands, shares in Millions</strong></div></th>
<th class="th" colspan="3">1 Months Ended</th>
<th class="th" colspan="3">12 Months Ended</th>
<th class="th" colspan="1"></th>
<th class="th" colspan="1"></th>
</tr>
<tr>
<th class="th"><div>Nov. 30, 2021</div></th>
<th class="th"><div>Apr. 30, 2021</div></th>
<th class="th"><div>Dec. 31, 2019</div></th>
<th class="th"><div>Dec. 31, 2021</div></th>
<th class="th"><div>Dec. 31, 2020</div></th>
<th class="th"><div>Dec. 31, 2019</div></th>
<th class="th"><div>Dec. 31, 2016</div></th>
<th class="th"><div>Nov. 30, 2014</div></th>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ConvertibleLongtermNotesPayableCurrentAndNoncurrentAbstract', window );"><strong>Convertible Debt [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RepaymentsOfConvertibleDebt', window );">Repurchase of convertible notes</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 61,967<span></span>
</td>
<td class="nump">$ 0<span></span>
</td>
<td class="nump">$ 0<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DeferredFinanceCostsNet', window );">Unamortized debt issuance costs</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">20,302<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CallSpread', window );">Cost of call spread</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 46,900<span></span>
</td>
<td class="nump">$ 52,600<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_PaymentsForHedgeFinancingActivities', window );">Purchase of note hedges</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">136,700<span></span>
</td>
<td class="nump">108,700<span></span>
</td>
<td class="nump">136,620<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="nump">108,684<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ProceedsFromIssuanceOfWarrants', window );">Proceeds from issuance of warrants</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">89,800<span></span>
</td>
<td class="nump">$ 56,100<span></span>
</td>
<td class="nump">89,752<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="nump">56,110<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_GainsLossesOnExtinguishmentOfDebt', window );">Loss on early retirement of debt</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="num">(8,627)<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="num">(66,196)<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AmortizationOfFinancingCostsAndDiscounts', window );">Amortization of debt discount and debt issuance costs</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">4,900<span></span>
</td>
<td class="nump">$ 3,200<span></span>
</td>
<td class="nump">$ 2,900<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DebtInstrumentAxis=ions_ConvertibleSeniorNotes0PercentMember', window );">0% Notes [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ConvertibleLongtermNotesPayableCurrentAndNoncurrentAbstract', window );"><strong>Convertible Debt [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DebtInstrumentFaceAmount', window );">Face amount of offering</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 632,500<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DebtInstrumentCarryingAmount', window );">Outstanding principal balance</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">632,500<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DeferredFinanceCostsNet', window );">Unamortized debt issuance costs</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 13,400<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DebtInstrumentMaturityDate', window );">Maturity date</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">Apr. 30,  2026<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DebtInstrumentInterestRateStatedPercentage', window );">Interest rate</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">0.00%<span></span>
</td>
<td class="nump">0.00%<span></span>
</td>
<td class="nump">0.00%<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">0.00%<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DebtInstrumentInterestRateEffectivePercentage', window );">Effective interest rate</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">0.50%<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DebtInstrumentConvertibleConversionPrice1', window );">Conversion price per share (in dollars per share)</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 57.84<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_DebtInstrumentConvertibleConversionPriceIncludingCallSpread', window );">Effective conversion price per share with call spread (in dollars per share)</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 76.39<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_DebtInstrumentConvertibleSharesSubjectToConversion', window );">Total shares of common stock subject to conversion (in shares)</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">10.9<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_DebtInstrumentConvertiblePercentageOfPrincipalAmountUsedAsPurchasePriceUponOccurrenceOfFundamentalChange', window );">Percentage of principal amount used as purchase price upon occurrence of fundamental change</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">100.00%<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DebtInstrumentAxis=ions_ConvertibleSeniorNotes0125PercentMember', window );">0.125% Notes [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ConvertibleLongtermNotesPayableCurrentAndNoncurrentAbstract', window );"><strong>Convertible Debt [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DebtInstrumentCarryingAmount', window );">Outstanding principal balance</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 548,800<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DeferredFinanceCostsNet', window );">Unamortized debt issuance costs</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 6,500<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DebtInstrumentMaturityDate', window );">Maturity date</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">Dec. 31,  2024<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DebtInstrumentInterestRateStatedPercentage', window );">Interest rate</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">0.125%<span></span>
</td>
<td class="nump">0.125%<span></span>
</td>
<td class="nump">0.125%<span></span>
</td>
<td class="nump">0.125%<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DebtInstrumentInterestRateEffectivePercentage', window );">Effective interest rate</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">0.50%<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DebtInstrumentConvertibleConversionPrice1', window );">Conversion price per share (in dollars per share)</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 83.28<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_DebtInstrumentConvertibleConversionPriceIncludingCallSpread', window );">Effective conversion price per share with call spread (in dollars per share)</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 123.38<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_DebtInstrumentConvertibleSharesSubjectToConversion', window );">Total shares of common stock subject to conversion (in shares)</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">6.6<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_DebtInstrumentConvertiblePercentageOfPrincipalAmountUsedAsPurchasePriceUponOccurrenceOfFundamentalChange', window );">Percentage of principal amount used as purchase price upon occurrence of fundamental change</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">100.00%<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DebtInstrumentAxis=ions_ConvertibleSeniorNotes0125PercentIssuedInExchangeFor1PercentNotesMember', window );">0.125% Convertible Senior Notes Issued in Exchange for 1 Percent Notes [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ConvertibleLongtermNotesPayableCurrentAndNoncurrentAbstract', window );"><strong>Convertible Debt [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DebtInstrumentFaceAmount', window );">Face amount of offering</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 439,300<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 439,300<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DebtInstrumentAxis=ions_ConvertibleSeniorNotes0125PercentIssuedUnderSubscriptionAgreementsMember', window );">0.125% Convertible Senior Notes Issued under Subscription Agreements [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ConvertibleLongtermNotesPayableCurrentAndNoncurrentAbstract', window );"><strong>Convertible Debt [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DebtInstrumentFaceAmount', window );">Face amount of offering</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">109,500<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">109,500<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DebtInstrumentAxis=ions_ConvertibleSeniorNotes1PercentMember', window );">1% Notes [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ConvertibleLongtermNotesPayableCurrentAndNoncurrentAbstract', window );"><strong>Convertible Debt [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DebtInstrumentFaceAmount', window );">Face amount of offering</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 185,500<span></span>
</td>
<td class="nump">$ 500,000<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DebtInstrumentRepurchasedFaceAmount', window );">Principal amount repurchased</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 247,900<span></span>
</td>
<td class="nump">375,600<span></span>
</td>
<td class="nump">$ 247,900<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">375,600<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RepaymentsOfConvertibleDebt', window );">Repurchase of convertible notes</a></td>
<td class="nump">$ 62,000<span></span>
</td>
<td class="nump">$ 257,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DebtInstrumentCarryingAmount', window );">Outstanding principal balance</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 309,900<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 309,900<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DebtInstrumentInterestRateStatedPercentage', window );">Interest rate</a></td>
<td class="nump">1.00%<span></span>
</td>
<td class="nump">1.00%<span></span>
</td>
<td class="nump">1.00%<span></span>
</td>
<td class="nump">1.00%<span></span>
</td>
<td class="nump">1.00%<span></span>
</td>
<td class="nump">1.00%<span></span>
</td>
<td class="nump">1.00%<span></span>
</td>
<td class="nump">1.00%<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DebtInstrumentInterestRateEffectivePercentage', window );">Effective interest rate</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">1.40%<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_GainsLossesOnExtinguishmentOfDebt', window );">Loss on early retirement of debt</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 8,600<span></span>
</td>
<td class="num">$ (66,200)<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_DebtInstrumentConvertiblePercentageOfPrincipalAmountUsedAsPurchasePriceUponOccurrenceOfFundamentalChange', window );">Percentage of principal amount used as purchase price upon occurrence of fundamental change</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">100.00%<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DebtInstrumentAxis=ions_ConvertibleSeniorNotes275PercentMember', window );">2.75% Convertible Senior Notes [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ConvertibleLongtermNotesPayableCurrentAndNoncurrentAbstract', window );"><strong>Convertible Debt [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DebtInstrumentInterestRateStatedPercentage', window );">Interest rate</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">2.75%<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
</table>
<div style="display: none;">
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_CallSpread">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The net cash outflow from payments for hedge transactions and proceeds from the issuance of warrants. The call spread transaction was entered into to minimize the impact of potential economic dilution upon conversion of the 0.125% notes issued.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_CallSpread</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_DebtInstrumentConvertibleConversionPriceIncludingCallSpread">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The computed conversion price per share of the debt instrument based on the the conversion feature embedded in the debt instrument and the impact of the purchased hedges in the call spread transaction.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_DebtInstrumentConvertibleConversionPriceIncludingCallSpread</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>dtr-types:perShareItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_DebtInstrumentConvertiblePercentageOfPrincipalAmountUsedAsPurchasePriceUponOccurrenceOfFundamentalChange">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The percentage of the principal amount of the notes to be purchased, plus accrued and unpaid interest, upon the occurrence of certain fundamental changes, as set forth in the indenture governing the convertible notes.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_DebtInstrumentConvertiblePercentageOfPrincipalAmountUsedAsPurchasePriceUponOccurrenceOfFundamentalChange</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>dtr-types:percentItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_DebtInstrumentConvertibleSharesSubjectToConversion">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The number of shares of common stock subject to conversion if the debt was converted to equity.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_DebtInstrumentConvertibleSharesSubjectToConversion</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:sharesItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_AmortizationOfFinancingCostsAndDiscounts">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of amortization expense attributable to debt discount (premium) and debt issuance costs.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2009/role/commonPracticeRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 230<br> -SubTopic 10<br> -Section 45<br> -Paragraph 28<br> -Subparagraph (b)<br> -URI http://asc.fasb.org/extlink&amp;oid=123570139&amp;loc=d3e3602-108585<br><br>Reference 2: http://www.xbrl.org/2003/role/exampleRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 470<br> -SubTopic 20<br> -Section 55<br> -Paragraph 69E<br> -URI http://asc.fasb.org/extlink&amp;oid=123466577&amp;loc=SL123495743-112612<br><br>Reference 3: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 835<br> -SubTopic 30<br> -Section 45<br> -Paragraph 3<br> -URI http://asc.fasb.org/extlink&amp;oid=124435984&amp;loc=d3e28555-108399<br><br>Reference 4: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 470<br> -SubTopic 20<br> -Section 50<br> -Paragraph 1F<br> -Subparagraph (b)(2)<br> -URI http://asc.fasb.org/extlink&amp;oid=123466505&amp;loc=SL123495355-112611<br><br>Reference 5: http://www.xbrl.org/2003/role/exampleRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 470<br> -SubTopic 20<br> -Section 55<br> -Paragraph 69F<br> -URI http://asc.fasb.org/extlink&amp;oid=123466577&amp;loc=SL123495745-112612<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_AmortizationOfFinancingCostsAndDiscounts</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_ConvertibleLongtermNotesPayableCurrentAndNoncurrentAbstract">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ConvertibleLongtermNotesPayableCurrentAndNoncurrentAbstract</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:stringItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_DebtInstrumentCarryingAmount">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount, before unamortized (discount) premium and debt issuance costs, of long-term debt. Includes, but is not limited to, notes payable, bonds payable, commercial loans, mortgage loans, convertible debt, subordinated debt and other types of debt.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 470<br> -SubTopic 20<br> -Section 50<br> -Paragraph 4<br> -Subparagraph (b)(1)<br> -URI http://asc.fasb.org/extlink&amp;oid=123466204&amp;loc=SL6031897-161870<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 944<br> -SubTopic 210<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.7-03(16))<br> -URI http://asc.fasb.org/extlink&amp;oid=120400017&amp;loc=d3e572229-122910<br><br>Reference 3: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 210<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.5-02(22))<br> -URI http://asc.fasb.org/extlink&amp;oid=120391452&amp;loc=d3e13212-122682<br><br>Reference 4: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 942<br> -SubTopic 210<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.9-03(16))<br> -URI http://asc.fasb.org/extlink&amp;oid=120398452&amp;loc=d3e534808-122878<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_DebtInstrumentCarryingAmount</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_DebtInstrumentConvertibleConversionPrice1">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The price per share of the conversion feature embedded in the debt instrument.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 470<br> -SubTopic 20<br> -Section 50<br> -Paragraph 5<br> -Subparagraph (b)<br> -URI http://asc.fasb.org/extlink&amp;oid=123466204&amp;loc=SL6031898-161870<br><br>Reference 2: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 470<br> -SubTopic 20<br> -Section 50<br> -Paragraph 1B<br> -Subparagraph (c)<br> -URI http://asc.fasb.org/extlink&amp;oid=123466505&amp;loc=SL123495323-112611<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_DebtInstrumentConvertibleConversionPrice1</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>dtr-types:perShareItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_DebtInstrumentFaceAmount">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Face (par) amount of debt instrument at time of issuance.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 470<br> -SubTopic 20<br> -Section 50<br> -Paragraph 1B<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=123466505&amp;loc=SL123495323-112611<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 835<br> -SubTopic 30<br> -Section 45<br> -Paragraph 2<br> -URI http://asc.fasb.org/extlink&amp;oid=124435984&amp;loc=d3e28551-108399<br><br>Reference 3: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 835<br> -SubTopic 30<br> -Section 55<br> -Paragraph 8<br> -URI http://asc.fasb.org/extlink&amp;oid=114775985&amp;loc=d3e28878-108400<br><br>Reference 4: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 835<br> -SubTopic 30<br> -Section 50<br> -Paragraph 1<br> -URI http://asc.fasb.org/extlink&amp;oid=124429444&amp;loc=SL124452920-239629<br><br>Reference 5: http://www.xbrl.org/2003/role/exampleRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 470<br> -SubTopic 20<br> -Section 55<br> -Paragraph 69C<br> -URI http://asc.fasb.org/extlink&amp;oid=123466577&amp;loc=SL123495737-112612<br><br>Reference 6: http://www.xbrl.org/2003/role/exampleRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 470<br> -SubTopic 20<br> -Section 55<br> -Paragraph 69B<br> -URI http://asc.fasb.org/extlink&amp;oid=123466577&amp;loc=SL123495735-112612<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_DebtInstrumentFaceAmount</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_DebtInstrumentInterestRateEffectivePercentage">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Effective interest rate for the funds borrowed under the debt agreement considering interest compounding and original issue discount or premium.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 470<br> -SubTopic 20<br> -Section 50<br> -Paragraph 6<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=123466204&amp;loc=SL6036836-161870<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 835<br> -SubTopic 30<br> -Section 45<br> -Paragraph 2<br> -URI http://asc.fasb.org/extlink&amp;oid=124435984&amp;loc=d3e28551-108399<br><br>Reference 3: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 835<br> -SubTopic 30<br> -Section 50<br> -Paragraph 1<br> -URI http://asc.fasb.org/extlink&amp;oid=124429444&amp;loc=SL124452920-239629<br><br>Reference 4: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 210<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.5-02.22(a)(1))<br> -URI http://asc.fasb.org/extlink&amp;oid=120391452&amp;loc=d3e13212-122682<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_DebtInstrumentInterestRateEffectivePercentage</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>dtr-types:percentItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_DebtInstrumentInterestRateStatedPercentage">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Contractual interest rate for funds borrowed, under the debt agreement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 470<br> -SubTopic 20<br> -Section 50<br> -Paragraph 1B<br> -Subparagraph (b)<br> -URI http://asc.fasb.org/extlink&amp;oid=123466505&amp;loc=SL123495323-112611<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 210<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.5-02.22(a)(1))<br> -URI http://asc.fasb.org/extlink&amp;oid=120391452&amp;loc=d3e13212-122682<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_DebtInstrumentInterestRateStatedPercentage</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>dtr-types:percentItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_DebtInstrumentMaturityDate">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Date when the debt instrument is scheduled to be fully repaid, in YYYY-MM-DD format.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 210<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.5-02.22(a)(2))<br> -URI http://asc.fasb.org/extlink&amp;oid=120391452&amp;loc=d3e13212-122682<br><br>Reference 2: http://www.xbrl.org/2003/role/exampleRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 470<br> -SubTopic 20<br> -Section 50<br> -Paragraph 1B<br> -Subparagraph (d)<br> -URI http://asc.fasb.org/extlink&amp;oid=123466505&amp;loc=SL123495323-112611<br><br>Reference 3: http://www.xbrl.org/2009/role/commonPracticeRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 820<br> -SubTopic 10<br> -Section 50<br> -Paragraph 2<br> -Subparagraph (bbb)(2)<br> -URI http://asc.fasb.org/extlink&amp;oid=123874694&amp;loc=d3e19207-110258<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_DebtInstrumentMaturityDate</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:dateItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
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</div></td></tr>
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<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Face (par) amount of the original debt instrument that was repurchased.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_DebtInstrumentRepurchasedFaceAmount</td>
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<td><strong> Balance Type:</strong></td>
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<tr>
<td><strong> Period Type:</strong></td>
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<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_DeferredFinanceCostsNet">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount, after accumulated amortization, of debt issuance costs. Includes, but is not limited to, legal, accounting, underwriting, printing, and registration costs.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 210<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.5-02.17)<br> -URI http://asc.fasb.org/extlink&amp;oid=120391452&amp;loc=d3e13212-122682<br><br>Reference 2: http://www.xbrl.org/2009/role/commonPracticeRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 470<br> -SubTopic 20<br> -Section 50<br> -Paragraph 1D<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=123466505&amp;loc=SL123495340-112611<br><br>Reference 3: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 835<br> -SubTopic 30<br> -Section 45<br> -Paragraph 3<br> -URI http://asc.fasb.org/extlink&amp;oid=124435984&amp;loc=d3e28555-108399<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_DeferredFinanceCostsNet</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
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<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
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<tr>
<td><strong> Balance Type:</strong></td>
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<tr>
<td><strong> Period Type:</strong></td>
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<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_GainsLossesOnExtinguishmentOfDebt">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Difference between the fair value of payments made and the carrying amount of debt which is extinguished prior to maturity.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 470<br> -SubTopic 50<br> -Section 40<br> -Paragraph 4<br> -URI http://asc.fasb.org/extlink&amp;oid=123467658&amp;loc=d3e12355-112629<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 470<br> -SubTopic 50<br> -Section 40<br> -Paragraph 2<br> -URI http://asc.fasb.org/extlink&amp;oid=123467658&amp;loc=d3e12317-112629<br><br>Reference 3: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 230<br> -SubTopic 10<br> -Section 45<br> -Paragraph 28<br> -Subparagraph (b)<br> -URI http://asc.fasb.org/extlink&amp;oid=123570139&amp;loc=d3e3602-108585<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_GainsLossesOnExtinguishmentOfDebt</td>
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<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
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<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
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<td><strong> Balance Type:</strong></td>
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<td><strong> Period Type:</strong></td>
<td>duration</td>
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<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_PaymentsForHedgeFinancingActivities">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The cash outflow for a financial contract that meets the hedge criteria as either cash flow hedge, fair value hedge or hedge of net investment in foreign operations.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2009/role/commonPracticeRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 230<br> -SubTopic 10<br> -Section 45<br> -Paragraph 15<br> -URI http://asc.fasb.org/extlink&amp;oid=123570139&amp;loc=d3e3291-108585<br><br>Reference 2: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 230<br> -SubTopic 10<br> -Section 45<br> -Paragraph 27<br> -URI http://asc.fasb.org/extlink&amp;oid=123570139&amp;loc=d3e3581-108585<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_PaymentsForHedgeFinancingActivities</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
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<td><strong> Period Type:</strong></td>
<td>duration</td>
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</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_ProceedsFromIssuanceOfWarrants">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The cash inflow from issuance of rights to purchase common shares at predetermined price (usually issued together with corporate debt).</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 230<br> -SubTopic 10<br> -Section 45<br> -Paragraph 14<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=123570139&amp;loc=d3e3255-108585<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ProceedsFromIssuanceOfWarrants</td>
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<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
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<td><strong> Balance Type:</strong></td>
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<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The cash outflow from the repayment of a long-term debt instrument which can be exchanged for a specified amount of another security, typically the entity's common stock, at the option of the issuer or the holder.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 230<br> -SubTopic 10<br> -Section 45<br> -Paragraph 15<br> -Subparagraph (b)<br> -URI http://asc.fasb.org/extlink&amp;oid=123570139&amp;loc=d3e3291-108585<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_RepaymentsOfConvertibleDebt</td>
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<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
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<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
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<th class="tl" colspan="1" rowspan="2"><div style="width: 200px;"><strong>Long-Term Obligations and Commitments, Research and Development and Manufacturing Facilities (Details)<br> $ in Millions</strong></div></th>
<th class="th" colspan="1">1 Months Ended</th>
<th class="th" colspan="1">12 Months Ended</th>
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<div>Jul. 31, 2017 </div>
<div>USD ($) </div>
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<td class="text">&#160;<span></span>
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<td class="text">&#160;<span></span>
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<td class="text">&#160;<span></span>
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<td class="text">&#160;<span></span>
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<td class="text">&#160;<span></span>
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<td class="text">&#160;<span></span>
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<td class="text">&#160;<span></span>
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<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_PaymentsToAcquireBuildings', window );">Payment to acquire building</a></td>
<td class="nump">$ 79.4<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DebtInstrumentInterestRateStatedPercentage', window );">Interest rate</a></td>
<td class="nump">3.88%<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_PeriodToMakeInterestOnlyPaymentsOnMortgageLoan', window );">Period to make interest only payments on mortgage loan</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">5 years<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_PropertyPlantAndEquipmentByTypeAxis=us-gaap_ManufacturingFacilityMember', window );">Manufacturing Facility [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_PaymentsToAcquirePropertyPlantAndEquipmentAbstract', window );"><strong>Research and Development and Manufacturing Facilities [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_PaymentsToAcquireBuildings', window );">Payment to acquire building</a></td>
<td class="nump">$ 14.0<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DebtInstrumentInterestRateStatedPercentage', window );">Interest rate</a></td>
<td class="nump">4.20%<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_PeriodToMakeInterestOnlyPaymentsOnMortgageLoan', window );">Period to make interest only payments on mortgage loan</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">5 years<span></span>
</td>
</tr>
</table>
<div style="display: none;">
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_NumberOfPurchasedFacilitiesFinancedWithMortgageDebt">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The number of purchased facilities financed with mortgage debt.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_NumberOfPurchasedFacilitiesFinancedWithMortgageDebt</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:integerItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_PeriodToMakeInterestOnlyPaymentsOnMortgageLoan">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Period of time to make only payments of interest on the mortgage loan, in 'PnYnMnDTnHnMnS' format, for example, 'P1Y5M13D' represents the reported fact of one year, five months, and thirteen days.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_PeriodToMakeInterestOnlyPaymentsOnMortgageLoan</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:durationItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_DebtInstrumentFaceAmount">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Face (par) amount of debt instrument at time of issuance.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 470<br> -SubTopic 20<br> -Section 50<br> -Paragraph 1B<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=123466505&amp;loc=SL123495323-112611<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 835<br> -SubTopic 30<br> -Section 45<br> -Paragraph 2<br> -URI http://asc.fasb.org/extlink&amp;oid=124435984&amp;loc=d3e28551-108399<br><br>Reference 3: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 835<br> -SubTopic 30<br> -Section 55<br> -Paragraph 8<br> -URI http://asc.fasb.org/extlink&amp;oid=114775985&amp;loc=d3e28878-108400<br><br>Reference 4: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 835<br> -SubTopic 30<br> -Section 50<br> -Paragraph 1<br> -URI http://asc.fasb.org/extlink&amp;oid=124429444&amp;loc=SL124452920-239629<br><br>Reference 5: http://www.xbrl.org/2003/role/exampleRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 470<br> -SubTopic 20<br> -Section 55<br> -Paragraph 69C<br> -URI http://asc.fasb.org/extlink&amp;oid=123466577&amp;loc=SL123495737-112612<br><br>Reference 6: http://www.xbrl.org/2003/role/exampleRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 470<br> -SubTopic 20<br> -Section 55<br> -Paragraph 69B<br> -URI http://asc.fasb.org/extlink&amp;oid=123466577&amp;loc=SL123495735-112612<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_DebtInstrumentFaceAmount</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_DebtInstrumentInterestRateStatedPercentage">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Contractual interest rate for funds borrowed, under the debt agreement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 470<br> -SubTopic 20<br> -Section 50<br> -Paragraph 1B<br> -Subparagraph (b)<br> -URI http://asc.fasb.org/extlink&amp;oid=123466505&amp;loc=SL123495323-112611<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 210<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.5-02.22(a)(1))<br> -URI http://asc.fasb.org/extlink&amp;oid=120391452&amp;loc=d3e13212-122682<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_DebtInstrumentInterestRateStatedPercentage</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>dtr-types:percentItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
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<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_PaymentsToAcquireBuildings">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The cash outflow for acquisition of buildings (properties) whether for investment or use.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 230<br> -SubTopic 10<br> -Section 45<br> -Paragraph 13<br> -Subparagraph (c)<br> -URI http://asc.fasb.org/extlink&amp;oid=123570139&amp;loc=d3e3213-108585<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_PaymentsToAcquireBuildings</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_PaymentsToAcquirePropertyPlantAndEquipmentAbstract">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_PaymentsToAcquirePropertyPlantAndEquipmentAbstract</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
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<td><strong> Data Type:</strong></td>
<td>xbrli:stringItemType</td>
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<td><strong> Balance Type:</strong></td>
<td>na</td>
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<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
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<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_DebtInstrumentAxis=ions_LongTermMortgageDebtMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_DebtInstrumentAxis=ions_LongTermMortgageDebtMember</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td></td>
</tr>
</table></div>
</div></td></tr>
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<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_PropertyPlantAndEquipmentByTypeAxis=ions_PrimaryResearchAndDevelopmentFacilityMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_PropertyPlantAndEquipmentByTypeAxis=ions_PrimaryResearchAndDevelopmentFacilityMember</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td></td>
</tr>
</table></div>
</div></td></tr>
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<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_PropertyPlantAndEquipmentByTypeAxis=us-gaap_ManufacturingFacilityMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_PropertyPlantAndEquipmentByTypeAxis=us-gaap_ManufacturingFacilityMember</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td></td>
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<span style="display: none;">v3.22.0.1</span><table class="report" border="0" cellspacing="2" id="idm139691008363928">
<tr>
<th class="tl" colspan="2" rowspan="1"><div style="width: 200px;"><strong>Long-Term Obligations and Commitments, Maturity Schedules for Annual Debt and Other Obligations (Details) - USD ($)<br> $ in Thousands</strong></div></th>
<th class="th"><div>Dec. 31, 2021</div></th>
<th class="th" colspan="2"><div>Dec. 31, 2020</div></th>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_MaturitiesOfLongtermDebtAndCapitalLeaseObligationsAbstract', window );"><strong>Annual Debt and Other Obligation Maturities [Abstract]</strong></a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ContractualObligationDueInNextTwelveMonths', window );">2022</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">$ 3,498<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ContractualObligationDueInSecondYear', window );">2023</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">4,180<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ContractualObligationDueInThirdYear', window );">2024</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">4,180<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ContractualObligationDueInFourthYear', window );">2025</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">1,184,820<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ContractualObligationDueInFifthYear', window );">2026</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">3,494<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ContractualObligationDueAfterFifthYear', window );">Thereafter</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">57,439<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
</tr>
<tr class="rou">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ContractualObligation', window );">Subtotal</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">1,257,611<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_LongTermObligationsCurrent', window );">Less: current portion</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="num">(3,526)<span></span>
</td>
<td class="num">$ (316,110)<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"><sup>[1]</sup></td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_InterestPayableCurrentAndNoncurrent', window );">Less: fixed and determinable interest</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="num">(15,498)<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DeferredFinanceCostsNet', window );">Less: debt issuance costs</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="num">(20,302)<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_OperatingLeaseLiability', window );">Plus: lease liabilities</a></td>
<td class="th" style="border-bottom: 0px;"><sup>[2]</sup></td>
<td class="nump">22,058<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_OtherLiabilities', window );">Plus: other other liabilities</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">7,181<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_LongTermObligationsNoncurrent', window );">Total long-term debt</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">$ 1,247,524<span></span>
</td>
<td class="nump">$ 623,529<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
</tr>
<tr><td colspan="4"></td></tr>
<tr><td colspan="4"><table class="outerFootnotes" width="100%">
<tr class="outerFootnote">
<td style="vertical-align: top; width: 12pt;" valign="top">[1]</td>
<td style="vertical-align: top;" valign="top">We classified the carrying value of
            our 1% Notes as a current liability on our consolidated balance sheet at December 31, 2020 because it matured in November 2021.</td>
</tr>
<tr class="outerFootnote">
<td style="vertical-align: top; width: 12pt;" valign="top">[2]</td>
<td style="vertical-align: top;" valign="top">Current portion of $2.6 million was included in <span style="-sec-ix-hidden:Fact_b2b58e46aca04158b3b03811dd0a9c0f">current portion of long-term obligations</span> on our consolidated balance sheet, with the difference included in <span style="-sec-ix-hidden:Fact_9c37cb3853f74a4f821bbe4ed37a06ba">long-term obligations</span>.</td>
</tr>
</table></td></tr>
</table>
<div style="display: none;">
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_LongTermObligationsCurrent">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of long-term debt and lease obligations, classified as current.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_LongTermObligationsCurrent</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_LongTermObligationsNoncurrent">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of long-term debt and lease obligations, classified as noncurrent.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_LongTermObligationsNoncurrent</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_ContractualObligation">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of contractual obligation, including but not limited to, long-term debt, capital lease obligations, operating lease obligations, purchase obligations, and other commitments.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ContractualObligation</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_ContractualObligationDueAfterFifthYear">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of contractual obligation to be paid after fifth fiscal year following current fiscal year. Excludes interim and annual periods when interim periods are reported from current statement of financial position date (rolling approach).</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ContractualObligationDueAfterFifthYear</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_ContractualObligationDueInFifthYear">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of contractual obligation to be paid in fifth fiscal year following current fiscal year. Excludes interim and annual periods when interim periods are reported from current statement of financial position date (rolling approach).</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ContractualObligationDueInFifthYear</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_ContractualObligationDueInFourthYear">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of contractual obligation to be paid in fourth fiscal year following current fiscal year. Excludes interim and annual periods when interim periods are reported from current statement of financial position date (rolling approach).</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ContractualObligationDueInFourthYear</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_ContractualObligationDueInNextTwelveMonths">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of contractual obligation to be paid in next fiscal year following current fiscal year. Excludes interim and annual periods when interim periods are reported from current statement of financial position date (rolling approach).</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ContractualObligationDueInNextTwelveMonths</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_ContractualObligationDueInSecondYear">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of contractual obligation to be paid in second fiscal year following current fiscal year. Excludes interim and annual periods when interim periods are reported from current statement of financial position date (rolling approach).</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ContractualObligationDueInSecondYear</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_ContractualObligationDueInThirdYear">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of contractual obligation to be paid in third fiscal year following current fiscal year. Excludes interim and annual periods when interim periods are reported from current statement of financial position date (rolling approach).</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ContractualObligationDueInThirdYear</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_DeferredFinanceCostsNet">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount, after accumulated amortization, of debt issuance costs. Includes, but is not limited to, legal, accounting, underwriting, printing, and registration costs.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 210<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.5-02.17)<br> -URI http://asc.fasb.org/extlink&amp;oid=120391452&amp;loc=d3e13212-122682<br><br>Reference 2: http://www.xbrl.org/2009/role/commonPracticeRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 470<br> -SubTopic 20<br> -Section 50<br> -Paragraph 1D<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=123466505&amp;loc=SL123495340-112611<br><br>Reference 3: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 835<br> -SubTopic 30<br> -Section 45<br> -Paragraph 3<br> -URI http://asc.fasb.org/extlink&amp;oid=124435984&amp;loc=d3e28555-108399<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_DeferredFinanceCostsNet</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_InterestPayableCurrentAndNoncurrent">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of interest payable on debt, including, but not limited to, trade payables.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 942<br> -SubTopic 210<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.9-03.15(5))<br> -URI http://asc.fasb.org/extlink&amp;oid=120398452&amp;loc=d3e534808-122878<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 944<br> -SubTopic 210<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.7-03.15(a))<br> -URI http://asc.fasb.org/extlink&amp;oid=120400017&amp;loc=d3e572229-122910<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_InterestPayableCurrentAndNoncurrent</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_MaturitiesOfLongtermDebtAndCapitalLeaseObligationsAbstract">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_MaturitiesOfLongtermDebtAndCapitalLeaseObligationsAbstract</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:stringItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_OperatingLeaseLiability">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Present value of lessee's discounted obligation for lease payments from operating lease.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 842<br> -SubTopic 20<br> -Section 45<br> -Paragraph 1<br> -Subparagraph (b)<br> -URI http://asc.fasb.org/extlink&amp;oid=123391704&amp;loc=SL77918627-209977<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_OperatingLeaseLiability</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_OtherLiabilities">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of liabilities classified as other.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 942<br> -SubTopic 210<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.9-03.15)<br> -URI http://asc.fasb.org/extlink&amp;oid=120398452&amp;loc=d3e534808-122878<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_OtherLiabilities</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
</div>
</body>
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<span style="display: none;">v3.22.0.1</span><table class="report" border="0" cellspacing="2" id="idm139691001008408">
<tr>
<th class="tl" colspan="2" rowspan="2"><div style="width: 200px;"><strong>Long-Term Obligations and Commitments, Operating Leases (Details)<br> $ in Thousands</strong></div></th>
<th class="th" colspan="1">1 Months Ended</th>
<th class="th" colspan="3">12 Months Ended</th>
</tr>
<tr>
<th class="th">
<div>Jan. 31, 2022 </div>
<div>USD ($)</div>
</th>
<th class="th">
<div>Dec. 31, 2021 </div>
<div>USD ($) </div>
<div>Option</div>
</th>
<th class="th">
<div>Dec. 31, 2020 </div>
<div>USD ($)</div>
</th>
<th class="th">
<div>Dec. 31, 2019 </div>
<div>USD ($)</div>
</th>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_LesseeDisclosureAbstract', window );"><strong>Operating Leases [Abstract]</strong></a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_LesseeOperatingLeaseLiabilityPaymentsDue', window );">Lease payments to be made over initial term of lease</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 27,487<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_OperatingLeaseRightOfUseAsset', window );">Right-of-use operating lease assets</a></td>
<td class="th" style="border-bottom: 0px;"><sup>[1]</sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 18,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_OperatingLeaseRightOfUseAssetStatementOfFinancialPositionExtensibleList', window );">Operating Lease, Right-of-Use Asset, Statement of Financial Position [Extensible List]</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">Other Assets, Noncurrent<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_OperatingLeaseLiability', window );">Operating lease liabilities</a></td>
<td class="th" style="border-bottom: 0px;"><sup>[2]</sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 22,058<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_OperatingLeaseWeightedAverageRemainingLeaseTerm1', window );">Weighted average remaining lease term</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">6 years 7 months 6 days<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_OperatingLeaseWeightedAverageDiscountRatePercent', window );">Weighted average discount rate</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">6.00%<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_OperatingLeaseLiabilityCurrent', window );">Current portion of operating lease liabilities</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 2,600<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_OperatingLeaseLiabilityCurrentStatementOfFinancialPositionExtensibleList', window );">Operating Lease, Liability, Current, Statement of Financial Position [Extensible List]</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">Long-term Obligations, Excluding Convertible Debt, Current<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_OperatingLeaseLiabilityNoncurrentStatementOfFinancialPositionExtensibleList', window );">Operating Lease, Liability, Noncurrent, Statement of Financial Position [Extensible List]</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">Long-term Obligations Excluding Convertible Debt, Noncurrent<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_OperatingLeasePayments', window );">Operating lease cash payments</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 3,300<span></span>
</td>
<td class="nump">$ 3,800<span></span>
</td>
<td class="nump">$ 3,900<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_GeographicDistributionAxis=ions_CarlsbadFacilityMember', window );">Carlsbad Facility [Member]</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_LesseeDisclosureAbstract', window );"><strong>Operating Leases [Abstract]</strong></a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_LesseeLeasingArrangementsOperatingLeasesNumberOfOptionsToExtendLease', window );">Number of options to extend lease | Option</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">1<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_LesseeOperatingLeaseRenewalTerm', window );">Term of lease extension</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">5 years<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_GeographicDistributionAxis=ions_CarlsbadOfficeSpacesMember', window );">Carlsbad Office Spaces [Member]</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_LesseeDisclosureAbstract', window );"><strong>Operating Leases [Abstract]</strong></a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_LesseeLeasingArrangementsOperatingLeasesNumberOfOptionsToExtendLease', window );">Number of options to extend lease | Option</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">1<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_LesseeOperatingLeaseRenewalTerm', window );">Term of lease extension</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">5 years<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_GeographicDistributionAxis=ions_BostonOfficeSpaceMember', window );">Boston Office Space [Member]</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_LesseeDisclosureAbstract', window );"><strong>Operating Leases [Abstract]</strong></a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_LesseeOperatingLeaseRenewalTerm', window );">Term of lease extension</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">5 years<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_LesseeOperatingLeaseTermOfContract', window );">Initial term of operating lease</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">123 months<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_LesseeOperatingLeasePeriodOfFreeRent', window );">Period of free rent under lease</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">3 months<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_LesseeOperatingLeaseAllowanceForTenantImprovements', window );">Tenant improvement allowance</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 3,800<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_GeographicDistributionAxis=ions_SubleasedOfficeSpaceInBostonMember', window );">Subleased Office Space in Boston [Member] | Subsequent Event [Member]</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_LesseeDisclosureAbstract', window );"><strong>Operating Leases [Abstract]</strong></a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_LessorOperatingLeaseTermOfContract', window );">Term of sublease</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">83 months<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_LessorOperatingLeasePeriodOfFreeRent', window );">Period of free rent under sublease</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">7 months<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_LessorOperatingLeasePaymentsToBeReceived', window );">Lease payments to be received under sublease</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">$ 9,600<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_GeographicDistributionAxis=ions_AnotherOfficeSpaceInBostonMember', window );">Another Office Space in Boston [Member]</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_LesseeDisclosureAbstract', window );"><strong>Operating Leases [Abstract]</strong></a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_LesseeLeasingArrangementsOperatingLeasesNumberOfOptionsToExtendLease', window );">Number of options to extend lease | Option</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">1<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_LesseeOperatingLeaseRenewalTerm', window );">Term of lease extension</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">5 years<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_LesseeOperatingLeaseTermOfContract', window );">Initial term of operating lease</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">91 months<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_LesseeOperatingLeasePeriodOfFreeRent', window );">Period of free rent under lease</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">7 months<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_LesseeOperatingLeaseLiabilityPaymentsDue', window );">Lease payments to be made over initial term of lease</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 6,800<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr><td colspan="5"></td></tr>
<tr><td colspan="5"><table class="outerFootnotes" width="100%">
<tr class="outerFootnote">
<td style="vertical-align: top; width: 12pt;" valign="top">[1]</td>
<td style="vertical-align: top;" valign="top">Included in <span style="-sec-ix-hidden:Fact_f81ca57385a04657b8ecd0f06d505159">deposits and other assets</span> on our consolidated balance sheet.</td>
</tr>
<tr class="outerFootnote">
<td style="vertical-align: top; width: 12pt;" valign="top">[2]</td>
<td style="vertical-align: top;" valign="top">Current portion of $2.6 million was included in <span style="-sec-ix-hidden:Fact_b2b58e46aca04158b3b03811dd0a9c0f">current portion of long-term obligations</span> on our consolidated balance sheet, with the difference included in <span style="-sec-ix-hidden:Fact_9c37cb3853f74a4f821bbe4ed37a06ba">long-term obligations</span>.</td>
</tr>
</table></td></tr>
</table>
<div style="display: none;">
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_LesseeLeasingArrangementsOperatingLeasesNumberOfOptionsToExtendLease">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The number of options to extend the lease under the lessee's operating leasing arrangement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_LesseeLeasingArrangementsOperatingLeasesNumberOfOptionsToExtendLease</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:integerItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_LesseeOperatingLeaseAllowanceForTenantImprovements">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Allowance for tenant improvements to the office space included in the lessee's operating lease.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_LesseeOperatingLeaseAllowanceForTenantImprovements</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_LesseeOperatingLeasePeriodOfFreeRent">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Period of time in which the rent is free under operating lease, in 'PnYnMnDTnHnMnS' format, for example, 'P1Y5M13D' represents reported fact of one year, five months, and thirteen days.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_LesseeOperatingLeasePeriodOfFreeRent</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:durationItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_LessorOperatingLeasePeriodOfFreeRent">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Period of time in which the lessor provides free rent under operating lease to the lessee, in 'PnYnMnDTnHnMnS' format, for example, 'P1Y5M13D' represents reported fact of one year, five months, and thirteen days.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_LessorOperatingLeasePeriodOfFreeRent</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:durationItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_LesseeDisclosureAbstract">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_LesseeDisclosureAbstract</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:stringItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_LesseeOperatingLeaseLiabilityPaymentsDue">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of lessee's undiscounted obligation for lease payment for operating lease.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 842<br> -SubTopic 20<br> -Section 50<br> -Paragraph 6<br> -URI http://asc.fasb.org/extlink&amp;oid=123408670&amp;loc=SL77918701-209980<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_LesseeOperatingLeaseLiabilityPaymentsDue</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_LesseeOperatingLeaseRenewalTerm">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Term of lessee's operating lease renewal, in 'PnYnMnDTnHnMnS' format, for example, 'P1Y5M13D' represents reported fact of one year, five months, and thirteen days.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2009/role/commonPracticeRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 842<br> -SubTopic 20<br> -Section 50<br> -Paragraph 3<br> -Subparagraph (a)(3)<br> -URI http://asc.fasb.org/extlink&amp;oid=123408670&amp;loc=SL77918673-209980<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_LesseeOperatingLeaseRenewalTerm</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:durationItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_LesseeOperatingLeaseTermOfContract">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Term of lessee's operating lease, in 'PnYnMnDTnHnMnS' format, for example, 'P1Y5M13D' represents reported fact of one year, five months, and thirteen days.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2009/role/commonPracticeRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 842<br> -SubTopic 20<br> -Section 50<br> -Paragraph 3<br> -Subparagraph (a)(3)<br> -URI http://asc.fasb.org/extlink&amp;oid=123408670&amp;loc=SL77918673-209980<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_LesseeOperatingLeaseTermOfContract</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:durationItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_LessorOperatingLeasePaymentsToBeReceived">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of lease payments to be received by lessor for operating lease.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 842<br> -SubTopic 30<br> -Section 50<br> -Paragraph 12<br> -URI http://asc.fasb.org/extlink&amp;oid=124258985&amp;loc=SL77919396-209981<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_LessorOperatingLeasePaymentsToBeReceived</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_LessorOperatingLeaseTermOfContract">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Term of lessor's operating lease, in 'PnYnMnDTnHnMnS' format, for example, 'P1Y5M13D' represents reported fact of one year, five months, and thirteen days.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2009/role/commonPracticeRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 842<br> -SubTopic 30<br> -Section 50<br> -Paragraph 3<br> -Subparagraph (a)(3)<br> -URI http://asc.fasb.org/extlink&amp;oid=124258985&amp;loc=SL77919359-209981<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_LessorOperatingLeaseTermOfContract</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:durationItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_OperatingLeaseLiability">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Present value of lessee's discounted obligation for lease payments from operating lease.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 842<br> -SubTopic 20<br> -Section 45<br> -Paragraph 1<br> -Subparagraph (b)<br> -URI http://asc.fasb.org/extlink&amp;oid=123391704&amp;loc=SL77918627-209977<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_OperatingLeaseLiability</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_OperatingLeaseLiabilityCurrent">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Present value of lessee's discounted obligation for lease payments from operating lease, classified as current.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 842<br> -SubTopic 20<br> -Section 45<br> -Paragraph 1<br> -Subparagraph (b)<br> -URI http://asc.fasb.org/extlink&amp;oid=123391704&amp;loc=SL77918627-209977<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_OperatingLeaseLiabilityCurrent</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_OperatingLeaseLiabilityCurrentStatementOfFinancialPositionExtensibleList">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Indicates line item in statement of financial position that includes current operating lease liability.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 842<br> -SubTopic 20<br> -Section 45<br> -Paragraph 2<br> -URI http://asc.fasb.org/extlink&amp;oid=123391704&amp;loc=SL77918631-209977<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_OperatingLeaseLiabilityCurrentStatementOfFinancialPositionExtensibleList</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>enum2:enumerationSetItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_OperatingLeaseLiabilityNoncurrentStatementOfFinancialPositionExtensibleList">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Indicates line item in statement of financial position that includes noncurrent operating lease liability.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 842<br> -SubTopic 20<br> -Section 45<br> -Paragraph 2<br> -URI http://asc.fasb.org/extlink&amp;oid=123391704&amp;loc=SL77918631-209977<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_OperatingLeaseLiabilityNoncurrentStatementOfFinancialPositionExtensibleList</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>enum2:enumerationSetItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_OperatingLeasePayments">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of cash outflow from operating lease, excluding payments to bring another asset to condition and location necessary for its intended use.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 842<br> -SubTopic 20<br> -Section 45<br> -Paragraph 5<br> -Subparagraph (c)<br> -URI http://asc.fasb.org/extlink&amp;oid=123391704&amp;loc=SL77918643-209977<br><br>Reference 2: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 842<br> -SubTopic 20<br> -Section 50<br> -Paragraph 4<br> -Subparagraph (g)(1)<br> -URI http://asc.fasb.org/extlink&amp;oid=123408670&amp;loc=SL77918686-209980<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_OperatingLeasePayments</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_OperatingLeaseRightOfUseAsset">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of lessee's right to use underlying asset under operating lease.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 842<br> -SubTopic 20<br> -Section 45<br> -Paragraph 1<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=123391704&amp;loc=SL77918627-209977<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_OperatingLeaseRightOfUseAsset</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_OperatingLeaseRightOfUseAssetStatementOfFinancialPositionExtensibleList">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Indicates line item in statement of financial position that includes operating lease right-of-use asset.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 842<br> -SubTopic 20<br> -Section 45<br> -Paragraph 2<br> -URI http://asc.fasb.org/extlink&amp;oid=123391704&amp;loc=SL77918631-209977<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_OperatingLeaseRightOfUseAssetStatementOfFinancialPositionExtensibleList</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>enum2:enumerationSetItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_OperatingLeaseWeightedAverageDiscountRatePercent">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Weighted average discount rate for operating lease calculated at point in time.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 842<br> -SubTopic 20<br> -Section 50<br> -Paragraph 4<br> -Subparagraph (g)(4)<br> -URI http://asc.fasb.org/extlink&amp;oid=123408670&amp;loc=SL77918686-209980<br><br>Reference 2: http://www.xbrl.org/2003/role/exampleRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 842<br> -SubTopic 20<br> -Section 55<br> -Paragraph 53<br> -URI http://asc.fasb.org/extlink&amp;oid=123414884&amp;loc=SL77918982-209971<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_OperatingLeaseWeightedAverageDiscountRatePercent</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>dtr-types:percentItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_OperatingLeaseWeightedAverageRemainingLeaseTerm1">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Weighted average remaining lease term for operating lease, in 'PnYnMnDTnHnMnS' format, for example, 'P1Y5M13D' represents reported fact of one year, five months, and thirteen days.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/exampleRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 842<br> -SubTopic 20<br> -Section 55<br> -Paragraph 53<br> -URI http://asc.fasb.org/extlink&amp;oid=123414884&amp;loc=SL77918982-209971<br><br>Reference 2: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 842<br> -SubTopic 20<br> -Section 50<br> -Paragraph 4<br> -Subparagraph (g)(3)<br> -URI http://asc.fasb.org/extlink&amp;oid=123408670&amp;loc=SL77918686-209980<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_OperatingLeaseWeightedAverageRemainingLeaseTerm1</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:durationItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_GeographicDistributionAxis=ions_CarlsbadFacilityMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_GeographicDistributionAxis=ions_CarlsbadFacilityMember</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td></td>
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<tr>
<td><strong> Data Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td></td>
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<tr>
<td><strong> Period Type:</strong></td>
<td></td>
</tr>
</table></div>
</div></td></tr>
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<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_GeographicDistributionAxis=ions_CarlsbadOfficeSpacesMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_GeographicDistributionAxis=ions_CarlsbadOfficeSpacesMember</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td></td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_GeographicDistributionAxis=ions_BostonOfficeSpaceMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_GeographicDistributionAxis=ions_BostonOfficeSpaceMember</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td></td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_GeographicDistributionAxis=ions_SubleasedOfficeSpaceInBostonMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_GeographicDistributionAxis=ions_SubleasedOfficeSpaceInBostonMember</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td></td>
</tr>
</table></div>
</div></td></tr>
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<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_SubsequentEventTypeAxis=us-gaap_SubsequentEventMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_SubsequentEventTypeAxis=us-gaap_SubsequentEventMember</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td></td>
</tr>
</table></div>
</div></td></tr>
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<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_GeographicDistributionAxis=ions_AnotherOfficeSpaceInBostonMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_GeographicDistributionAxis=ions_AnotherOfficeSpaceInBostonMember</td>
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<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td></td>
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<td><strong> Data Type:</strong></td>
<td>na</td>
</tr>
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<td><strong> Balance Type:</strong></td>
<td></td>
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<span style="display: none;">v3.22.0.1</span><table class="report" border="0" cellspacing="2" id="idm139691008380488">
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<th class="tl" colspan="2" rowspan="2"><div style="width: 200px;"><strong>Long-Term Obligations and Commitments, Future Payments for Operating Lease Liabilities (Details) - USD ($)<br> $ in Thousands</strong></div></th>
<th class="th" colspan="3">12 Months Ended</th>
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<tr>
<th class="th"><div>Dec. 31, 2021</div></th>
<th class="th"><div>Dec. 31, 2020</div></th>
<th class="th"><div>Dec. 31, 2019</div></th>
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<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_OperatingLeaseLiabilitiesPaymentsDueAbstract', window );"><strong>Annual Future Payments for Operating Lease Liabilities [Abstract]</strong></a></td>
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<td class="text">&#160;<span></span>
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<td class="text">&#160;<span></span>
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<td class="text">&#160;<span></span>
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<td class="nump">$ 4,075<span></span>
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<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
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<tr class="re">
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<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">4,314<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
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<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_LesseeOperatingLeaseLiabilityPaymentsDueYearThree', window );">2024</a></td>
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<td class="nump">4,223<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_LesseeOperatingLeaseLiabilityPaymentsDueYearFour', window );">2025</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">4,062<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_LesseeOperatingLeaseLiabilityPaymentsDueYearFive', window );">2026</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">3,778<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_LesseeOperatingLeaseLiabilityPaymentsDueAfterYearFive', window );">Thereafter</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">7,035<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rou">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_LesseeOperatingLeaseLiabilityPaymentsDue', window );">Total minimum lease payments</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">27,487<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_LesseeOperatingLeaseLiabilityUndiscountedExcessAmount', window );">Less: Imputed interest</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="num">(5,429)<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_OperatingLeaseLiability', window );">Total operating lease liabilities</a></td>
<td class="th" style="border-bottom: 0px;"><sup>[1]</sup></td>
<td class="nump">22,058<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_OperatingLeaseExpense', window );">Rent expense</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">$ 3,400<span></span>
</td>
<td class="nump">$ 3,700<span></span>
</td>
<td class="nump">$ 3,600<span></span>
</td>
</tr>
<tr><td colspan="4"></td></tr>
<tr><td colspan="4"><table class="outerFootnotes" width="100%"><tr class="outerFootnote">
<td style="vertical-align: top; width: 12pt;" valign="top">[1]</td>
<td style="vertical-align: top;" valign="top">Current portion of $2.6 million was included in <span style="-sec-ix-hidden:Fact_b2b58e46aca04158b3b03811dd0a9c0f">current portion of long-term obligations</span> on our consolidated balance sheet, with the difference included in <span style="-sec-ix-hidden:Fact_9c37cb3853f74a4f821bbe4ed37a06ba">long-term obligations</span>.</td>
</tr></table></td></tr>
</table>
<div style="display: none;">
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_LesseeOperatingLeaseLiabilityPaymentsDue">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of lessee's undiscounted obligation for lease payment for operating lease.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 842<br> -SubTopic 20<br> -Section 50<br> -Paragraph 6<br> -URI http://asc.fasb.org/extlink&amp;oid=123408670&amp;loc=SL77918701-209980<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_LesseeOperatingLeaseLiabilityPaymentsDue</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_LesseeOperatingLeaseLiabilityPaymentsDueAfterYearFive">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of lessee's undiscounted obligation for lease payment for operating lease due after fifth fiscal year following current fiscal year. Excludes interim and annual periods when interim periods are reported from current statement of financial position date (rolling approach).</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 842<br> -SubTopic 20<br> -Section 50<br> -Paragraph 6<br> -URI http://asc.fasb.org/extlink&amp;oid=123408670&amp;loc=SL77918701-209980<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_LesseeOperatingLeaseLiabilityPaymentsDueAfterYearFive</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_LesseeOperatingLeaseLiabilityPaymentsDueNextTwelveMonths">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of lessee's undiscounted obligation for lease payment for operating lease to be paid in next fiscal year following current fiscal year. Excludes interim and annual periods when interim periods are reported from current statement of financial position date (rolling approach).</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 842<br> -SubTopic 20<br> -Section 50<br> -Paragraph 6<br> -URI http://asc.fasb.org/extlink&amp;oid=123408670&amp;loc=SL77918701-209980<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_LesseeOperatingLeaseLiabilityPaymentsDueNextTwelveMonths</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_LesseeOperatingLeaseLiabilityPaymentsDueYearFive">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of lessee's undiscounted obligation for lease payment for operating lease to be paid in fifth fiscal year following current fiscal year. Excludes interim and annual periods when interim periods are reported from current statement of financial position date (rolling approach).</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 842<br> -SubTopic 20<br> -Section 50<br> -Paragraph 6<br> -URI http://asc.fasb.org/extlink&amp;oid=123408670&amp;loc=SL77918701-209980<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_LesseeOperatingLeaseLiabilityPaymentsDueYearFive</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_LesseeOperatingLeaseLiabilityPaymentsDueYearFour">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of lessee's undiscounted obligation for lease payment for operating lease to be paid in fourth fiscal year following current fiscal year. Excludes interim and annual periods when interim periods are reported from current statement of financial position date (rolling approach).</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 842<br> -SubTopic 20<br> -Section 50<br> -Paragraph 6<br> -URI http://asc.fasb.org/extlink&amp;oid=123408670&amp;loc=SL77918701-209980<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_LesseeOperatingLeaseLiabilityPaymentsDueYearFour</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_LesseeOperatingLeaseLiabilityPaymentsDueYearThree">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of lessee's undiscounted obligation for lease payment for operating lease to be paid in third fiscal year following current fiscal year. Excludes interim and annual periods when interim periods are reported from current statement of financial position date (rolling approach).</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 842<br> -SubTopic 20<br> -Section 50<br> -Paragraph 6<br> -URI http://asc.fasb.org/extlink&amp;oid=123408670&amp;loc=SL77918701-209980<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_LesseeOperatingLeaseLiabilityPaymentsDueYearThree</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_LesseeOperatingLeaseLiabilityPaymentsDueYearTwo">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of lessee's undiscounted obligation for lease payment for operating lease to be paid in second fiscal year following current fiscal year. Excludes interim and annual periods when interim periods are reported from current statement of financial position date (rolling approach).</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 842<br> -SubTopic 20<br> -Section 50<br> -Paragraph 6<br> -URI http://asc.fasb.org/extlink&amp;oid=123408670&amp;loc=SL77918701-209980<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_LesseeOperatingLeaseLiabilityPaymentsDueYearTwo</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_LesseeOperatingLeaseLiabilityUndiscountedExcessAmount">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of lessee's undiscounted obligation for lease payments in excess of discounted obligation for lease payments for operating lease.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 842<br> -SubTopic 20<br> -Section 50<br> -Paragraph 6<br> -URI http://asc.fasb.org/extlink&amp;oid=123408670&amp;loc=SL77918701-209980<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_LesseeOperatingLeaseLiabilityUndiscountedExcessAmount</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_OperatingLeaseExpense">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of operating lease expense. Excludes sublease income.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2009/role/commonPracticeRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 842<br> -SubTopic 20<br> -Section 45<br> -Paragraph 4<br> -Subparagraph (b)<br> -URI http://asc.fasb.org/extlink&amp;oid=123391704&amp;loc=SL77918638-209977<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_OperatingLeaseExpense</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_OperatingLeaseLiabilitiesPaymentsDueAbstract">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_OperatingLeaseLiabilitiesPaymentsDueAbstract</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:stringItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_OperatingLeaseLiability">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Present value of lessee's discounted obligation for lease payments from operating lease.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 842<br> -SubTopic 20<br> -Section 45<br> -Paragraph 1<br> -Subparagraph (b)<br> -URI http://asc.fasb.org/extlink&amp;oid=123391704&amp;loc=SL77918627-209977<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_OperatingLeaseLiability</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
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<span style="display: none;">v3.22.0.1</span><table class="report" border="0" cellspacing="2" id="idm139691000858024">
<tr>
<th class="tl" colspan="1" rowspan="2"><div style="width: 200px;"><strong>Stockholders' Equity, Preferred and Common Stock (Details) - USD ($)<br> $ in Thousands</strong></div></th>
<th class="th" colspan="3">12 Months Ended</th>
</tr>
<tr>
<th class="th"><div>Dec. 31, 2021</div></th>
<th class="th"><div>Dec. 31, 2020</div></th>
<th class="th"><div>Dec. 31, 2019</div></th>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_CommonStockNumberOfSharesParValueAndOtherDisclosuresAbstract', window );"><strong>Common Stock [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_CommonStockSharesAuthorized', window );">Common stock, shares authorized to issue (in shares)</a></td>
<td class="nump">300,000,000<span></span>
</td>
<td class="nump">300,000,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_CommonStockSharesIssued', window );">Common stock, shares issued (in shares)</a></td>
<td class="nump">141,210,015<span></span>
</td>
<td class="nump">140,365,594<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_CommonStockSharesOutstanding', window );">Common stock, shares outstanding (in shares)</a></td>
<td class="nump">141,210,015<span></span>
</td>
<td class="nump">140,365,594<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ProceedsFromIssuanceOfSharesUnderIncentiveAndShareBasedCompensationPlansIncludingStockOptions', window );">Net proceeds from stock option exercises, vesting of restricted stock units, and ESPP purchases</a></td>
<td class="nump">$ 11,565<span></span>
</td>
<td class="nump">$ 52,036<span></span>
</td>
<td class="nump">$ 119,657<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_StatementClassOfStockAxis=us-gaap_PreferredStockMember', window );">Preferred Stock [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_PreferredStockNumberOfSharesParValueAndOtherDisclosuresAbstract', window );"><strong>Preferred Stock [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_PreferredStockSharesAuthorized', window );">Preferred stock, shares authorized (in shares)</a></td>
<td class="nump">15,000,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_PreferredStockSharesOutstanding', window );">Preferred stock, shares outstanding (in shares)</a></td>
<td class="nump">0<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_StatementClassOfStockAxis=us-gaap_SeriesCPreferredStockMember', window );">Series C Junior Participating Preferred Stock [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_PreferredStockNumberOfSharesParValueAndOtherDisclosuresAbstract', window );"><strong>Preferred Stock [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_PreferredStockSharesIssued', window );">Preferred stock, shares issued (in shares)</a></td>
<td class="nump">0<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_PreferredStockSharesOutstanding', window );">Preferred stock, shares outstanding (in shares)</a></td>
<td class="nump">0<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_StatementClassOfStockAxis=us-gaap_CommonStockMember', window );">Common Stock [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_CommonStockNumberOfSharesParValueAndOtherDisclosuresAbstract', window );"><strong>Common Stock [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_CommonStockSharesAuthorized', window );">Common stock, shares authorized to issue (in shares)</a></td>
<td class="nump">300,000,000<span></span>
</td>
<td class="nump">300,000,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_CommonStockSharesIssued', window );">Common stock, shares issued (in shares)</a></td>
<td class="nump">141,200,000<span></span>
</td>
<td class="nump">140,400,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_CommonStockSharesOutstanding', window );">Common stock, shares outstanding (in shares)</a></td>
<td class="nump">141,200,000<span></span>
</td>
<td class="nump">140,400,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_CommonStockCapitalSharesReservedForFutureIssuance', window );">Common shares reserved for future issuance (in shares)</a></td>
<td class="nump">46,200,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_StockIssuedDuringPeriodSharesShareBasedCompensationGross', window );">Number of shares issued for stock option exercises, vesting of restricted stock units, and ESPP purchases (in shares)</a></td>
<td class="nump">1,100,000<span></span>
</td>
<td class="nump">1,700,000<span></span>
</td>
<td class="nump">3,100,000<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ProceedsFromIssuanceOfSharesUnderIncentiveAndShareBasedCompensationPlansIncludingStockOptions', window );">Net proceeds from stock option exercises, vesting of restricted stock units, and ESPP purchases</a></td>
<td class="nump">$ 11,600<span></span>
</td>
<td class="nump">$ 52,000<span></span>
</td>
<td class="nump">$ 119,700<span></span>
</td>
</tr>
</table>
<div style="display: none;">
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_CommonStockCapitalSharesReservedForFutureIssuance">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Aggregate number of common shares reserved for future issuance.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 210<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.5-02.29)<br> -URI http://asc.fasb.org/extlink&amp;oid=120391452&amp;loc=d3e13212-122682<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_CommonStockCapitalSharesReservedForFutureIssuance</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:sharesItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
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<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_CommonStockNumberOfSharesParValueAndOtherDisclosuresAbstract">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_CommonStockNumberOfSharesParValueAndOtherDisclosuresAbstract</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
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<td><strong> Data Type:</strong></td>
<td>xbrli:stringItemType</td>
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<td><strong> Balance Type:</strong></td>
<td>na</td>
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<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
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<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_CommonStockSharesAuthorized">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The maximum number of common shares permitted to be issued by an entity's charter and bylaws.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 210<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.5-02(29))<br> -URI http://asc.fasb.org/extlink&amp;oid=120391452&amp;loc=d3e13212-122682<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_CommonStockSharesAuthorized</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:sharesItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_CommonStockSharesIssued">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Total number of common shares of an entity that have been sold or granted to shareholders (includes common shares that were issued, repurchased and remain in the treasury). These shares represent capital invested by the firm's shareholders and owners, and may be all or only a portion of the number of shares authorized. Shares issued include shares outstanding and shares held in the treasury.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 210<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.5-02(29))<br> -URI http://asc.fasb.org/extlink&amp;oid=120391452&amp;loc=d3e13212-122682<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_CommonStockSharesIssued</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:sharesItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
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<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_CommonStockSharesOutstanding">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Number of shares of common stock outstanding. Common stock represent the ownership interest in a corporation.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 505<br> -SubTopic 10<br> -Section 50<br> -Paragraph 2<br> -URI http://asc.fasb.org/extlink&amp;oid=123467817&amp;loc=d3e21463-112644<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 210<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.5-02(29))<br> -URI http://asc.fasb.org/extlink&amp;oid=120391452&amp;loc=d3e13212-122682<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_CommonStockSharesOutstanding</td>
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<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
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<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:sharesItemType</td>
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<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
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<td><strong> Period Type:</strong></td>
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</tr>
</table></div>
</div></td></tr>
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<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_PreferredStockNumberOfSharesParValueAndOtherDisclosuresAbstract</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
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<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:stringItemType</td>
</tr>
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<td><strong> Balance Type:</strong></td>
<td>na</td>
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<td><strong> Period Type:</strong></td>
<td>duration</td>
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</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_PreferredStockSharesAuthorized">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The maximum number of nonredeemable preferred shares (or preferred stock redeemable solely at the option of the issuer) permitted to be issued by an entity's charter and bylaws.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 210<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.5-02(28))<br> -URI http://asc.fasb.org/extlink&amp;oid=120391452&amp;loc=d3e13212-122682<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_PreferredStockSharesAuthorized</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:sharesItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_PreferredStockSharesIssued">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Total number of nonredeemable preferred shares (or preferred stock redeemable solely at the option of the issuer) issued to shareholders (includes related preferred shares that were issued, repurchased, and remain in the treasury). May be all or portion of the number of preferred shares authorized. Excludes preferred shares that are classified as debt.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 210<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.5-02(28))<br> -URI http://asc.fasb.org/extlink&amp;oid=120391452&amp;loc=d3e13212-122682<br><br>Reference 2: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 505<br> -SubTopic 10<br> -Section 50<br> -Paragraph 13<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=123467817&amp;loc=SL123496158-112644<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_PreferredStockSharesIssued</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:sharesItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_PreferredStockSharesOutstanding">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Aggregate share number for all nonredeemable preferred stock (or preferred stock redeemable solely at the option of the issuer) held by stockholders. Does not include preferred shares that have been repurchased.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 210<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.5-02(28))<br> -URI http://asc.fasb.org/extlink&amp;oid=120391452&amp;loc=d3e13212-122682<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_PreferredStockSharesOutstanding</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:sharesItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_ProceedsFromIssuanceOfSharesUnderIncentiveAndShareBasedCompensationPlansIncludingStockOptions">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of cash inflow from issuance of shares under share-based payment arrangement. Includes, but is not limited to, option exercised.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 718<br> -SubTopic 10<br> -Section 50<br> -Paragraph 2A<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=120381028&amp;loc=SL79508275-113901<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 230<br> -SubTopic 10<br> -Section 45<br> -Paragraph 14<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=123570139&amp;loc=d3e3255-108585<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ProceedsFromIssuanceOfSharesUnderIncentiveAndShareBasedCompensationPlansIncludingStockOptions</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
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<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_StockIssuedDuringPeriodSharesShareBasedCompensationGross">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Number, before forfeiture, of shares issued under share-based payment arrangement. Excludes employee stock ownership plan (ESOP).</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_StockIssuedDuringPeriodSharesShareBasedCompensationGross</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
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<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:sharesItemType</td>
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<td><strong> Balance Type:</strong></td>
<td>na</td>
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<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
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</div></td></tr>
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<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_StatementClassOfStockAxis=us-gaap_PreferredStockMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_StatementClassOfStockAxis=us-gaap_PreferredStockMember</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td></td>
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<tr>
<td><strong> Data Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td></td>
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<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_StatementClassOfStockAxis=us-gaap_SeriesCPreferredStockMember</td>
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<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td></td>
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<tr>
<td><strong> Data Type:</strong></td>
<td>na</td>
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<tr>
<td><strong> Balance Type:</strong></td>
<td></td>
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<td><strong> Period Type:</strong></td>
<td></td>
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<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_StatementClassOfStockAxis=us-gaap_CommonStockMember</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td></td>
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<tr>
<td><strong> Data Type:</strong></td>
<td>na</td>
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<tr>
<td><strong> Balance Type:</strong></td>
<td></td>
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<tr>
<td><strong> Period Type:</strong></td>
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<span style="display: none;">v3.22.0.1</span><table class="report" border="0" cellspacing="2" id="idm139691013619016">
<tr>
<th class="tl" colspan="1" rowspan="2"><div style="width: 200px;"><strong>Stockholders' Equity, Share Repurchase Program (Details) - USD ($)<br> $ in Thousands</strong></div></th>
<th class="th" colspan="1">3 Months Ended</th>
<th class="th" colspan="3">12 Months Ended</th>
<th class="th" colspan="1"></th>
</tr>
<tr>
<th class="th"><div>Mar. 31, 2020</div></th>
<th class="th"><div>Dec. 31, 2021</div></th>
<th class="th"><div>Dec. 31, 2020</div></th>
<th class="th"><div>Dec. 31, 2019</div></th>
<th class="th"><div>Sep. 30, 2019</div></th>
</tr>
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<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ClassOfStockDisclosuresAbstract', window );"><strong>Share Repurchase Program [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_StockRepurchaseProgramAuthorizedAmount1', window );">Authorized amount of share repurchase program</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 125,000<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_StockRepurchasedDuringPeriodShares', window );">Shares repurchased (in shares)</a></td>
<td class="nump">1,500,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">535,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_PaymentsForRepurchaseOfCommonStock', window );">Shares repurchased</a></td>
<td class="nump">$ 90,500<span></span>
</td>
<td class="nump">$ 0<span></span>
</td>
<td class="nump">$ 90,548<span></span>
</td>
<td class="nump">$ 34,392<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
</table>
<div style="display: none;">
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_ClassOfStockDisclosuresAbstract">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ClassOfStockDisclosuresAbstract</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:stringItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
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</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_PaymentsForRepurchaseOfCommonStock">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The cash outflow to reacquire common stock during the period.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 230<br> -SubTopic 10<br> -Section 45<br> -Paragraph 15<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=123570139&amp;loc=d3e3291-108585<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_PaymentsForRepurchaseOfCommonStock</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_StockRepurchaseProgramAuthorizedAmount1">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of stock repurchase plan authorized.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_StockRepurchaseProgramAuthorizedAmount1</td>
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<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
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<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
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<td><strong> Balance Type:</strong></td>
<td>credit</td>
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<td><strong> Period Type:</strong></td>
<td>instant</td>
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</table></div>
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<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Number of shares that have been repurchased during the period and have not been retired and are not held in treasury. Some state laws may govern the circumstances under which an entity may acquire its own stock and prescribe the accounting treatment therefore. This element is used when state law does not recognize treasury stock.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 505<br> -SubTopic 10<br> -Section 50<br> -Paragraph 2<br> -URI http://asc.fasb.org/extlink&amp;oid=123467817&amp;loc=d3e21463-112644<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 210<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.5-02(29))<br> -URI http://asc.fasb.org/extlink&amp;oid=120391452&amp;loc=d3e13212-122682<br><br>Reference 3: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 505<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.3-04)<br> -URI http://asc.fasb.org/extlink&amp;oid=120397183&amp;loc=d3e187085-122770<br><br>Reference 4: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 210<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.5-02(28))<br> -URI http://asc.fasb.org/extlink&amp;oid=120391452&amp;loc=d3e13212-122682<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_StockRepurchasedDuringPeriodShares</td>
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<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
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<td><strong> Data Type:</strong></td>
<td>xbrli:sharesItemType</td>
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<td><strong> Balance Type:</strong></td>
<td>na</td>
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<td><strong> Period Type:</strong></td>
<td>duration</td>
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<span style="display: none;">v3.22.0.1</span><table class="report" border="0" cellspacing="2" id="idm139691003900376">
<tr>
<th class="tl" colspan="1" rowspan="2"><div style="width: 200px;"><strong>Stockholders' Equity, Stock Plans (Details)<br></strong></div></th>
<th class="th" colspan="1">1 Months Ended</th>
<th class="th" colspan="1">12 Months Ended</th>
<th class="th" colspan="1"></th>
<th class="th" colspan="1"></th>
<th class="th" colspan="1"></th>
<th class="th" colspan="1"></th>
<th class="th" colspan="1"></th>
<th class="th" colspan="1"></th>
<th class="th" colspan="1"></th>
</tr>
<tr>
<th class="th">
<div>Jun. 30, 2009 </div>
<div>shares</div>
</th>
<th class="th">
<div>Dec. 31, 2021 </div>
<div>Officer </div>
<div>$ / shares </div>
<div>shares</div>
</th>
<th class="th">
<div>Jun. 30, 2021 </div>
<div>shares</div>
</th>
<th class="th">
<div>Dec. 31, 2020 </div>
<div>shares</div>
</th>
<th class="th">
<div>Jun. 30, 2020 </div>
<div>shares</div>
</th>
<th class="th">
<div>Jun. 30, 2019 </div>
<div>shares</div>
</th>
<th class="th">
<div>May 31, 2017 </div>
<div>shares</div>
</th>
<th class="th">
<div>Jun. 30, 2015 </div>
<div>shares</div>
</th>
<th class="th">
<div>May 31, 2015 </div>
<div>shares</div>
</th>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AwardTypeAxis=us-gaap_StockOptionMember', window );">Stock Options [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedArrangementsToObtainGoodsAndServicesAbstract', window );"><strong>Stock Plans [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsOutstandingNumber', window );">Number of options outstanding (in shares)</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">14,089,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">12,439,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsExercisableNumber', window );">Number of options exercisable (in shares)</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">9,175,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_PlanNameAxis=ions_StockOptionPlan1989Member', window );">1989 Stock Option Plan [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedArrangementsToObtainGoodsAndServicesAbstract', window );"><strong>Stock Plans [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardNumberOfSharesAuthorized', window );">Number of shares authorized for issuance under the Plan (in shares)</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">20,000,000.0<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsOutstandingNumber', window );">Number of options outstanding (in shares)</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">28,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsExercisableNumber', window );">Number of options exercisable (in shares)</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">28,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardNumberOfSharesAvailableForGrant', window );">Number of shares available for grant (in shares)</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">49,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_PlanNameAxis=ions_StockOptionPlan1989Member', window );">1989 Stock Option Plan [Member] | Stock Options [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedArrangementsToObtainGoodsAndServicesAbstract', window );"><strong>Stock Plans [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardAwardVestingPeriod1', window );">Vesting period</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">4 years<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_SharebasedCompensationArrangementBySharebasedPaymentAwardExpirationPeriod', window );">Award term</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">7 years<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_PlanNameAxis=ions_StockOptionPlan1989Member', window );">1989 Stock Option Plan [Member] | Stock Options [Member] | One Year from Date of Grant [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedArrangementsToObtainGoodsAndServicesAbstract', window );"><strong>Stock Plans [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_SharebasedCompensationArrangementBySharebasedPaymentAwardAwardVestingRightsPercentage', window );">Vesting percentage</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">25.00%<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardAwardRequisiteServicePeriod1', window );">Period before options are exercisable</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">1 year<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_PlanNameAxis=ions_EquityIncentivePlan2011Member', window );">2011 Equity Incentive Plan [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedArrangementsToObtainGoodsAndServicesAbstract', window );"><strong>Stock Plans [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardNumberOfSharesAuthorized', window );">Number of shares authorized for issuance under the Plan (in shares)</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">29,700,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">23,000,000.0<span></span>
</td>
<td class="nump">16,000,000.0<span></span>
</td>
<td class="nump">11,000,000.0<span></span>
</td>
<td class="nump">5,500,000<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_IncreaseDecreaseInFungibleShareReserveForEachShareIssuedPursuantToFullValueAward', window );">Reduction in fungible share reserve for each share issued pursuant to full value award (n shares)</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="num">(1.7)<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_IncreaseDecreaseInFungibleShareReserveForEachShareReturningFromFullValueAward', window );">Increase in fungible share reserve for each share returning from a full value award (in shares)</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">1.7<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsOutstandingNumber', window );">Number of options outstanding (in shares)</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">12,800,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsExercisableNumber', window );">Number of options exercisable (in shares)</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">8,300,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardNumberOfSharesAvailableForGrant', window );">Number of shares available for grant (in shares)</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">8,500,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_NumberOfExecutiveOfficersTerminatedBeforeChangeInControlWhenVestingWillAccelerateForExecutiveOfficers', window );">Number of executive officers terminated before change in control when vesting will accelerate for executive officers | Officer</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">1<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_PeriodBeforeChangeInControlWhenVestingWillAccelerateForExecutiveOfficers', window );">Period before change in control when vesting will accelerate for executive officers</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">3 months<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_PeriodAfterChangeInControlWhenVestingWillAccelerateForExecutiveOfficers', window );">Period after change in control when vesting will accelerate for executive officers</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">12 months<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_PlanNameAxis=ions_EquityIncentivePlan2011Member', window );">2011 Equity Incentive Plan [Member] | Stock Options [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedArrangementsToObtainGoodsAndServicesAbstract', window );"><strong>Stock Plans [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardAwardVestingPeriod1', window );">Vesting period</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">4 years<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_SharebasedCompensationArrangementBySharebasedPaymentAwardExpirationPeriod', window );">Award term</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">7 years<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_PlanNameAxis=ions_EquityIncentivePlan2011Member', window );">2011 Equity Incentive Plan [Member] | Stock Options [Member] | Issued after December 31, 2021 [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedArrangementsToObtainGoodsAndServicesAbstract', window );"><strong>Stock Plans [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardAwardVestingPeriod1', window );">Vesting period</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">10 years<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_PlanNameAxis=ions_EquityIncentivePlan2011Member', window );">2011 Equity Incentive Plan [Member] | Stock Options [Member] | One Year from Date of Grant [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedArrangementsToObtainGoodsAndServicesAbstract', window );"><strong>Stock Plans [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_SharebasedCompensationArrangementBySharebasedPaymentAwardAwardVestingRightsPercentage', window );">Vesting percentage</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">25.00%<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardAwardRequisiteServicePeriod1', window );">Period before options are exercisable</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">1 year<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_PlanNameAxis=ions_EquityIncentivePlan2011Member', window );">2011 Equity Incentive Plan [Member] | Restricted Stock Units [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedArrangementsToObtainGoodsAndServicesAbstract', window );"><strong>Stock Plans [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardAwardVestingPeriod1', window );">Vesting period</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">4 years<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardNonOptionEquityInstrumentsOutstandingNumber', window );">Number of awards outstanding (in shares)</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">2,500,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_PlanNameAxis=ions_EquityIncentivePlan2020Member', window );">2020 Equity Incentive Plan [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedArrangementsToObtainGoodsAndServicesAbstract', window );"><strong>Stock Plans [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardNumberOfSharesAuthorized', window );">Number of shares authorized for issuance under the Plan (in shares)</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">1,600,000<span></span>
</td>
<td class="nump">2,600,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsOutstandingNumber', window );">Number of options outstanding (in shares)</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">200,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsExercisableNumber', window );">Number of options exercisable (in shares)</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardNumberOfSharesAvailableForGrant', window );">Number of shares available for grant (in shares)</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">1,300,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_PlanNameAxis=ions_EquityIncentivePlan2020Member', window );">2020 Equity Incentive Plan [Member] | Stock Options [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedArrangementsToObtainGoodsAndServicesAbstract', window );"><strong>Stock Plans [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardAwardVestingPeriod1', window );">Vesting period</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">4 years<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_SharebasedCompensationArrangementBySharebasedPaymentAwardExpirationPeriod', window );">Award term</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">7 years<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_PlanNameAxis=ions_EquityIncentivePlan2020Member', window );">2020 Equity Incentive Plan [Member] | Stock Options [Member] | Issued after December 31, 2021 [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedArrangementsToObtainGoodsAndServicesAbstract', window );"><strong>Stock Plans [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardAwardVestingPeriod1', window );">Vesting period</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">10 years<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_PlanNameAxis=ions_EquityIncentivePlan2020Member', window );">2020 Equity Incentive Plan [Member] | Stock Options [Member] | One Year from Date of Grant [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedArrangementsToObtainGoodsAndServicesAbstract', window );"><strong>Stock Plans [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_SharebasedCompensationArrangementBySharebasedPaymentAwardAwardVestingRightsPercentage', window );">Vesting percentage</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">25.00%<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardAwardRequisiteServicePeriod1', window );">Period before options are exercisable</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">1 year<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_PlanNameAxis=ions_EquityIncentivePlan2020Member', window );">2020 Equity Incentive Plan [Member] | Restricted Stock Units [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedArrangementsToObtainGoodsAndServicesAbstract', window );"><strong>Stock Plans [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardAwardVestingPeriod1', window );">Vesting period</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">4 years<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardNonOptionEquityInstrumentsOutstandingNumber', window );">Number of awards outstanding (in shares)</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">100,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_PlanNameAxis=ions_NonemployeeDirectorsStockOptionPlan2002Member', window );">2002 Non-Employee Directors' Stock Option Plan [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedArrangementsToObtainGoodsAndServicesAbstract', window );"><strong>Stock Plans [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardNumberOfSharesAuthorized', window );">Number of shares authorized for issuance under the Plan (in shares)</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">2,800,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">2,000,000.0<span></span>
</td>
<td class="nump">1,200,000<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsOutstandingNumber', window );">Number of options outstanding (in shares)</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">1,000,000.0<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsExercisableNumber', window );">Number of options exercisable (in shares)</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">800,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardNumberOfSharesAvailableForGrant', window );">Number of shares available for grant (in shares)</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">700,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_PlanNameAxis=ions_NonemployeeDirectorsStockOptionPlan2002Member', window );">2002 Non-Employee Directors' Stock Option Plan [Member] | Stock Options [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedArrangementsToObtainGoodsAndServicesAbstract', window );"><strong>Stock Plans [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_SharebasedCompensationArrangementBySharebasedPaymentAwardExpirationPeriod', window );">Award term</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">10 years<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_PlanNameAxis=ions_NonemployeeDirectorsStockOptionPlan2002Member', window );">2002 Non-Employee Directors' Stock Option Plan [Member] | Restricted Stock Units [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedArrangementsToObtainGoodsAndServicesAbstract', window );"><strong>Stock Plans [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardNonOptionEquityInstrumentsOutstandingNumber', window );">Number of awards outstanding (in shares)</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">100,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_PlanNameAxis=ions_EmployeeStockPurchasePlanMember', window );">Employee Stock Purchase Plan [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedArrangementsToObtainGoodsAndServicesAbstract', window );"><strong>Stock Plans [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardNumberOfSharesAuthorized', window );">Number of shares authorized for issuance under the Plan (in shares)</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">3,200,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardNumberOfAdditionalSharesAuthorized', window );">Number of additional shares reserved for issuance (in shares)</a></td>
<td class="nump">150,000<span></span>
</td>
<td class="nump">150,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardMaximumEmployeeSubscriptionRate', window );">Maximum percentage of employee compensation used to purchase shares</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">10.00%<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_SharebasedCompensationArrangementBySharebasedPaymentAwardPurchasePriceOfCommonStockPercent', window );">Percentage of fair market value used to determine purchase price of stock</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">85.00%<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_ShareBasedCompensationArrangementByShareBasedPaymentAwardHoldingPeriod', window );">Holding period for purchased stock</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">6 months<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_StockIssuedDuringPeriodSharesEmployeeStockPurchasePlans', window );">Shares purchased and issued under ESPP (in shares)</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">70,000.00<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_EmployeeStockPurchasePlanWeightedAverageSalesPriceOfSharesPurchased', window );">Weighted average purchase price (in dollars per share) | $ / shares</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 39.26<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_EmployeeStockPurchasePlanSharesAvailableForPurchase', window );">Shares available for purchase under ESPP (in shares)</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">600,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
</table>
<div style="display: none;">
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_EmployeeStockPurchasePlanSharesAvailableForPurchase">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The number of shares available for purchase under an employee stock purchase plan.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_EmployeeStockPurchasePlanSharesAvailableForPurchase</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:sharesItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_EmployeeStockPurchasePlanWeightedAverageSalesPriceOfSharesPurchased">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Weighted average sales price of shares purchased through an employee stock purchase plan.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_EmployeeStockPurchasePlanWeightedAverageSalesPriceOfSharesPurchased</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>dtr-types:perShareItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_IncreaseDecreaseInFungibleShareReserveForEachShareIssuedPursuantToFullValueAward">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Increase (decrease) in the number of shares in the "fungible" share reserve for each share issued pursuant to full value award.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_IncreaseDecreaseInFungibleShareReserveForEachShareIssuedPursuantToFullValueAward</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:sharesItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_IncreaseDecreaseInFungibleShareReserveForEachShareReturningFromFullValueAward">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Increase (decrease) in the number of shares in the "fungible" share reserve for each share of common stock returning from a full value award.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_IncreaseDecreaseInFungibleShareReserveForEachShareReturningFromFullValueAward</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:sharesItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_NumberOfExecutiveOfficersTerminatedBeforeChangeInControlWhenVestingWillAccelerateForExecutiveOfficers">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The number of executive officers terminated by the Company during the period that begins three months before and ends twelve months following a change in control of the Company when vesting will accelerate for options and RSUs outstanding as of the termination date for executive officers</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_NumberOfExecutiveOfficersTerminatedBeforeChangeInControlWhenVestingWillAccelerateForExecutiveOfficers</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:integerItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_PeriodAfterChangeInControlWhenVestingWillAccelerateForExecutiveOfficers">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Period of time after a change in control of the Company when vesting will accelerate for options and RSUs outstanding as of the termination date for executive officers, in 'PnYnMnDTnHnMnS' format, for example, 'P1Y5M13D' represents the reported fact of one year, five months, and thirteen days.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_PeriodAfterChangeInControlWhenVestingWillAccelerateForExecutiveOfficers</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:durationItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_PeriodBeforeChangeInControlWhenVestingWillAccelerateForExecutiveOfficers">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Period of time before a change in control of the Company when vesting will accelerate for options and RSUs outstanding as of the termination date for executive officers, in 'PnYnMnDTnHnMnS' format, for example, 'P1Y5M13D' represents the reported fact of one year, five months, and thirteen days.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_PeriodBeforeChangeInControlWhenVestingWillAccelerateForExecutiveOfficers</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:durationItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_ShareBasedCompensationArrangementByShareBasedPaymentAwardHoldingPeriod">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Represents the holding period from the date of purchase for stock purchased under the plan.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_ShareBasedCompensationArrangementByShareBasedPaymentAwardHoldingPeriod</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:durationItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_ShareBasedArrangementsToObtainGoodsAndServicesAbstract">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ShareBasedArrangementsToObtainGoodsAndServicesAbstract</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:stringItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardAwardRequisiteServicePeriod1">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Estimated period over which an employee is required to provide service in exchange for the equity-based payment award, in 'PnYnMnDTnHnMnS' format, for example, 'P1Y5M13D' represents the reported fact of one year, five months, and thirteen days.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 718<br> -SubTopic 10<br> -Section 50<br> -Paragraph 2<br> -Subparagraph (a)(1)<br> -URI http://asc.fasb.org/extlink&amp;oid=120381028&amp;loc=d3e5070-113901<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardAwardRequisiteServicePeriod1</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:durationItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardAwardVestingPeriod1">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Period over which grantee's right to exercise award under share-based payment arrangement is no longer contingent on satisfaction of service or performance condition, in 'PnYnMnDTnHnMnS' format, for example, 'P1Y5M13D' represents reported fact of one year, five months, and thirteen days. Includes, but is not limited to, combination of market, performance or service condition.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 718<br> -SubTopic 10<br> -Section 50<br> -Paragraph 2<br> -Subparagraph (a)(1)<br> -URI http://asc.fasb.org/extlink&amp;oid=120381028&amp;loc=d3e5070-113901<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardAwardVestingPeriod1</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:durationItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardMaximumEmployeeSubscriptionRate">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The highest percentage of annual salary that an employee is permitted to utilize with respect to the plan.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 718<br> -SubTopic 10<br> -Section 50<br> -Paragraph 2<br> -URI http://asc.fasb.org/extlink&amp;oid=120381028&amp;loc=d3e5070-113901<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardMaximumEmployeeSubscriptionRate</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>dtr-types:percentItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardNonOptionEquityInstrumentsOutstandingNumber">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Number of equity instruments other than options outstanding, including both vested and non-vested instruments.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 718<br> -SubTopic 10<br> -Section 50<br> -Paragraph 2<br> -Subparagraph (c)(1)(ii)<br> -URI http://asc.fasb.org/extlink&amp;oid=120381028&amp;loc=d3e5070-113901<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 718<br> -SubTopic 10<br> -Section 50<br> -Paragraph 2<br> -Subparagraph (c)(1)(i)<br> -URI http://asc.fasb.org/extlink&amp;oid=120381028&amp;loc=d3e5070-113901<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardNonOptionEquityInstrumentsOutstandingNumber</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:sharesItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardNumberOfAdditionalSharesAuthorized">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Number of additional shares authorized for issuance under share-based payment arrangement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardNumberOfAdditionalSharesAuthorized</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:sharesItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardNumberOfSharesAuthorized">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Number of shares authorized for issuance under share-based payment arrangement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 718<br> -SubTopic 10<br> -Section 50<br> -Paragraph 2<br> -Subparagraph (a)(3)<br> -URI http://asc.fasb.org/extlink&amp;oid=120381028&amp;loc=d3e5070-113901<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardNumberOfSharesAuthorized</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:sharesItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardNumberOfSharesAvailableForGrant">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The difference between the maximum number of shares (or other type of equity) authorized for issuance under the plan (including the effects of amendments and adjustments), and the sum of: 1) the number of shares (or other type of equity) already issued upon exercise of options or other equity-based awards under the plan; and 2) shares (or other type of equity) reserved for issuance on granting of outstanding awards, net of cancellations and forfeitures, if applicable.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 718<br> -SubTopic 10<br> -Section 50<br> -Paragraph 2<br> -URI http://asc.fasb.org/extlink&amp;oid=120381028&amp;loc=d3e5070-113901<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardNumberOfSharesAvailableForGrant</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:sharesItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsExercisableNumber">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The number of shares into which fully or partially vested stock options outstanding as of the balance sheet date can be currently converted under the option plan.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 718<br> -SubTopic 10<br> -Section 50<br> -Paragraph 2<br> -Subparagraph (c)(1)(iii)<br> -URI http://asc.fasb.org/extlink&amp;oid=120381028&amp;loc=d3e5070-113901<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsExercisableNumber</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:sharesItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsOutstandingNumber">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Number of options outstanding, including both vested and non-vested options.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 718<br> -SubTopic 10<br> -Section 50<br> -Paragraph 2<br> -URI http://asc.fasb.org/extlink&amp;oid=120381028&amp;loc=d3e5070-113901<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 718<br> -SubTopic 10<br> -Section 50<br> -Paragraph 2<br> -Subparagraph (c)(1)(i)-(ii)<br> -URI http://asc.fasb.org/extlink&amp;oid=120381028&amp;loc=d3e5070-113901<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsOutstandingNumber</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:sharesItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_SharebasedCompensationArrangementBySharebasedPaymentAwardAwardVestingRightsPercentage">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Percentage of vesting of award under share-based payment arrangement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 718<br> -SubTopic 10<br> -Section 50<br> -Paragraph 2<br> -Subparagraph (a)(1)<br> -URI http://asc.fasb.org/extlink&amp;oid=120381028&amp;loc=d3e5070-113901<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_SharebasedCompensationArrangementBySharebasedPaymentAwardAwardVestingRightsPercentage</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>dtr-types:percentItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_SharebasedCompensationArrangementBySharebasedPaymentAwardExpirationPeriod">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Period from grant date that an equity-based award expires, in 'PnYnMnDTnHnMnS' format, for example, 'P1Y5M13D' represents the reported fact of one year, five months, and thirteen days.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 718<br> -SubTopic 10<br> -Section 50<br> -Paragraph 2<br> -Subparagraph (a)(2)<br> -URI http://asc.fasb.org/extlink&amp;oid=120381028&amp;loc=d3e5070-113901<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_SharebasedCompensationArrangementBySharebasedPaymentAwardExpirationPeriod</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:durationItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_SharebasedCompensationArrangementBySharebasedPaymentAwardPurchasePriceOfCommonStockPercent">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Purchase price of common stock expressed as a percentage of its fair value.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_SharebasedCompensationArrangementBySharebasedPaymentAwardPurchasePriceOfCommonStockPercent</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>dtr-types:percentItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_StockIssuedDuringPeriodSharesEmployeeStockPurchasePlans">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Number of shares issued during the period as a result of an employee stock purchase plan.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 505<br> -SubTopic 10<br> -Section 50<br> -Paragraph 2<br> -URI http://asc.fasb.org/extlink&amp;oid=123467817&amp;loc=d3e21463-112644<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 505<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.3-04)<br> -URI http://asc.fasb.org/extlink&amp;oid=120397183&amp;loc=d3e187085-122770<br><br>Reference 3: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 210<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.5-02(28))<br> -URI http://asc.fasb.org/extlink&amp;oid=120391452&amp;loc=d3e13212-122682<br><br>Reference 4: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 210<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.5-02(29))<br> -URI http://asc.fasb.org/extlink&amp;oid=120391452&amp;loc=d3e13212-122682<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_StockIssuedDuringPeriodSharesEmployeeStockPurchasePlans</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:sharesItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_AwardTypeAxis=us-gaap_StockOptionMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_AwardTypeAxis=us-gaap_StockOptionMember</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td></td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_PlanNameAxis=ions_StockOptionPlan1989Member">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_PlanNameAxis=ions_StockOptionPlan1989Member</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td></td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_VestingAxis=us-gaap_ShareBasedCompensationAwardTrancheOneMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_VestingAxis=us-gaap_ShareBasedCompensationAwardTrancheOneMember</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td></td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_PlanNameAxis=ions_EquityIncentivePlan2011Member">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_PlanNameAxis=ions_EquityIncentivePlan2011Member</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td></td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_AwardDateAxis=ions_IssuedAfterDecember312021Member">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_AwardDateAxis=ions_IssuedAfterDecember312021Member</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td></td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_AwardTypeAxis=us-gaap_RestrictedStockUnitsRSUMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_AwardTypeAxis=us-gaap_RestrictedStockUnitsRSUMember</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td></td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_PlanNameAxis=ions_EquityIncentivePlan2020Member">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_PlanNameAxis=ions_EquityIncentivePlan2020Member</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td></td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_PlanNameAxis=ions_NonemployeeDirectorsStockOptionPlan2002Member">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_PlanNameAxis=ions_NonemployeeDirectorsStockOptionPlan2002Member</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td></td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_PlanNameAxis=ions_EmployeeStockPurchasePlanMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_PlanNameAxis=ions_EmployeeStockPurchasePlanMember</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td></td>
</tr>
</table></div>
</div></td></tr>
</table>
</div>
</body>
</html>
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</DOCUMENT>
<DOCUMENT>
<TYPE>XML
<SEQUENCE>91
<FILENAME>R61.htm
<DESCRIPTION>IDEA: XBRL DOCUMENT
<TEXT>
<html>
<head>
<title></title>
<link rel="stylesheet" type="text/css" href="report.css">
<script type="text/javascript" src="Show.js">/* Do Not Remove This Comment */</script><script type="text/javascript">
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<span style="display: none;">v3.22.0.1</span><table class="report" border="0" cellspacing="2" id="idm139691008342472">
<tr>
<th class="tl" colspan="1" rowspan="2"><div style="width: 200px;"><strong>Stockholders' Equity, Stock Option Activity (Details) - Stock Options [Member] - USD ($)<br> $ / shares in Units, shares in Thousands, $ in Thousands</strong></div></th>
<th class="th" colspan="3">12 Months Ended</th>
</tr>
<tr>
<th class="th"><div>Dec. 31, 2021</div></th>
<th class="th"><div>Dec. 31, 2020</div></th>
<th class="th"><div>Dec. 31, 2019</div></th>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsOutstandingRollForward', window );"><strong>Number of Shares [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsOutstandingNumber', window );">Outstanding at beginning of period (in shares)</a></td>
<td class="nump">12,439<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsGrantsInPeriodGross', window );">Granted (in shares)</a></td>
<td class="nump">3,382<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_StockIssuedDuringPeriodSharesStockOptionsExercised', window );">Exercised (in shares)</a></td>
<td class="num">(219)<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsForfeituresAndExpirationsInPeriod', window );">Cancelled/forfeited/expired (in shares)</a></td>
<td class="num">(1,513)<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsOutstandingNumber', window );">Outstanding at end of period (in shares)</a></td>
<td class="nump">14,089<span></span>
</td>
<td class="nump">12,439<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsExercisableNumber', window );">Exercisable at end of period (in shares)</a></td>
<td class="nump">9,175<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsOutstandingWeightedAverageExercisePriceRollforward', window );"><strong>Weighted Average Exercise Price Per Share [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsOutstandingWeightedAverageExercisePrice', window );">Outstanding at beginning of period (in dollars per share)</a></td>
<td class="nump">$ 54.11<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationArrangementsByShareBasedPaymentAwardOptionsGrantsInPeriodWeightedAverageExercisePrice', window );">Granted (in dollars per share)</a></td>
<td class="nump">53.07<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationArrangementsByShareBasedPaymentAwardOptionsExercisesInPeriodWeightedAverageExercisePrice', window );">Exercised (in dollars per share)</a></td>
<td class="nump">38.69<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationArrangementsByShareBasedPaymentAwardOptionsForfeituresInPeriodWeightedAverageExercisePrice', window );">Cancelled/forfeited/expired (in dollars per share)</a></td>
<td class="nump">54.65<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsOutstandingWeightedAverageExercisePrice', window );">Outstanding at end of period (in dollars per share)</a></td>
<td class="nump">54.04<span></span>
</td>
<td class="nump">$ 54.11<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsExercisableWeightedAverageExercisePrice', window );">Exercisable at end of period (in dollars per share)</a></td>
<td class="nump">$ 53.65<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsAdditionalDisclosuresAbstract', window );"><strong>Average Remaining Contractual Term, Aggregate Intrinsic Value and Other [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_SharebasedCompensationArrangementBySharebasedPaymentAwardOptionsOutstandingWeightedAverageRemainingContractualTerm2', window );">Average remaining contractual term, outstanding at end of period</a></td>
<td class="text">3 years 10 months 20 days<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_SharebasedCompensationArrangementBySharebasedPaymentAwardOptionsExercisableWeightedAverageRemainingContractualTerm1', window );">Average remaining contractual term, exercisable at end of period</a></td>
<td class="text">2 years 11 months 8 days<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsOutstandingIntrinsicValue', window );">Aggregate intrinsic value, outstanding at end of period</a></td>
<td class="nump">$ 1,131<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_SharebasedCompensationArrangementBySharebasedPaymentAwardOptionsExercisableIntrinsicValue1', window );">Aggregate intrinsic value, exercisable at end of period</a></td>
<td class="nump">$ 1,067<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsGrantsInPeriodWeightedAverageGrantDateFairValue', window );">Weighted average fair value of options granted (in dollars per share)</a></td>
<td class="nump">$ 24.35<span></span>
</td>
<td class="nump">$ 29.43<span></span>
</td>
<td class="nump">$ 28.76<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsExercisesInPeriodTotalIntrinsicValue', window );">Intrinsic value of options exercised</a></td>
<td class="nump">$ 2,500<span></span>
</td>
<td class="nump">$ 15,500<span></span>
</td>
<td class="nump">$ 83,800<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ProceedsFromStockOptionsExercised', window );">Cash received from exercise of stock options</a></td>
<td class="nump">$ 8,500<span></span>
</td>
<td class="nump">$ 43,700<span></span>
</td>
<td class="nump">$ 105,900<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsExercisesInPeriodWeightedAverageFairValue', window );">Weighted-average fair value of options exercised (in dollars per share)</a></td>
<td class="nump">$ 50.13<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_EmployeeServiceShareBasedCompensationNonvestedAwardsTotalCompensationCostNotYetRecognizedAbstract', window );"><strong>Unrecognized Compensation Expense [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_EmployeeServiceShareBasedCompensationNonvestedAwardsTotalCompensationCostNotYetRecognizedStockOptions', window );">Unrecognized compensation cost related to non-vested stock options</a></td>
<td class="nump">$ 49,600<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_EmployeeServiceShareBasedCompensationNonvestedAwardsTotalCompensationCostNotYetRecognizedPeriodForRecognition1', window );">Weighted average period for recognition</a></td>
<td class="text">1 year 1 month 6 days<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
</table>
<div style="display: none;">
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsExercisesInPeriodWeightedAverageFairValue">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The weighted average grant-date fair value of options exercised during the reporting period as calculated by applying the disclosed option pricing methodology.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsExercisesInPeriodWeightedAverageFairValue</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>dtr-types:perShareItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_EmployeeServiceShareBasedCompensationNonvestedAwardsTotalCompensationCostNotYetRecognizedAbstract">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_EmployeeServiceShareBasedCompensationNonvestedAwardsTotalCompensationCostNotYetRecognizedAbstract</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:stringItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_EmployeeServiceShareBasedCompensationNonvestedAwardsTotalCompensationCostNotYetRecognizedPeriodForRecognition1">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Weighted-average period over which cost not yet recognized is expected to be recognized for award under share-based payment arrangement, in 'PnYnMnDTnHnMnS' format, for example, 'P1Y5M13D' represents reported fact of one year, five months, and thirteen days.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 718<br> -SubTopic 10<br> -Section 50<br> -Paragraph 2<br> -Subparagraph (i)<br> -URI http://asc.fasb.org/extlink&amp;oid=120381028&amp;loc=d3e5070-113901<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_EmployeeServiceShareBasedCompensationNonvestedAwardsTotalCompensationCostNotYetRecognizedPeriodForRecognition1</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:durationItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_EmployeeServiceShareBasedCompensationNonvestedAwardsTotalCompensationCostNotYetRecognizedStockOptions">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of cost to be recognized for option under share-based payment arrangement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 718<br> -SubTopic 10<br> -Section 50<br> -Paragraph 2<br> -Subparagraph (i)<br> -URI http://asc.fasb.org/extlink&amp;oid=120381028&amp;loc=d3e5070-113901<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_EmployeeServiceShareBasedCompensationNonvestedAwardsTotalCompensationCostNotYetRecognizedStockOptions</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_ProceedsFromStockOptionsExercised">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of cash inflow from exercise of option under share-based payment arrangement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 718<br> -SubTopic 10<br> -Section 50<br> -Paragraph 2A<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=120381028&amp;loc=SL79508275-113901<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 230<br> -SubTopic 10<br> -Section 45<br> -Paragraph 14<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=123570139&amp;loc=d3e3255-108585<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ProceedsFromStockOptionsExercised</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsAdditionalDisclosuresAbstract">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsAdditionalDisclosuresAbstract</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:stringItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsExercisableNumber">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The number of shares into which fully or partially vested stock options outstanding as of the balance sheet date can be currently converted under the option plan.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 718<br> -SubTopic 10<br> -Section 50<br> -Paragraph 2<br> -Subparagraph (c)(1)(iii)<br> -URI http://asc.fasb.org/extlink&amp;oid=120381028&amp;loc=d3e5070-113901<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsExercisableNumber</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:sharesItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsExercisableWeightedAverageExercisePrice">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The weighted-average price as of the balance sheet date at which grantees can acquire the shares reserved for issuance on vested portions of options outstanding and currently exercisable under the stock option plan.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 718<br> -SubTopic 10<br> -Section 50<br> -Paragraph 2<br> -Subparagraph (c)(1)(iii)<br> -URI http://asc.fasb.org/extlink&amp;oid=120381028&amp;loc=d3e5070-113901<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsExercisableWeightedAverageExercisePrice</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>dtr-types:perShareItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsExercisesInPeriodTotalIntrinsicValue">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of accumulated difference between fair value of underlying shares on dates of exercise and exercise price on options exercised (or share units converted) into shares.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 718<br> -SubTopic 10<br> -Section 50<br> -Paragraph 2<br> -Subparagraph (d)(2)<br> -URI http://asc.fasb.org/extlink&amp;oid=120381028&amp;loc=d3e5070-113901<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsExercisesInPeriodTotalIntrinsicValue</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsForfeituresAndExpirationsInPeriod">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>For presentations that combine terminations, the number of shares under options that were cancelled during the reporting period as a result of occurrence of a terminating event specified in contractual agreements pertaining to the stock option plan or that expired.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 718<br> -SubTopic 10<br> -Section 50<br> -Paragraph 2<br> -Subparagraph (c)(1)(iv)(3)-(4)<br> -URI http://asc.fasb.org/extlink&amp;oid=120381028&amp;loc=d3e5070-113901<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsForfeituresAndExpirationsInPeriod</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:sharesItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsGrantsInPeriodGross">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Gross number of share options (or share units) granted during the period.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsGrantsInPeriodGross</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:sharesItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsGrantsInPeriodWeightedAverageGrantDateFairValue">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The weighted average grant-date fair value of options granted during the reporting period as calculated by applying the disclosed option pricing methodology.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 718<br> -SubTopic 10<br> -Section 50<br> -Paragraph 2<br> -Subparagraph (d)(1)<br> -URI http://asc.fasb.org/extlink&amp;oid=120381028&amp;loc=d3e5070-113901<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsGrantsInPeriodWeightedAverageGrantDateFairValue</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>dtr-types:perShareItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsOutstandingIntrinsicValue">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount by which the current fair value of the underlying stock exceeds the exercise price of options outstanding.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 718<br> -SubTopic 10<br> -Section 50<br> -Paragraph 2<br> -URI http://asc.fasb.org/extlink&amp;oid=120381028&amp;loc=d3e5070-113901<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsOutstandingIntrinsicValue</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsOutstandingNumber">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Number of options outstanding, including both vested and non-vested options.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 718<br> -SubTopic 10<br> -Section 50<br> -Paragraph 2<br> -URI http://asc.fasb.org/extlink&amp;oid=120381028&amp;loc=d3e5070-113901<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 718<br> -SubTopic 10<br> -Section 50<br> -Paragraph 2<br> -Subparagraph (c)(1)(i)-(ii)<br> -URI http://asc.fasb.org/extlink&amp;oid=120381028&amp;loc=d3e5070-113901<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsOutstandingNumber</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:sharesItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsOutstandingRollForward">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>A roll forward is a reconciliation of a concept from the beginning of a period to the end of a period.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsOutstandingRollForward</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:stringItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsOutstandingWeightedAverageExercisePrice">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Weighted average price at which grantees can acquire the shares reserved for issuance under the stock option plan.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 718<br> -SubTopic 10<br> -Section 50<br> -Paragraph 2<br> -Subparagraph (c)(1)(i)<br> -URI http://asc.fasb.org/extlink&amp;oid=120381028&amp;loc=d3e5070-113901<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsOutstandingWeightedAverageExercisePrice</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>dtr-types:perShareItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsOutstandingWeightedAverageExercisePriceRollforward">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsOutstandingWeightedAverageExercisePriceRollforward</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:stringItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
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<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_ShareBasedCompensationArrangementsByShareBasedPaymentAwardOptionsExercisesInPeriodWeightedAverageExercisePrice">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Weighted average price at which option holders acquired shares when converting their stock options into shares.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ShareBasedCompensationArrangementsByShareBasedPaymentAwardOptionsExercisesInPeriodWeightedAverageExercisePrice</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>dtr-types:perShareItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_ShareBasedCompensationArrangementsByShareBasedPaymentAwardOptionsForfeituresInPeriodWeightedAverageExercisePrice">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Weighted average price at which grantees could have acquired the underlying shares with respect to stock options that were terminated.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ShareBasedCompensationArrangementsByShareBasedPaymentAwardOptionsForfeituresInPeriodWeightedAverageExercisePrice</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>dtr-types:perShareItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_ShareBasedCompensationArrangementsByShareBasedPaymentAwardOptionsGrantsInPeriodWeightedAverageExercisePrice">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Weighted average per share amount at which grantees can acquire shares of common stock by exercise of options.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ShareBasedCompensationArrangementsByShareBasedPaymentAwardOptionsGrantsInPeriodWeightedAverageExercisePrice</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>dtr-types:perShareItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
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<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_SharebasedCompensationArrangementBySharebasedPaymentAwardOptionsExercisableIntrinsicValue1">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of difference between fair value of the underlying shares reserved for issuance and exercise price of vested portions of options outstanding and currently exercisable.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 718<br> -SubTopic 10<br> -Section 50<br> -Paragraph 2<br> -URI http://asc.fasb.org/extlink&amp;oid=120381028&amp;loc=d3e5070-113901<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_SharebasedCompensationArrangementBySharebasedPaymentAwardOptionsExercisableIntrinsicValue1</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
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<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
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<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
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<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_SharebasedCompensationArrangementBySharebasedPaymentAwardOptionsExercisableWeightedAverageRemainingContractualTerm1">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Weighted average remaining contractual term for vested portions of options outstanding and currently exercisable or convertible, in 'PnYnMnDTnHnMnS' format, for example, 'P1Y5M13D' represents the reported fact of one year, five months, and thirteen days.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 718<br> -SubTopic 10<br> -Section 50<br> -Paragraph 2<br> -URI http://asc.fasb.org/extlink&amp;oid=120381028&amp;loc=d3e5070-113901<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_SharebasedCompensationArrangementBySharebasedPaymentAwardOptionsExercisableWeightedAverageRemainingContractualTerm1</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
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<td><strong> Data Type:</strong></td>
<td>xbrli:durationItemType</td>
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<td><strong> Balance Type:</strong></td>
<td>na</td>
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<td><strong> Period Type:</strong></td>
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<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_SharebasedCompensationArrangementBySharebasedPaymentAwardOptionsOutstandingWeightedAverageRemainingContractualTerm2">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Weighted average remaining contractual term for option awards outstanding, in 'PnYnMnDTnHnMnS' format, for example, 'P1Y5M13D' represents the reported fact of one year, five months, and thirteen days.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 718<br> -SubTopic 10<br> -Section 50<br> -Paragraph 2<br> -Subparagraph (e)(1)<br> -URI http://asc.fasb.org/extlink&amp;oid=120381028&amp;loc=d3e5070-113901<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_SharebasedCompensationArrangementBySharebasedPaymentAwardOptionsOutstandingWeightedAverageRemainingContractualTerm2</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
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<td><strong> Data Type:</strong></td>
<td>xbrli:durationItemType</td>
</tr>
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<td><strong> Balance Type:</strong></td>
<td>na</td>
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<td><strong> Period Type:</strong></td>
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</table></div>
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<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_StockIssuedDuringPeriodSharesStockOptionsExercised">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Number of share options (or share units) exercised during the current period.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 718<br> -SubTopic 10<br> -Section 50<br> -Paragraph 2<br> -Subparagraph (c)(1)(iv)(2)<br> -URI http://asc.fasb.org/extlink&amp;oid=120381028&amp;loc=d3e5070-113901<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 505<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.3-04)<br> -URI http://asc.fasb.org/extlink&amp;oid=120397183&amp;loc=d3e187085-122770<br><br>Reference 3: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 210<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.5-02(28))<br> -URI http://asc.fasb.org/extlink&amp;oid=120391452&amp;loc=d3e13212-122682<br><br>Reference 4: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 210<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.5-02(29))<br> -URI http://asc.fasb.org/extlink&amp;oid=120391452&amp;loc=d3e13212-122682<br><br>Reference 5: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 505<br> -SubTopic 10<br> -Section 50<br> -Paragraph 2<br> -URI http://asc.fasb.org/extlink&amp;oid=123467817&amp;loc=d3e21463-112644<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_StockIssuedDuringPeriodSharesStockOptionsExercised</td>
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<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
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<td><strong> Data Type:</strong></td>
<td>xbrli:sharesItemType</td>
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<td><strong> Balance Type:</strong></td>
<td>na</td>
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<td><strong> Period Type:</strong></td>
<td>duration</td>
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<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_AwardTypeAxis=us-gaap_StockOptionMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_AwardTypeAxis=us-gaap_StockOptionMember</td>
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<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td></td>
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<td><strong> Data Type:</strong></td>
<td>na</td>
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<td><strong> Balance Type:</strong></td>
<td></td>
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<td><strong> Period Type:</strong></td>
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<span style="display: none;">v3.22.0.1</span><table class="report" border="0" cellspacing="2" id="idm139691000860392">
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<th class="tl" colspan="1" rowspan="2"><div style="width: 200px;"><strong>Stockholders' Equity, Restricted Stock Unit Activity (Details) - Restricted Stock Units [Member] - USD ($)<br> $ / shares in Units, shares in Thousands, $ in Millions</strong></div></th>
<th class="th" colspan="3">12 Months Ended</th>
</tr>
<tr>
<th class="th"><div>Dec. 31, 2021</div></th>
<th class="th"><div>Dec. 31, 2020</div></th>
<th class="th"><div>Dec. 31, 2019</div></th>
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<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardEquityInstrumentsOtherThanOptionsNonvestedRollForward', window );"><strong>Number of Shares [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
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<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardEquityInstrumentsOtherThanOptionsNonvestedNumber', window );">Non-vested at beginning of period (in shares)</a></td>
<td class="nump">2,374<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardEquityInstrumentsOtherThanOptionsGrantsInPeriod', window );">Granted (in shares)</a></td>
<td class="nump">1,548<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardEquityInstrumentsOtherThanOptionsVestedInPeriod', window );">Vested (in shares)</a></td>
<td class="num">(834)<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardEquityInstrumentsOtherThanOptionsForfeitedInPeriod', window );">Cancelled/forfeited (in shares)</a></td>
<td class="num">(411)<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardEquityInstrumentsOtherThanOptionsNonvestedNumber', window );">Non-vested at end of period (in shares)</a></td>
<td class="nump">2,677<span></span>
</td>
<td class="nump">2,374<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardEquityInstrumentsOtherThanOptionsNonvestedWeightedAverageGrantDateFairValueRollForward', window );"><strong>Weighted Average Grant Date Fair Value per Share [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardEquityInstrumentsOtherThanOptionsNonvestedWeightedAverageGrantDateFairValue', window );">Non-vested at beginning of period (in dollars per share)</a></td>
<td class="nump">$ 58.81<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardEquityInstrumentsOtherThanOptionsGrantsInPeriodWeightedAverageGrantDateFairValue', window );">Granted (in dollars per share)</a></td>
<td class="nump">57.69<span></span>
</td>
<td class="nump">$ 60.86<span></span>
</td>
<td class="nump">$ 60.23<span></span>
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<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardEquityInstrumentsOtherThanOptionsVestedInPeriodWeightedAverageGrantDateFairValue', window );">Vested (in dollars per share)</a></td>
<td class="nump">57.47<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
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<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardEquityInstrumentsOtherThanOptionsForfeituresWeightedAverageGrantDateFairValue', window );">Cancelled/forfeited (in dollars per share)</a></td>
<td class="nump">59.24<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardEquityInstrumentsOtherThanOptionsNonvestedWeightedAverageGrantDateFairValue', window );">Non-vested at end of period (in dollars per share)</a></td>
<td class="nump">$ 58.51<span></span>
</td>
<td class="nump">$ 58.81<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_EmployeeServiceShareBasedCompensationNonvestedAwardsTotalCompensationCostNotYetRecognizedAbstract', window );"><strong>Unrecognized Compensation Expense [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_EmployeeServiceShareBasedCompensationNonvestedAwardsTotalCompensationCostNotYetRecognizedShareBasedAwardsOtherThanOptions', window );">Unrecognized compensation cost related to non-vested units</a></td>
<td class="nump">$ 57.0<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_EmployeeServiceShareBasedCompensationNonvestedAwardsTotalCompensationCostNotYetRecognizedPeriodForRecognition1', window );">Weighted average period for recognition</a></td>
<td class="text">1 year 2 months 12 days<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
</table>
<div style="display: none;">
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_EmployeeServiceShareBasedCompensationNonvestedAwardsTotalCompensationCostNotYetRecognizedAbstract">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_EmployeeServiceShareBasedCompensationNonvestedAwardsTotalCompensationCostNotYetRecognizedAbstract</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:stringItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_EmployeeServiceShareBasedCompensationNonvestedAwardsTotalCompensationCostNotYetRecognizedPeriodForRecognition1">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Weighted-average period over which cost not yet recognized is expected to be recognized for award under share-based payment arrangement, in 'PnYnMnDTnHnMnS' format, for example, 'P1Y5M13D' represents reported fact of one year, five months, and thirteen days.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 718<br> -SubTopic 10<br> -Section 50<br> -Paragraph 2<br> -Subparagraph (i)<br> -URI http://asc.fasb.org/extlink&amp;oid=120381028&amp;loc=d3e5070-113901<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_EmployeeServiceShareBasedCompensationNonvestedAwardsTotalCompensationCostNotYetRecognizedPeriodForRecognition1</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:durationItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_EmployeeServiceShareBasedCompensationNonvestedAwardsTotalCompensationCostNotYetRecognizedShareBasedAwardsOtherThanOptions">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of cost to be recognized for nonvested award under share-based payment arrangement. Excludes share and unit options.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 718<br> -SubTopic 10<br> -Section 50<br> -Paragraph 2<br> -Subparagraph (i)<br> -URI http://asc.fasb.org/extlink&amp;oid=120381028&amp;loc=d3e5070-113901<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_EmployeeServiceShareBasedCompensationNonvestedAwardsTotalCompensationCostNotYetRecognizedShareBasedAwardsOtherThanOptions</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardEquityInstrumentsOtherThanOptionsForfeitedInPeriod">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The number of equity-based payment instruments, excluding stock (or unit) options, that were forfeited during the reporting period.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 718<br> -SubTopic 10<br> -Section 50<br> -Paragraph 2<br> -Subparagraph (c)(1)(iv)(3)<br> -URI http://asc.fasb.org/extlink&amp;oid=120381028&amp;loc=d3e5070-113901<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardEquityInstrumentsOtherThanOptionsForfeitedInPeriod</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:sharesItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardEquityInstrumentsOtherThanOptionsForfeituresWeightedAverageGrantDateFairValue">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Weighted average fair value as of the grant date of equity-based award plans other than stock (unit) option plans that were not exercised or put into effect as a result of the occurrence of a terminating event.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 718<br> -SubTopic 10<br> -Section 50<br> -Paragraph 2<br> -Subparagraph (c)(2)(iii)(3)<br> -URI http://asc.fasb.org/extlink&amp;oid=120381028&amp;loc=d3e5070-113901<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardEquityInstrumentsOtherThanOptionsForfeituresWeightedAverageGrantDateFairValue</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>dtr-types:perShareItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardEquityInstrumentsOtherThanOptionsGrantsInPeriod">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The number of grants made during the period on other than stock (or unit) option plans (for example, phantom stock or unit plan, stock or unit appreciation rights plan, performance target plan).</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 718<br> -SubTopic 10<br> -Section 50<br> -Paragraph 2<br> -Subparagraph (c)(2)(iii)(1)<br> -URI http://asc.fasb.org/extlink&amp;oid=120381028&amp;loc=d3e5070-113901<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardEquityInstrumentsOtherThanOptionsGrantsInPeriod</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:sharesItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardEquityInstrumentsOtherThanOptionsGrantsInPeriodWeightedAverageGrantDateFairValue">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The weighted average fair value at grant date for nonvested equity-based awards issued during the period on other than stock (or unit) option plans (for example, phantom stock or unit plan, stock or unit appreciation rights plan, performance target plan).</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 718<br> -SubTopic 10<br> -Section 50<br> -Paragraph 2<br> -Subparagraph (c)(2)(iii)(1)<br> -URI http://asc.fasb.org/extlink&amp;oid=120381028&amp;loc=d3e5070-113901<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardEquityInstrumentsOtherThanOptionsGrantsInPeriodWeightedAverageGrantDateFairValue</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>dtr-types:perShareItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardEquityInstrumentsOtherThanOptionsNonvestedNumber">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The number of non-vested equity-based payment instruments, excluding stock (or unit) options, that validly exist and are outstanding as of the balance sheet date.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 718<br> -SubTopic 10<br> -Section 50<br> -Paragraph 2<br> -Subparagraph (c)(2)(i)-(ii)<br> -URI http://asc.fasb.org/extlink&amp;oid=120381028&amp;loc=d3e5070-113901<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardEquityInstrumentsOtherThanOptionsNonvestedNumber</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:sharesItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardEquityInstrumentsOtherThanOptionsNonvestedRollForward">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>A roll forward is a reconciliation of a concept from the beginning of a period to the end of a period.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardEquityInstrumentsOtherThanOptionsNonvestedRollForward</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:stringItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardEquityInstrumentsOtherThanOptionsNonvestedWeightedAverageGrantDateFairValue">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Per share or unit weighted-average fair value of nonvested award under share-based payment arrangement. Excludes share and unit options.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 718<br> -SubTopic 10<br> -Section 50<br> -Paragraph 2<br> -Subparagraph (c)(2)(i)-(ii)<br> -URI http://asc.fasb.org/extlink&amp;oid=120381028&amp;loc=d3e5070-113901<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardEquityInstrumentsOtherThanOptionsNonvestedWeightedAverageGrantDateFairValue</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>dtr-types:perShareItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardEquityInstrumentsOtherThanOptionsNonvestedWeightedAverageGrantDateFairValueRollForward">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>A roll forward is a reconciliation of a concept from the beginning of a period to the end of a period.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardEquityInstrumentsOtherThanOptionsNonvestedWeightedAverageGrantDateFairValueRollForward</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:stringItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
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<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardEquityInstrumentsOtherThanOptionsVestedInPeriod">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The number of equity-based payment instruments, excluding stock (or unit) options, that vested during the reporting period.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 718<br> -SubTopic 10<br> -Section 50<br> -Paragraph 2<br> -Subparagraph (c)(2)(iii)(2)<br> -URI http://asc.fasb.org/extlink&amp;oid=120381028&amp;loc=d3e5070-113901<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardEquityInstrumentsOtherThanOptionsVestedInPeriod</td>
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<tr>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 718<br> -SubTopic 10<br> -Section 50<br> -Paragraph 2<br> -Subparagraph (c)(2)(iii)(2)<br> -URI http://asc.fasb.org/extlink&amp;oid=120381028&amp;loc=d3e5070-113901<br></p></div>
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<tr>
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<td style="white-space:nowrap;">us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardEquityInstrumentsOtherThanOptionsVestedInPeriodWeightedAverageGrantDateFairValue</td>
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<span style="display: none;">v3.22.0.1</span><table class="report" border="0" cellspacing="2" id="idm139691003331448">
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<th class="tl" colspan="1" rowspan="2"><div style="width: 200px;"><strong>Stockholders' Equity, Stock-based Compensation Expense (Details)<br> $ in Thousands</strong></div></th>
<th class="th" colspan="1">3 Months Ended</th>
<th class="th" colspan="3">12 Months Ended</th>
<th class="th" colspan="1"></th>
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<tr>
<th class="th">
<div>Sep. 30, 2019 </div>
<div>USD ($) </div>
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<div>Dec. 31, 2021 </div>
<div>USD ($)</div>
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<th class="th">
<div>Dec. 31, 2020 </div>
<div>USD ($)</div>
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<div>Dec. 31, 2019 </div>
<div>USD ($)</div>
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<div>Oct. 31, 2020 </div>
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<td class="text">&#160;<span></span>
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<td class="nump">$ 230,117<span></span>
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<td class="text">&#160;<span></span>
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<td class="text">&#160;<span></span>
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<td class="text">&#160;<span></span>
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<td class="text">&#160;<span></span>
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<td class="text">&#160;<span></span>
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<td class="text">&#160;<span></span>
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<td class="text">&#160;<span></span>
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<td class="text">&#160;<span></span>
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<td class="text">&#160;<span></span>
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<td class="text">&#160;<span></span>
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<td class="nump">456<span></span>
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<td class="nump">1,991<span></span>
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<td class="nump">438<span></span>
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<td class="text">&#160;<span></span>
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<td class="text">&#160;<span></span>
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<td class="text">&#160;<span></span>
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<td class="text">&#160;<span></span>
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<td class="text">&#160;<span></span>
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<td class="text">&#160;<span></span>
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<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationAbstract', window );"><strong>Stock-Based Compensation [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
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<td class="text">&#160;<span></span>
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<td class="text">&#160;<span></span>
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<td class="text">&#160;<span></span>
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<td class="nump">87,522<span></span>
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<td class="nump">115,584<span></span>
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<td class="text">&#160;<span></span>
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<td class="text">&#160;<span></span>
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<td class="text">&#160;<span></span>
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<td class="text">&#160;<span></span>
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<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationAbstract', window );"><strong>Stock-Based Compensation [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
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<td class="text">&#160;<span></span>
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<td class="text">&#160;<span></span>
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<td class="nump">$ 32,700<span></span>
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<td class="nump">$ 112,542<span></span>
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<td class="text">&#160;<span></span>
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<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_srt_ConsolidatedEntitiesAxis=ions_AkceaTherapeuticsIncMember', window );">Akcea [Member]</a></td>
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<td class="text">&#160;<span></span>
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<td class="text">&#160;<span></span>
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<td class="text">&#160;<span></span>
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<td class="text">&#160;<span></span>
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<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationAbstract', window );"><strong>Stock-Based Compensation [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
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<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
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<td class="text">&#160;<span></span>
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<td class="text">&#160;<span></span>
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<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AllocatedShareBasedCompensationExpense', window );">Stock-based compensation expense</a></td>
<td class="num">$ (19,100)<span></span>
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<td class="text">&#160;<span></span>
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<td class="text">&#160;<span></span>
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<td class="text">&#160;<span></span>
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<td class="text">&#160;<span></span>
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<td class="text">&#160;<span></span>
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<td class="text">&#160;<span></span>
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<td class="text">&#160;<span></span>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The number of executive officers terminating employment with the company.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 718<br> -SubTopic 10<br> -Section 50<br> -Paragraph 1<br> -Subparagraph (b)<br> -URI http://asc.fasb.org/extlink&amp;oid=120381028&amp;loc=d3e5047-113901<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 718<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SAB Topic 14.F)<br> -URI http://asc.fasb.org/extlink&amp;oid=122041274&amp;loc=d3e301413-122809<br><br>Reference 3: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 718<br> -SubTopic 10<br> -Section 50<br> -Paragraph 2<br> -Subparagraph (h)(1)(i)<br> -URI http://asc.fasb.org/extlink&amp;oid=120381028&amp;loc=d3e5070-113901<br></p></div>
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<td style="white-space:nowrap;">srt_ConsolidatedEntitiesAxis=ions_AkceaTherapeuticsIncMember</td>
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<head>
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<span style="display: none;">v3.22.0.1</span><table class="report" border="0" cellspacing="2" id="idm139691003422376">
<tr>
<th class="tl" colspan="1" rowspan="2"><div style="width: 200px;"><strong>Stockholders' Equity, Stock-based Valuation Information (Details)<br></strong></div></th>
<th class="th" colspan="3">12 Months Ended</th>
</tr>
<tr>
<th class="th"><div>Dec. 31, 2021</div></th>
<th class="th"><div>Dec. 31, 2020</div></th>
<th class="th"><div>Dec. 31, 2019</div></th>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AwardTypeAxis=us-gaap_EmployeeStockOptionMember', window );">Employee Stock Options [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardFairValueAssumptionsAndMethodologyAbstract', window );"><strong>Weighted-Average Assumptions [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardFairValueAssumptionsRiskFreeInterestRate', window );">Risk-free interest rate</a></td>
<td class="nump">0.60%<span></span>
</td>
<td class="nump">1.50%<span></span>
</td>
<td class="nump">2.30%<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardFairValueAssumptionsExpectedDividendRate', window );">Dividend yield</a></td>
<td class="nump">0.00%<span></span>
</td>
<td class="nump">0.00%<span></span>
</td>
<td class="nump">0.00%<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardFairValueAssumptionsWeightedAverageVolatilityRate', window );">Volatility</a></td>
<td class="nump">54.00%<span></span>
</td>
<td class="nump">58.60%<span></span>
</td>
<td class="nump">60.30%<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_SharebasedCompensationArrangementBySharebasedPaymentAwardFairValueAssumptionsExpectedTerm1', window );">Expected life</a></td>
<td class="text">4 years 10 months 24 days<span></span>
</td>
<td class="text">4 years 8 months 12 days<span></span>
</td>
<td class="text">4 years 9 months 18 days<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AwardTypeAxis=ions_BoardOfDirectorStockOptionMember', window );">Board of Director Stock Options [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardFairValueAssumptionsAndMethodologyAbstract', window );"><strong>Weighted-Average Assumptions [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardFairValueAssumptionsRiskFreeInterestRate', window );">Risk-free interest rate</a></td>
<td class="nump">1.20%<span></span>
</td>
<td class="nump">0.50%<span></span>
</td>
<td class="nump">1.90%<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardFairValueAssumptionsExpectedDividendRate', window );">Dividend yield</a></td>
<td class="nump">0.00%<span></span>
</td>
<td class="nump">0.00%<span></span>
</td>
<td class="nump">0.00%<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardFairValueAssumptionsWeightedAverageVolatilityRate', window );">Volatility</a></td>
<td class="nump">55.90%<span></span>
</td>
<td class="nump">57.60%<span></span>
</td>
<td class="nump">60.70%<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_SharebasedCompensationArrangementBySharebasedPaymentAwardFairValueAssumptionsExpectedTerm1', window );">Expected life</a></td>
<td class="text">7 years 3 months 18 days<span></span>
</td>
<td class="text">6 years 8 months 12 days<span></span>
</td>
<td class="text">6 years 7 months 6 days<span></span>
</td>
</tr>
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<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AwardTypeAxis=us-gaap_EmployeeStockMember', window );">ESPP [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardFairValueAssumptionsAndMethodologyAbstract', window );"><strong>Weighted-Average Assumptions [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardFairValueAssumptionsRiskFreeInterestRate', window );">Risk-free interest rate</a></td>
<td class="nump">0.10%<span></span>
</td>
<td class="nump">0.80%<span></span>
</td>
<td class="nump">2.40%<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardFairValueAssumptionsExpectedDividendRate', window );">Dividend yield</a></td>
<td class="nump">0.00%<span></span>
</td>
<td class="nump">0.00%<span></span>
</td>
<td class="nump">0.00%<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardFairValueAssumptionsWeightedAverageVolatilityRate', window );">Volatility</a></td>
<td class="nump">42.40%<span></span>
</td>
<td class="nump">47.90%<span></span>
</td>
<td class="nump">45.60%<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_SharebasedCompensationArrangementBySharebasedPaymentAwardFairValueAssumptionsExpectedTerm1', window );">Expected life</a></td>
<td class="text">6 months<span></span>
</td>
<td class="text">6 months<span></span>
</td>
<td class="text">6 months<span></span>
</td>
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<div style="display: none;">
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardFairValueAssumptionsAndMethodologyAbstract</td>
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<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
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<td>na</td>
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<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The estimated dividend rate (a percentage of the share price) to be paid (expected dividends) to holders of the underlying shares over the option's term.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 718<br> -SubTopic 10<br> -Section 50<br> -Paragraph 2<br> -Subparagraph (f)(2)(iii)<br> -URI http://asc.fasb.org/extlink&amp;oid=120381028&amp;loc=d3e5070-113901<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardFairValueAssumptionsExpectedDividendRate</td>
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<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
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<td>dtr-types:percentItemType</td>
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<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The risk-free interest rate assumption that is used in valuing an option on its own shares.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 718<br> -SubTopic 10<br> -Section 50<br> -Paragraph 2<br> -Subparagraph (f)(2)(iv)<br> -URI http://asc.fasb.org/extlink&amp;oid=120381028&amp;loc=d3e5070-113901<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardFairValueAssumptionsRiskFreeInterestRate</td>
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<tr>
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<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Rate of weighted-average expected volatility for award under share-based payment arrangement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 718<br> -SubTopic 10<br> -Section 50<br> -Paragraph 2<br> -Subparagraph (f)(2)(ii)<br> -URI http://asc.fasb.org/extlink&amp;oid=120381028&amp;loc=d3e5070-113901<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardFairValueAssumptionsWeightedAverageVolatilityRate</td>
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<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Expected term of award under share-based payment arrangement, in 'PnYnMnDTnHnMnS' format, for example, 'P1Y5M13D' represents reported fact of one year, five months, and thirteen days.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 718<br> -SubTopic 10<br> -Section 50<br> -Paragraph 2<br> -Subparagraph (f)(2)(i)<br> -URI http://asc.fasb.org/extlink&amp;oid=120381028&amp;loc=d3e5070-113901<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 718<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SAB Topic 14.D.2)<br> -URI http://asc.fasb.org/extlink&amp;oid=122041274&amp;loc=d3e301413-122809<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_SharebasedCompensationArrangementBySharebasedPaymentAwardFairValueAssumptionsExpectedTerm1</td>
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<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_AwardTypeAxis=us-gaap_EmployeeStockOptionMember</td>
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<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
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<head>
<title></title>
<link rel="stylesheet" type="text/css" href="report.css">
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<span style="display: none;">v3.22.0.1</span><table class="report" border="0" cellspacing="2" id="idm139691013792440">
<tr>
<th class="tl" colspan="1" rowspan="2"><div style="width: 200px;"><strong>Income Taxes, Income (Loss) Before Income Taxes (Details) - USD ($)<br> $ in Thousands</strong></div></th>
<th class="th" colspan="3">12 Months Ended</th>
</tr>
<tr>
<th class="th"><div>Dec. 31, 2021</div></th>
<th class="th"><div>Dec. 31, 2020</div></th>
<th class="th"><div>Dec. 31, 2019</div></th>
</tr>
<tr class="re">
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<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
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<td class="num">$ (137,222)<span></span>
</td>
<td class="nump">$ 336,277<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_IncomeLossFromContinuingOperationsBeforeIncomeTaxesForeign', window );">Foreign</a></td>
<td class="nump">818<span></span>
</td>
<td class="nump">2,670<span></span>
</td>
<td class="nump">2,489<span></span>
</td>
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<tr class="rou">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_IncomeLossFromContinuingOperationsBeforeIncomeTaxesExtraordinaryItemsNoncontrollingInterest', window );">Income (loss) before income tax benefit (expense)</a></td>
<td class="num">$ (29,148)<span></span>
</td>
<td class="num">$ (134,552)<span></span>
</td>
<td class="nump">$ 338,766<span></span>
</td>
</tr>
</table>
<div style="display: none;">
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_IncomeLossFromContinuingOperationsBeforeIncomeTaxesDomestic">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The portion of earnings or loss from continuing operations before income taxes that is attributable to domestic operations.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 235<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.4-08(h)(1))<br> -URI http://asc.fasb.org/extlink&amp;oid=120395691&amp;loc=d3e23780-122690<br><br>Reference 2: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SAB Topic 6.I.Fact.3)<br> -URI http://asc.fasb.org/extlink&amp;oid=122134291&amp;loc=d3e330036-122817<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_IncomeLossFromContinuingOperationsBeforeIncomeTaxesDomestic</td>
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<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
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<td><strong> Balance Type:</strong></td>
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<td><strong> Period Type:</strong></td>
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<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of income (loss) from continuing operations, including income (loss) from equity method investments, before deduction of income tax expense (benefit), and income (loss) attributable to noncontrolling interest.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 280<br> -SubTopic 10<br> -Section 50<br> -Paragraph 32<br> -Subparagraph (c)<br> -URI http://asc.fasb.org/extlink&amp;oid=123359005&amp;loc=d3e8933-108599<br><br>Reference 2: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 280<br> -SubTopic 10<br> -Section 50<br> -Paragraph 30<br> -Subparagraph (b)<br> -URI http://asc.fasb.org/extlink&amp;oid=123359005&amp;loc=d3e8906-108599<br><br>Reference 3: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 280<br> -SubTopic 10<br> -Section 50<br> -Paragraph 32<br> -Subparagraph (f)<br> -URI http://asc.fasb.org/extlink&amp;oid=123359005&amp;loc=d3e8933-108599<br><br>Reference 4: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 940<br> -SubTopic 20<br> -Section 25<br> -Paragraph 1<br> -URI http://asc.fasb.org/extlink&amp;oid=123384075&amp;loc=d3e41242-110953<br><br>Reference 5: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 280<br> -SubTopic 10<br> -Section 50<br> -Paragraph 22<br> -URI http://asc.fasb.org/extlink&amp;oid=123359005&amp;loc=d3e8736-108599<br><br>Reference 6: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 220<br> -SubTopic 10<br> -Section S99<br> -Paragraph 2<br> -Subparagraph (SX 210.5-03(10))<br> -URI http://asc.fasb.org/extlink&amp;oid=123367319&amp;loc=SL114868664-224227<br><br>Reference 7: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 944<br> -SubTopic 220<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.7-04(8))<br> -URI http://asc.fasb.org/extlink&amp;oid=120400993&amp;loc=SL114874131-224263<br><br>Reference 8: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 942<br> -SubTopic 235<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.9-05(b)(2))<br> -URI http://asc.fasb.org/extlink&amp;oid=120399901&amp;loc=d3e537907-122884<br><br>Reference 9: http://www.xbrl.org/2003/role/exampleRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 280<br> -SubTopic 10<br> -Section 50<br> -Paragraph 31<br> -URI http://asc.fasb.org/extlink&amp;oid=123359005&amp;loc=d3e8924-108599<br><br>Reference 10: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 942<br> -SubTopic 220<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.9-04(15))<br> -URI http://asc.fasb.org/extlink&amp;oid=120399700&amp;loc=SL114874048-224260<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_IncomeLossFromContinuingOperationsBeforeIncomeTaxesExtraordinaryItemsNoncontrollingInterest</td>
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<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
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<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
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<td><strong> Balance Type:</strong></td>
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<td><strong> Period Type:</strong></td>
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<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_IncomeLossFromContinuingOperationsBeforeIncomeTaxesForeign">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The portion of earnings or loss from continuing operations before income taxes that is attributable to foreign operations, which is defined as Income or Loss generated from operations located outside the entity's country of domicile.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 235<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.4-08(h)(1))<br> -URI http://asc.fasb.org/extlink&amp;oid=120395691&amp;loc=d3e23780-122690<br><br>Reference 2: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SAB Topic 6.I.Fact.3)<br> -URI http://asc.fasb.org/extlink&amp;oid=122134291&amp;loc=d3e330036-122817<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
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<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_IncomeTaxDisclosureAbstract</td>
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<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
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<DOCUMENT>
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<DESCRIPTION>IDEA: XBRL DOCUMENT
<TEXT>
<html>
<head>
<title></title>
<link rel="stylesheet" type="text/css" href="report.css">
<script type="text/javascript" src="Show.js">/* Do Not Remove This Comment */</script><script type="text/javascript">
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<span style="display: none;">v3.22.0.1</span><table class="report" border="0" cellspacing="2" id="idm139691007602264">
<tr>
<th class="tl" colspan="1" rowspan="2"><div style="width: 200px;"><strong>Income Taxes, Income Tax Expense (Benefit) (Details) - USD ($)<br> $ in Thousands</strong></div></th>
<th class="th" colspan="3">12 Months Ended</th>
</tr>
<tr>
<th class="th"><div>Dec. 31, 2021</div></th>
<th class="th"><div>Dec. 31, 2020</div></th>
<th class="th"><div>Dec. 31, 2019</div></th>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_CurrentIncomeTaxExpenseBenefitContinuingOperationsAbstract', window );"><strong>Current [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_CurrentFederalTaxExpenseBenefit', window );">Federal</a></td>
<td class="num">$ (200)<span></span>
</td>
<td class="num">$ (837)<span></span>
</td>
<td class="nump">$ 35,861<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_CurrentStateAndLocalTaxExpenseBenefit', window );">State</a></td>
<td class="num">(690)<span></span>
</td>
<td class="nump">3,782<span></span>
</td>
<td class="nump">14,329<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_CurrentForeignTaxExpenseBenefit', window );">Foreign</a></td>
<td class="nump">339<span></span>
</td>
<td class="nump">518<span></span>
</td>
<td class="nump">413<span></span>
</td>
</tr>
<tr class="reu">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_CurrentIncomeTaxExpenseBenefit', window );">Total current income tax expense (benefit)</a></td>
<td class="num">(551)<span></span>
</td>
<td class="nump">3,463<span></span>
</td>
<td class="nump">50,603<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DeferredIncomeTaxExpenseBenefitContinuingOperationsAbstract', window );"><strong>Deferred [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DeferredFederalIncomeTaxExpenseBenefit', window );">Federal</a></td>
<td class="nump">0<span></span>
</td>
<td class="nump">341,728<span></span>
</td>
<td class="nump">904<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DeferredStateAndLocalIncomeTaxExpenseBenefit', window );">State</a></td>
<td class="nump">0<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="nump">0<span></span>
</td>
</tr>
<tr class="reu">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DeferredIncomeTaxExpenseBenefit', window );">Total deferred income tax benefit</a></td>
<td class="nump">0<span></span>
</td>
<td class="nump">341,728<span></span>
</td>
<td class="nump">904<span></span>
</td>
</tr>
<tr class="rou">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_IncomeTaxExpenseBenefit', window );">Total income tax expense (benefit)</a></td>
<td class="num">$ (551)<span></span>
</td>
<td class="nump">$ 345,191<span></span>
</td>
<td class="nump">$ 51,507<span></span>
</td>
</tr>
</table>
<div style="display: none;">
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_CurrentFederalTaxExpenseBenefit">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of current federal tax expense (benefit) pertaining to income (loss) from continuing operations.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2009/role/commonPracticeRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 235<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.4-08(h)(1)(Note 1))<br> -URI http://asc.fasb.org/extlink&amp;oid=120395691&amp;loc=d3e23780-122690<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SAB Topic 6.I.7)<br> -URI http://asc.fasb.org/extlink&amp;oid=122134291&amp;loc=d3e330036-122817<br><br>Reference 3: http://www.xbrl.org/2009/role/commonPracticeRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section 50<br> -Paragraph 9<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=121826272&amp;loc=d3e32639-109319<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_CurrentFederalTaxExpenseBenefit</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
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</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_CurrentForeignTaxExpenseBenefit">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of current foreign income tax expense (benefit) pertaining to income (loss) from continuing operations.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2009/role/commonPracticeRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 235<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.4-08(h)(1)(Note 1))<br> -URI http://asc.fasb.org/extlink&amp;oid=120395691&amp;loc=d3e23780-122690<br><br>Reference 2: http://www.xbrl.org/2009/role/commonPracticeRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section 50<br> -Paragraph 9<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=121826272&amp;loc=d3e32639-109319<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_CurrentForeignTaxExpenseBenefit</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
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<tr>
<td><strong> Period Type:</strong></td>
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</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_CurrentIncomeTaxExpenseBenefit">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of current income tax expense (benefit) pertaining to taxable income (loss) from continuing operations.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SAB Topic 6.I.7)<br> -URI http://asc.fasb.org/extlink&amp;oid=122134291&amp;loc=d3e330036-122817<br><br>Reference 2: http://www.xbrl.org/2009/role/commonPracticeRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 235<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.4-08(h)(1)(Note 1))<br> -URI http://asc.fasb.org/extlink&amp;oid=120395691&amp;loc=d3e23780-122690<br><br>Reference 3: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section 50<br> -Paragraph 9<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=121826272&amp;loc=d3e32639-109319<br><br>Reference 4: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SAB Topic 6.I.Fact.2)<br> -URI http://asc.fasb.org/extlink&amp;oid=122134291&amp;loc=d3e330036-122817<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_CurrentIncomeTaxExpenseBenefit</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_CurrentIncomeTaxExpenseBenefitContinuingOperationsAbstract">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_CurrentIncomeTaxExpenseBenefitContinuingOperationsAbstract</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
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<td><strong> Data Type:</strong></td>
<td>xbrli:stringItemType</td>
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<td><strong> Balance Type:</strong></td>
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<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_CurrentStateAndLocalTaxExpenseBenefit">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of current state and local tax expense (benefit) pertaining to income (loss) from continuing operations.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SAB Topic 6.I.7)<br> -URI http://asc.fasb.org/extlink&amp;oid=122134291&amp;loc=d3e330036-122817<br><br>Reference 2: http://www.xbrl.org/2009/role/commonPracticeRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 235<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.4-08(h)(1)(Note 1))<br> -URI http://asc.fasb.org/extlink&amp;oid=120395691&amp;loc=d3e23780-122690<br><br>Reference 3: http://www.xbrl.org/2009/role/commonPracticeRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section 50<br> -Paragraph 9<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=121826272&amp;loc=d3e32639-109319<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_CurrentStateAndLocalTaxExpenseBenefit</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_DeferredFederalIncomeTaxExpenseBenefit">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of deferred federal income tax expense (benefit) pertaining to income (loss) from continuing operations.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2009/role/commonPracticeRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 235<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.4-08(h)(1)(Note 1))<br> -URI http://asc.fasb.org/extlink&amp;oid=120395691&amp;loc=d3e23780-122690<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SAB Topic 6.I.7)<br> -URI http://asc.fasb.org/extlink&amp;oid=122134291&amp;loc=d3e330036-122817<br><br>Reference 3: http://www.xbrl.org/2009/role/commonPracticeRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section 50<br> -Paragraph 9<br> -Subparagraph (b)<br> -URI http://asc.fasb.org/extlink&amp;oid=121826272&amp;loc=d3e32639-109319<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_DeferredFederalIncomeTaxExpenseBenefit</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_DeferredIncomeTaxExpenseBenefit">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of deferred income tax expense (benefit) pertaining to income (loss) from continuing operations.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SAB Topic 6.I.7)<br> -URI http://asc.fasb.org/extlink&amp;oid=122134291&amp;loc=d3e330036-122817<br><br>Reference 2: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SAB Topic 6.I.Fact.1)<br> -URI http://asc.fasb.org/extlink&amp;oid=122134291&amp;loc=d3e330036-122817<br><br>Reference 3: http://www.xbrl.org/2009/role/commonPracticeRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 235<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.4-08(h)(1)(Note 1))<br> -URI http://asc.fasb.org/extlink&amp;oid=120395691&amp;loc=d3e23780-122690<br><br>Reference 4: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SAB Topic 6.I.Fact.2)<br> -URI http://asc.fasb.org/extlink&amp;oid=122134291&amp;loc=d3e330036-122817<br><br>Reference 5: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 230<br> -SubTopic 10<br> -Section 45<br> -Paragraph 28<br> -Subparagraph (b)<br> -URI http://asc.fasb.org/extlink&amp;oid=123570139&amp;loc=d3e3602-108585<br><br>Reference 6: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section 50<br> -Paragraph 9<br> -Subparagraph (b)<br> -URI http://asc.fasb.org/extlink&amp;oid=121826272&amp;loc=d3e32639-109319<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_DeferredIncomeTaxExpenseBenefit</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_DeferredIncomeTaxExpenseBenefitContinuingOperationsAbstract">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_DeferredIncomeTaxExpenseBenefitContinuingOperationsAbstract</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
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<tr>
<td><strong> Data Type:</strong></td>
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<tr>
<td><strong> Balance Type:</strong></td>
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</tr>
<tr>
<td><strong> Period Type:</strong></td>
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</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_DeferredStateAndLocalIncomeTaxExpenseBenefit">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of deferred state and local tax expense (benefit) pertaining to income (loss) from continuing operations.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2009/role/commonPracticeRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section 50<br> -Paragraph 9<br> -Subparagraph (b)<br> -URI http://asc.fasb.org/extlink&amp;oid=121826272&amp;loc=d3e32639-109319<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SAB Topic 6.I.7)<br> -URI http://asc.fasb.org/extlink&amp;oid=122134291&amp;loc=d3e330036-122817<br><br>Reference 3: http://www.xbrl.org/2009/role/commonPracticeRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 235<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.4-08(h)(1)(Note 1))<br> -URI http://asc.fasb.org/extlink&amp;oid=120395691&amp;loc=d3e23780-122690<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_DeferredStateAndLocalIncomeTaxExpenseBenefit</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_IncomeTaxExpenseBenefit">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of current income tax expense (benefit) and deferred income tax expense (benefit) pertaining to continuing operations.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SAB TOPIC 6.I.7)<br> -URI http://asc.fasb.org/extlink&amp;oid=122134291&amp;loc=d3e330036-122817<br><br>Reference 2: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section 50<br> -Paragraph 10<br> -URI http://asc.fasb.org/extlink&amp;oid=121826272&amp;loc=d3e32672-109319<br><br>Reference 3: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 280<br> -SubTopic 10<br> -Section 50<br> -Paragraph 22<br> -Subparagraph (h)<br> -URI http://asc.fasb.org/extlink&amp;oid=123359005&amp;loc=d3e8736-108599<br><br>Reference 4: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 235<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.4-08(h))<br> -URI http://asc.fasb.org/extlink&amp;oid=120395691&amp;loc=d3e23780-122690<br><br>Reference 5: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 250<br> -SubTopic 10<br> -Section 50<br> -Paragraph 9<br> -URI http://asc.fasb.org/extlink&amp;oid=124431687&amp;loc=d3e22663-107794<br><br>Reference 6: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 20<br> -Section 45<br> -Paragraph 2<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=123586238&amp;loc=d3e38679-109324<br><br>Reference 7: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 944<br> -SubTopic 220<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.7-04(9))<br> -URI http://asc.fasb.org/extlink&amp;oid=120400993&amp;loc=SL114874131-224263<br><br>Reference 8: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 250<br> -SubTopic 10<br> -Section 50<br> -Paragraph 8<br> -URI http://asc.fasb.org/extlink&amp;oid=124431687&amp;loc=d3e22658-107794<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_IncomeTaxExpenseBenefit</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
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</DOCUMENT>
<DOCUMENT>
<TYPE>XML
<SEQUENCE>97
<FILENAME>R67.htm
<DESCRIPTION>IDEA: XBRL DOCUMENT
<TEXT>
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<span style="display: none;">v3.22.0.1</span><table class="report" border="0" cellspacing="2" id="idm139691000995352">
<tr>
<th class="tl" colspan="1" rowspan="2"><div style="width: 200px;"><strong>Income Taxes, Reconciliation of Statutory to Effective Tax Rate (Details) - USD ($)<br> $ in Thousands</strong></div></th>
<th class="th" colspan="3">12 Months Ended</th>
</tr>
<tr>
<th class="th"><div>Dec. 31, 2021</div></th>
<th class="th"><div>Dec. 31, 2020</div></th>
<th class="th"><div>Dec. 31, 2019</div></th>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_IncomeTaxExpenseBenefitContinuingOperationsIncomeTaxReconciliationAbstract', window );"><strong>Reconciliation Between Effective and Statutory Tax Rate [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_IncomeLossFromContinuingOperationsBeforeIncomeTaxesExtraordinaryItemsNoncontrollingInterest', window );">Pre-tax income (loss)</a></td>
<td class="num">$ (29,148)<span></span>
</td>
<td class="num">$ (134,552)<span></span>
</td>
<td class="nump">$ 338,766<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_IncomeTaxReconciliationIncomeTaxExpenseBenefitAtFederalStatutoryIncomeTaxRate', window );">Statutory rate</a></td>
<td class="num">(6,121)<span></span>
</td>
<td class="num">(28,256)<span></span>
</td>
<td class="nump">71,141<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_IncomeTaxReconciliationStateAndLocalIncomeTaxes', window );">State income tax net of federal benefit</a></td>
<td class="nump">4,278<span></span>
</td>
<td class="num">(37,705)<span></span>
</td>
<td class="nump">49,000<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_IncomeTaxReconciliationForeignIncomeTaxRateDifferential', window );">Foreign</a></td>
<td class="nump">143<span></span>
</td>
<td class="nump">49<span></span>
</td>
<td class="nump">340<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_IncomeTaxReconciliationChangeInDeferredTaxAssetsValuationAllowance', window );">Net change in valuation allowance</a></td>
<td class="nump">2,885<span></span>
</td>
<td class="nump">460,898<span></span>
</td>
<td class="num">(37,314)<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_EffectiveIncomeTaxRateReconciliationNondeductibleExpenseLossOnDebtTransactionsAmount', window );">Loss on debt transactions</a></td>
<td class="nump">262<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="nump">9,911<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_EffectiveIncomeTaxRateReconciliationImpactFromOutsideBasisDifferencesAmount', window );">Impact from outside basis differences</a></td>
<td class="nump">0<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="num">(16,344)<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_IncomeTaxReconciliationTaxCredits', window );">Tax credits</a></td>
<td class="num">(23,198)<span></span>
</td>
<td class="num">(18,774)<span></span>
</td>
<td class="num">(22,296)<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_IncomeTaxReconciliationPriorYearIncomeTaxes', window );">Deferred tax true-up</a></td>
<td class="num">(24)<span></span>
</td>
<td class="num">(206)<span></span>
</td>
<td class="nump">646<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_IncomeTaxReconciliationChangeInEnactedTaxRate', window );">Tax rate change</a></td>
<td class="nump">12,838<span></span>
</td>
<td class="num">(32,951)<span></span>
</td>
<td class="nump">1,248<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_EffectiveIncomeTaxRateReconciliationNondeductibleExpenseExcessCompensationAmount', window );">Non-deductible compensation</a></td>
<td class="nump">5,085<span></span>
</td>
<td class="nump">7,931<span></span>
</td>
<td class="nump">3,361<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_IncomeTaxReconciliationNondeductibleExpenseOther', window );">Other non-deductible items</a></td>
<td class="nump">84<span></span>
</td>
<td class="nump">193<span></span>
</td>
<td class="nump">329<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_IncomeTaxReconciliationNondeductibleExpenseShareBasedCompensationCost', window );">Stock-based compensation</a></td>
<td class="nump">4,720<span></span>
</td>
<td class="nump">17,435<span></span>
</td>
<td class="num">(4,837)<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_EffectiveIncomeTaxRateReconciliationForeignDerivedIntangibleIncomeBenefitAmount', window );">Foreign-derived intangible income benefit</a></td>
<td class="nump">0<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="num">(2,071)<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_EffectiveIncomeTaxRateReconciliationAcquisitionOfNoncontrollingInterestAmount', window );">Impacts from Akcea Merger</a></td>
<td class="nump">0<span></span>
</td>
<td class="num">(22,032)<span></span>
</td>
<td class="nump">0<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_IncomeTaxReconciliationOtherAdjustments', window );">Other</a></td>
<td class="num">(1,503)<span></span>
</td>
<td class="num">(1,391)<span></span>
</td>
<td class="num">(1,607)<span></span>
</td>
</tr>
<tr class="rou">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_IncomeTaxExpenseBenefit', window );">Total income tax expense (benefit)</a></td>
<td class="num">$ (551)<span></span>
</td>
<td class="nump">$ 345,191<span></span>
</td>
<td class="nump">$ 51,507<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_EffectiveIncomeTaxRateContinuingOperationsTaxRateReconciliationAbstract', window );"><strong>Reconciliation Between Effective and Statutory Tax Rate Percentage [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_EffectiveIncomeTaxRateReconciliationAtFederalStatutoryIncomeTaxRate', window );">Statutory rate</a></td>
<td class="nump">21.00%<span></span>
</td>
<td class="nump">21.00%<span></span>
</td>
<td class="nump">21.00%<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_EffectiveIncomeTaxRateReconciliationStateAndLocalIncomeTaxes', window );">State income tax net of federal benefit</a></td>
<td class="num">(14.70%)<span></span>
</td>
<td class="nump">28.00%<span></span>
</td>
<td class="nump">14.50%<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_EffectiveIncomeTaxRateReconciliationForeignIncomeTaxRateDifferential', window );">Foreign</a></td>
<td class="num">(0.50%)<span></span>
</td>
<td class="nump">0.00%<span></span>
</td>
<td class="nump">0.10%<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_EffectiveIncomeTaxRateReconciliationChangeInDeferredTaxAssetsValuationAllowance', window );">Net change in valuation allowance</a></td>
<td class="num">(9.90%)<span></span>
</td>
<td class="num">(342.50%)<span></span>
</td>
<td class="num">(11.00%)<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_EffectiveIncomeTaxRateReconciliationNondeductibleExpenseLossOnDebtTransactionsPercent', window );">Loss on debt transactions</a></td>
<td class="num">(0.90%)<span></span>
</td>
<td class="nump">0.00%<span></span>
</td>
<td class="nump">2.90%<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_EffectiveIncomeTaxRateReconciliationImpactFromOutsideBasisDifferencesPercent', window );">Impact from outside basis differences</a></td>
<td class="nump">0.00%<span></span>
</td>
<td class="nump">0.00%<span></span>
</td>
<td class="num">(4.80%)<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_EffectiveIncomeTaxRateReconciliationTaxCredits', window );">Tax credits</a></td>
<td class="nump">79.60%<span></span>
</td>
<td class="nump">14.00%<span></span>
</td>
<td class="num">(6.60%)<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_EffectiveIncomeTaxRateReconciliationPriorYearIncomeTaxes', window );">Deferred tax true-up</a></td>
<td class="nump">0.10%<span></span>
</td>
<td class="nump">0.20%<span></span>
</td>
<td class="nump">0.20%<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_EffectiveIncomeTaxRateReconciliationChangeInEnactedTaxRate', window );">Tax rate change</a></td>
<td class="num">(44.00%)<span></span>
</td>
<td class="nump">24.50%<span></span>
</td>
<td class="nump">0.40%<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_EffectiveIncomeTaxRateReconciliationNondeductibleExpenseExcessCompensationPercent', window );">Non-deductible compensation</a></td>
<td class="num">(17.40%)<span></span>
</td>
<td class="num">(5.90%)<span></span>
</td>
<td class="nump">1.00%<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_EffectiveIncomeTaxRateReconciliationNondeductibleExpenseOther', window );">Other nondeductible items</a></td>
<td class="num">(0.30%)<span></span>
</td>
<td class="num">(0.10%)<span></span>
</td>
<td class="nump">0.10%<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_EffectiveIncomeTaxRateReconciliationNondeductibleExpenseShareBasedCompensationCost', window );">Stock-based compensation</a></td>
<td class="num">(16.20%)<span></span>
</td>
<td class="num">(13.00%)<span></span>
</td>
<td class="num">(1.40%)<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_EffectiveIncomeTaxRateReconciliationForeignDerivedIntangibleIncomeBenefitPercent', window );">Foreign-derived intangible income benefit</a></td>
<td class="nump">0.00%<span></span>
</td>
<td class="nump">0.00%<span></span>
</td>
<td class="num">(0.60%)<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_EffectiveIncomeTaxRateReconciliationAcquisitionOfNoncontrollingInterestPercent', window );">Impacts from Akcea Merger</a></td>
<td class="nump">0.00%<span></span>
</td>
<td class="nump">16.40%<span></span>
</td>
<td class="nump">0.00%<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_EffectiveIncomeTaxRateReconciliationOtherAdjustments', window );">Other</a></td>
<td class="nump">5.10%<span></span>
</td>
<td class="nump">0.90%<span></span>
</td>
<td class="num">(0.60%)<span></span>
</td>
</tr>
<tr class="reu">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_EffectiveIncomeTaxRateContinuingOperations', window );">Effective rate</a></td>
<td class="nump">1.90%<span></span>
</td>
<td class="num">(256.50%)<span></span>
</td>
<td class="nump">15.20%<span></span>
</td>
</tr>
</table>
<div style="display: none;">
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_EffectiveIncomeTaxRateReconciliationAcquisitionOfNoncontrollingInterestAmount">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of the difference between reported income tax expense (benefit) and expected income tax expense (benefit) computed by applying the domestic federal statutory income tax rates to pretax income (loss) from continuing operations attributable to acquisition of noncontrolling interest.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_EffectiveIncomeTaxRateReconciliationAcquisitionOfNoncontrollingInterestAmount</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_EffectiveIncomeTaxRateReconciliationAcquisitionOfNoncontrollingInterestPercent">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Percentage of the difference between reported income tax expense (benefit) and expected income tax expense (benefit) computed by applying the domestic federal statutory income tax rates to pretax income (loss) from continuing operations attributable to acquisition of noncontrolling interest.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_EffectiveIncomeTaxRateReconciliationAcquisitionOfNoncontrollingInterestPercent</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>dtr-types:percentItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_EffectiveIncomeTaxRateReconciliationForeignDerivedIntangibleIncomeBenefitAmount">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of the difference between reported income tax expense (benefit) and expected income tax expense (benefit) computed by applying the domestic federal statutory income tax rates to pretax income (loss) from continuing operations attributable to foreign-derived intangible income benefit.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_EffectiveIncomeTaxRateReconciliationForeignDerivedIntangibleIncomeBenefitAmount</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_EffectiveIncomeTaxRateReconciliationForeignDerivedIntangibleIncomeBenefitPercent">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Percentage of the difference between reported income tax expense (benefit) and expected income tax expense (benefit) computed by applying the domestic federal statutory income tax rates to pretax income (loss) from continuing operations attributable to foreign-derived intangible income benefit.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_EffectiveIncomeTaxRateReconciliationForeignDerivedIntangibleIncomeBenefitPercent</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>dtr-types:percentItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
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<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_EffectiveIncomeTaxRateReconciliationImpactFromOutsideBasisDifferencesAmount">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of the difference between reported income tax expense (benefit) and expected income tax expense (benefit) computed by applying the domestic federal statutory income tax rates to pretax income (loss) from continuing operations attributable to the impact from outside basis differences.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_EffectiveIncomeTaxRateReconciliationImpactFromOutsideBasisDifferencesAmount</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_EffectiveIncomeTaxRateReconciliationImpactFromOutsideBasisDifferencesPercent">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Percentage of the difference between reported income tax expense (benefit) and expected income tax expense (benefit) computed by applying the domestic federal statutory income tax rates to pretax income (loss) from continuing operations attributable to the impact from outside basis differences.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_EffectiveIncomeTaxRateReconciliationImpactFromOutsideBasisDifferencesPercent</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>dtr-types:percentItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_EffectiveIncomeTaxRateReconciliationNondeductibleExpenseExcessCompensationAmount">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of the difference between reported income tax expense (benefit) and expected income tax expense (benefit) computed by applying the domestic federal statutory income tax rates to pretax income (loss) from continuing operations attributable to compensation in excess of $1 million paid to any "covered employee" of the corporation under Section 162(m) of the Tax Act.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_EffectiveIncomeTaxRateReconciliationNondeductibleExpenseExcessCompensationAmount</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_EffectiveIncomeTaxRateReconciliationNondeductibleExpenseExcessCompensationPercent">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Percentage of the difference between reported income tax expense (benefit) and expected income tax expense (benefit) computed by applying the domestic federal statutory income tax rates to pretax income (loss) from continuing operations attributable to compensation in excess of $1 million paid to any "covered employee" of the corporation under Section 162(m) of the Tax Act.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_EffectiveIncomeTaxRateReconciliationNondeductibleExpenseExcessCompensationPercent</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>dtr-types:percentItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_EffectiveIncomeTaxRateReconciliationNondeductibleExpenseLossOnDebtTransactionsAmount">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of the difference between reported income tax expense (benefit) and expected income tax expense (benefit) computed by applying the domestic federal statutory income tax rates to pretax income (loss) from continuing operations attributable to loss on debt transactions.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_EffectiveIncomeTaxRateReconciliationNondeductibleExpenseLossOnDebtTransactionsAmount</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_EffectiveIncomeTaxRateReconciliationNondeductibleExpenseLossOnDebtTransactionsPercent">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Percentage of the difference between reported income tax expense (benefit) and expected income tax expense (benefit) computed by applying the domestic federal statutory income tax rates to pretax income (loss) from continuing operations attributable to loss on debt transactions.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_EffectiveIncomeTaxRateReconciliationNondeductibleExpenseLossOnDebtTransactionsPercent</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>dtr-types:percentItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_EffectiveIncomeTaxRateContinuingOperations">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Percentage of current income tax expense (benefit) and deferred income tax expense (benefit) pertaining to continuing operations.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section 50<br> -Paragraph 12<br> -URI http://asc.fasb.org/extlink&amp;oid=121826272&amp;loc=d3e32687-109319<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_EffectiveIncomeTaxRateContinuingOperations</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>dtr-types:percentItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_EffectiveIncomeTaxRateContinuingOperationsTaxRateReconciliationAbstract">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_EffectiveIncomeTaxRateContinuingOperationsTaxRateReconciliationAbstract</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:stringItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_EffectiveIncomeTaxRateReconciliationAtFederalStatutoryIncomeTaxRate">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Percentage of domestic federal statutory tax rate applicable to pretax income (loss).</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SAB Topic 6.I.Fact.4)<br> -URI http://asc.fasb.org/extlink&amp;oid=122134291&amp;loc=d3e330036-122817<br><br>Reference 2: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 235<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.4-08(h)(2))<br> -URI http://asc.fasb.org/extlink&amp;oid=120395691&amp;loc=d3e23780-122690<br><br>Reference 3: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section 50<br> -Paragraph 12<br> -URI http://asc.fasb.org/extlink&amp;oid=121826272&amp;loc=d3e32687-109319<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_EffectiveIncomeTaxRateReconciliationAtFederalStatutoryIncomeTaxRate</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>dtr-types:percentItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_EffectiveIncomeTaxRateReconciliationChangeInDeferredTaxAssetsValuationAllowance">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Percentage of the difference between reported income tax expense (benefit) and expected income tax expense (benefit) computed by applying the domestic federal statutory income tax rates to pretax income (loss) from continuing operations attributable to changes in the valuation allowance for deferred tax assets.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2009/role/commonPracticeRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SAB Topic 6.I.Fact.4)<br> -URI http://asc.fasb.org/extlink&amp;oid=122134291&amp;loc=d3e330036-122817<br><br>Reference 2: http://www.xbrl.org/2009/role/commonPracticeRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section 50<br> -Paragraph 12<br> -URI http://asc.fasb.org/extlink&amp;oid=121826272&amp;loc=d3e32687-109319<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_EffectiveIncomeTaxRateReconciliationChangeInDeferredTaxAssetsValuationAllowance</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>dtr-types:percentItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_EffectiveIncomeTaxRateReconciliationChangeInEnactedTaxRate">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Percentage of the difference between reported income tax expense (benefit) and expected income tax expense (benefit) computed by applying the domestic federal statutory income tax rates to pretax income (loss) from continuing operations attributable to changes in the income tax rates.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SAB Topic 6.I.Fact.4)<br> -URI http://asc.fasb.org/extlink&amp;oid=122134291&amp;loc=d3e330036-122817<br><br>Reference 2: http://www.xbrl.org/2009/role/commonPracticeRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section 50<br> -Paragraph 12<br> -URI http://asc.fasb.org/extlink&amp;oid=121826272&amp;loc=d3e32687-109319<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_EffectiveIncomeTaxRateReconciliationChangeInEnactedTaxRate</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>dtr-types:percentItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_EffectiveIncomeTaxRateReconciliationForeignIncomeTaxRateDifferential">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Percentage of the difference between reported income tax expense (benefit) and expected income tax expense (benefit) computed by applying the domestic federal statutory income tax rates to pretax income (loss) from continuing operations applicable to statutory income tax expense (benefit) outside of the country of domicile.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2009/role/commonPracticeRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section 50<br> -Paragraph 12<br> -URI http://asc.fasb.org/extlink&amp;oid=121826272&amp;loc=d3e32687-109319<br><br>Reference 2: http://www.xbrl.org/2009/role/commonPracticeRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SAB Topic 6.I.Fact.4)<br> -URI http://asc.fasb.org/extlink&amp;oid=122134291&amp;loc=d3e330036-122817<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_EffectiveIncomeTaxRateReconciliationForeignIncomeTaxRateDifferential</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>dtr-types:percentItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_EffectiveIncomeTaxRateReconciliationNondeductibleExpenseOther">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Percentage of the difference between reported income tax expense (benefit) and expected income tax expense (benefit) computed by applying the domestic federal statutory income tax rates to pretax income (loss) from continuing operations attributable to other nondeductible expenses.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2009/role/commonPracticeRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section 50<br> -Paragraph 12<br> -URI http://asc.fasb.org/extlink&amp;oid=121826272&amp;loc=d3e32687-109319<br><br>Reference 2: http://www.xbrl.org/2009/role/commonPracticeRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SAB Topic 6.I.Fact.4)<br> -URI http://asc.fasb.org/extlink&amp;oid=122134291&amp;loc=d3e330036-122817<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_EffectiveIncomeTaxRateReconciliationNondeductibleExpenseOther</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>dtr-types:percentItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_EffectiveIncomeTaxRateReconciliationNondeductibleExpenseShareBasedCompensationCost">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Percentage of difference between reported income tax expense (benefit) and expected income tax expense (benefit) computed by applying domestic federal statutory income tax rate to pretax income (loss) from continuing operation, attributable to nondeductible expense for share-based payment arrangement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2009/role/commonPracticeRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section 50<br> -Paragraph 12<br> -URI http://asc.fasb.org/extlink&amp;oid=121826272&amp;loc=d3e32687-109319<br><br>Reference 2: http://www.xbrl.org/2009/role/commonPracticeRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SAB Topic 6.I.Fact.4)<br> -URI http://asc.fasb.org/extlink&amp;oid=122134291&amp;loc=d3e330036-122817<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_EffectiveIncomeTaxRateReconciliationNondeductibleExpenseShareBasedCompensationCost</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>dtr-types:percentItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_EffectiveIncomeTaxRateReconciliationOtherAdjustments">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Percentage of the difference between reported income tax expense (benefit) and expected income tax expense (benefit) computed by applying the domestic federal statutory income tax rates to pretax income (loss) from continuing operations attributable to other adjustments.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2009/role/commonPracticeRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section 50<br> -Paragraph 12<br> -URI http://asc.fasb.org/extlink&amp;oid=121826272&amp;loc=d3e32687-109319<br><br>Reference 2: http://www.xbrl.org/2009/role/commonPracticeRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SAB Topic 6.I.Fact.4)<br> -URI http://asc.fasb.org/extlink&amp;oid=122134291&amp;loc=d3e330036-122817<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_EffectiveIncomeTaxRateReconciliationOtherAdjustments</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>dtr-types:percentItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_EffectiveIncomeTaxRateReconciliationPriorYearIncomeTaxes">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Percentage of the difference between reported income tax expense (benefit) and expected income tax expense (benefit) computed by applying the domestic federal statutory income tax rates to pretax income (loss) from continuing operations attributable to revisions of previously reported income tax expense.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2009/role/commonPracticeRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section 50<br> -Paragraph 12<br> -URI http://asc.fasb.org/extlink&amp;oid=121826272&amp;loc=d3e32687-109319<br><br>Reference 2: http://www.xbrl.org/2009/role/commonPracticeRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SAB Topic 6.I.Fact.4)<br> -URI http://asc.fasb.org/extlink&amp;oid=122134291&amp;loc=d3e330036-122817<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_EffectiveIncomeTaxRateReconciliationPriorYearIncomeTaxes</td>
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<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>dtr-types:percentItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_EffectiveIncomeTaxRateReconciliationStateAndLocalIncomeTaxes">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Percentage of the difference between reported income tax expense (benefit) and expected income tax expense (benefit) computed by applying the domestic federal statutory income tax rates to pretax income (loss) from continuing operations applicable to state and local income tax expense (benefit), net of federal tax expense (benefit).</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2009/role/commonPracticeRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SAB Topic 6.I.Fact.4)<br> -URI http://asc.fasb.org/extlink&amp;oid=122134291&amp;loc=d3e330036-122817<br><br>Reference 2: http://www.xbrl.org/2009/role/commonPracticeRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section 50<br> -Paragraph 12<br> -URI http://asc.fasb.org/extlink&amp;oid=121826272&amp;loc=d3e32687-109319<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_EffectiveIncomeTaxRateReconciliationStateAndLocalIncomeTaxes</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>dtr-types:percentItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_EffectiveIncomeTaxRateReconciliationTaxCredits">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Percentage of the difference between reported income tax expense (benefit) and expected income tax expense (benefit) computed by applying the domestic federal statutory income tax rates to pretax income (loss) from continuing operations attributable to tax credits. Including, but not limited to, research credit, foreign tax credit, investment tax credit, and other tax credits.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2009/role/commonPracticeRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section 50<br> -Paragraph 12<br> -URI http://asc.fasb.org/extlink&amp;oid=121826272&amp;loc=d3e32687-109319<br><br>Reference 2: http://www.xbrl.org/2009/role/commonPracticeRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SAB Topic 6.I.Fact.4)<br> -URI http://asc.fasb.org/extlink&amp;oid=122134291&amp;loc=d3e330036-122817<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_EffectiveIncomeTaxRateReconciliationTaxCredits</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>dtr-types:percentItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_IncomeLossFromContinuingOperationsBeforeIncomeTaxesExtraordinaryItemsNoncontrollingInterest">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of income (loss) from continuing operations, including income (loss) from equity method investments, before deduction of income tax expense (benefit), and income (loss) attributable to noncontrolling interest.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 280<br> -SubTopic 10<br> -Section 50<br> -Paragraph 32<br> -Subparagraph (c)<br> -URI http://asc.fasb.org/extlink&amp;oid=123359005&amp;loc=d3e8933-108599<br><br>Reference 2: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 280<br> -SubTopic 10<br> -Section 50<br> -Paragraph 30<br> -Subparagraph (b)<br> -URI http://asc.fasb.org/extlink&amp;oid=123359005&amp;loc=d3e8906-108599<br><br>Reference 3: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 280<br> -SubTopic 10<br> -Section 50<br> -Paragraph 32<br> -Subparagraph (f)<br> -URI http://asc.fasb.org/extlink&amp;oid=123359005&amp;loc=d3e8933-108599<br><br>Reference 4: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 940<br> -SubTopic 20<br> -Section 25<br> -Paragraph 1<br> -URI http://asc.fasb.org/extlink&amp;oid=123384075&amp;loc=d3e41242-110953<br><br>Reference 5: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 280<br> -SubTopic 10<br> -Section 50<br> -Paragraph 22<br> -URI http://asc.fasb.org/extlink&amp;oid=123359005&amp;loc=d3e8736-108599<br><br>Reference 6: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 220<br> -SubTopic 10<br> -Section S99<br> -Paragraph 2<br> -Subparagraph (SX 210.5-03(10))<br> -URI http://asc.fasb.org/extlink&amp;oid=123367319&amp;loc=SL114868664-224227<br><br>Reference 7: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 944<br> -SubTopic 220<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.7-04(8))<br> -URI http://asc.fasb.org/extlink&amp;oid=120400993&amp;loc=SL114874131-224263<br><br>Reference 8: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 942<br> -SubTopic 235<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.9-05(b)(2))<br> -URI http://asc.fasb.org/extlink&amp;oid=120399901&amp;loc=d3e537907-122884<br><br>Reference 9: http://www.xbrl.org/2003/role/exampleRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 280<br> -SubTopic 10<br> -Section 50<br> -Paragraph 31<br> -URI http://asc.fasb.org/extlink&amp;oid=123359005&amp;loc=d3e8924-108599<br><br>Reference 10: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 942<br> -SubTopic 220<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.9-04(15))<br> -URI http://asc.fasb.org/extlink&amp;oid=120399700&amp;loc=SL114874048-224260<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_IncomeLossFromContinuingOperationsBeforeIncomeTaxesExtraordinaryItemsNoncontrollingInterest</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_IncomeTaxExpenseBenefit">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of current income tax expense (benefit) and deferred income tax expense (benefit) pertaining to continuing operations.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SAB TOPIC 6.I.7)<br> -URI http://asc.fasb.org/extlink&amp;oid=122134291&amp;loc=d3e330036-122817<br><br>Reference 2: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section 50<br> -Paragraph 10<br> -URI http://asc.fasb.org/extlink&amp;oid=121826272&amp;loc=d3e32672-109319<br><br>Reference 3: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 280<br> -SubTopic 10<br> -Section 50<br> -Paragraph 22<br> -Subparagraph (h)<br> -URI http://asc.fasb.org/extlink&amp;oid=123359005&amp;loc=d3e8736-108599<br><br>Reference 4: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 235<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.4-08(h))<br> -URI http://asc.fasb.org/extlink&amp;oid=120395691&amp;loc=d3e23780-122690<br><br>Reference 5: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 250<br> -SubTopic 10<br> -Section 50<br> -Paragraph 9<br> -URI http://asc.fasb.org/extlink&amp;oid=124431687&amp;loc=d3e22663-107794<br><br>Reference 6: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 20<br> -Section 45<br> -Paragraph 2<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=123586238&amp;loc=d3e38679-109324<br><br>Reference 7: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 944<br> -SubTopic 220<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.7-04(9))<br> -URI http://asc.fasb.org/extlink&amp;oid=120400993&amp;loc=SL114874131-224263<br><br>Reference 8: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 250<br> -SubTopic 10<br> -Section 50<br> -Paragraph 8<br> -URI http://asc.fasb.org/extlink&amp;oid=124431687&amp;loc=d3e22658-107794<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_IncomeTaxExpenseBenefit</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_IncomeTaxExpenseBenefitContinuingOperationsIncomeTaxReconciliationAbstract">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_IncomeTaxExpenseBenefitContinuingOperationsIncomeTaxReconciliationAbstract</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
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<td><strong> Period Type:</strong></td>
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<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_IncomeTaxReconciliationChangeInDeferredTaxAssetsValuationAllowance">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of the difference between reported income tax expense (benefit) and expected income tax expense (benefit) computed by applying the domestic federal statutory income tax rates to pretax income (loss) from continuing operations attributable to increase (decrease) in the valuation allowance for deferred tax assets.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2009/role/commonPracticeRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section 50<br> -Paragraph 12<br> -URI http://asc.fasb.org/extlink&amp;oid=121826272&amp;loc=d3e32687-109319<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_IncomeTaxReconciliationChangeInDeferredTaxAssetsValuationAllowance</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
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<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
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<td><strong> Balance Type:</strong></td>
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<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_IncomeTaxReconciliationChangeInEnactedTaxRate">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of the difference between reported income tax expense (benefit) and expected income tax expense (benefit) computed by applying the domestic federal statutory income tax rates to pretax income (loss) from continuing operations, attributable to increase (decrease) in the income tax rates.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section 45<br> -Paragraph 15<br> -URI http://asc.fasb.org/extlink&amp;oid=123427490&amp;loc=d3e32059-109318<br><br>Reference 2: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section 50<br> -Paragraph 12<br> -URI http://asc.fasb.org/extlink&amp;oid=121826272&amp;loc=d3e32687-109319<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_IncomeTaxReconciliationChangeInEnactedTaxRate</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
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<td><strong> Period Type:</strong></td>
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</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_IncomeTaxReconciliationForeignIncomeTaxRateDifferential">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of the difference between reported income tax expense (benefit) and expected income tax expense (benefit) computed by applying the domestic federal statutory income tax rates to pretax income (loss) from continuing operations attributable to foreign income tax expense (benefit).</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2009/role/commonPracticeRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section 50<br> -Paragraph 12<br> -URI http://asc.fasb.org/extlink&amp;oid=121826272&amp;loc=d3e32687-109319<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_IncomeTaxReconciliationForeignIncomeTaxRateDifferential</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
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<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_IncomeTaxReconciliationIncomeTaxExpenseBenefitAtFederalStatutoryIncomeTaxRate">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The amount of income tax expense or benefit for the period computed by applying the domestic federal statutory tax rates to pretax income from continuing operations.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section 50<br> -Paragraph 12<br> -URI http://asc.fasb.org/extlink&amp;oid=121826272&amp;loc=d3e32687-109319<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_IncomeTaxReconciliationIncomeTaxExpenseBenefitAtFederalStatutoryIncomeTaxRate</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
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<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_IncomeTaxReconciliationNondeductibleExpenseOther">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of the difference between reported income tax expense (benefit) and expected income tax expense (benefit) computed by applying the domestic federal statutory income tax rates to pretax income (loss) from continuing operations attributable to other nondeductible expenses.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2009/role/commonPracticeRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section 50<br> -Paragraph 12<br> -URI http://asc.fasb.org/extlink&amp;oid=121826272&amp;loc=d3e32687-109319<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_IncomeTaxReconciliationNondeductibleExpenseOther</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_IncomeTaxReconciliationNondeductibleExpenseShareBasedCompensationCost">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of reported income tax expense (benefit) in excess of (less than) expected income tax expense (benefit) computed by applying domestic federal statutory income tax rate to pretax income (loss) from continuing operation, attributable to nondeductible expense for award under share-based payment arrangement. Includes, but is not limited to, expense determined to be nondeductible upon grant or after for award under share-based payment arrangement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2009/role/commonPracticeRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section 50<br> -Paragraph 12<br> -URI http://asc.fasb.org/extlink&amp;oid=121826272&amp;loc=d3e32687-109319<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_IncomeTaxReconciliationNondeductibleExpenseShareBasedCompensationCost</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
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<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
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</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_IncomeTaxReconciliationOtherAdjustments">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of the difference between reported income tax expense (benefit) and expected income tax expense (benefit) computed by applying the domestic federal statutory income tax rates to pretax income (loss) from continuing operations attributable to other adjustments.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2009/role/commonPracticeRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section 50<br> -Paragraph 12<br> -URI http://asc.fasb.org/extlink&amp;oid=121826272&amp;loc=d3e32687-109319<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_IncomeTaxReconciliationOtherAdjustments</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
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<td><strong> Balance Type:</strong></td>
<td>debit</td>
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<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
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<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_IncomeTaxReconciliationPriorYearIncomeTaxes">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of the difference between reported income tax expense (benefit) and expected income tax expense (benefit) computed by applying the domestic federal statutory income tax rates to pretax income (loss) from continuing operations attributable to revisions of previously reported income tax expense (benefit).</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2009/role/commonPracticeRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section 50<br> -Paragraph 12<br> -URI http://asc.fasb.org/extlink&amp;oid=121826272&amp;loc=d3e32687-109319<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_IncomeTaxReconciliationPriorYearIncomeTaxes</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_IncomeTaxReconciliationStateAndLocalIncomeTaxes">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of the difference between reported income tax expense (benefit) and expected income tax expense (benefit) computed by applying the domestic federal statutory income tax rates to pretax income (loss) from continuing operations attributable to state and local income tax expense (benefit).</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2009/role/commonPracticeRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section 50<br> -Paragraph 12<br> -URI http://asc.fasb.org/extlink&amp;oid=121826272&amp;loc=d3e32687-109319<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_IncomeTaxReconciliationStateAndLocalIncomeTaxes</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
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<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_IncomeTaxReconciliationTaxCredits">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of the difference between reported income tax expense (benefit) and expected income tax expense (benefit) computed by applying the domestic federal statutory income tax rates to pretax income (loss) from continuing operations attributable to tax credits. Including, but not limited to, research credit, foreign tax credit, investment tax credit, and other tax credits.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2009/role/commonPracticeRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section 50<br> -Paragraph 12<br> -URI http://asc.fasb.org/extlink&amp;oid=121826272&amp;loc=d3e32687-109319<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_IncomeTaxReconciliationTaxCredits</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
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<span style="display: none;">v3.22.0.1</span><table class="report" border="0" cellspacing="2" id="idm139691000845416">
<tr>
<th class="tl" colspan="1" rowspan="2"><div style="width: 200px;"><strong>Income Taxes, Deferred Tax Assets and Liabilities (Details) - USD ($)<br> $ in Thousands</strong></div></th>
<th class="th" colspan="1">3 Months Ended</th>
<th class="th" colspan="1">12 Months Ended</th>
</tr>
<tr>
<th class="th"><div>Dec. 31, 2020</div></th>
<th class="th"><div>Dec. 31, 2021</div></th>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DeferredTaxAssetsGrossAbstract', window );"><strong>Deferred Tax Assets [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DeferredTaxAssetsOperatingLossCarryforwards', window );">Net operating loss carryovers</a></td>
<td class="nump">$ 83,681<span></span>
</td>
<td class="nump">$ 85,600<span></span>
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<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DeferredTaxAssetsTaxCreditCarryforwards', window );">Tax credits</a></td>
<td class="nump">245,746<span></span>
</td>
<td class="nump">269,538<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DeferredTaxAssetsDeferredIncome', window );">Deferred revenue</a></td>
<td class="nump">124,452<span></span>
</td>
<td class="nump">104,330<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DeferredTaxAssetsTaxDeferredExpenseCompensationAndBenefitsShareBasedCompensationCost', window );">Stock-based compensation</a></td>
<td class="nump">80,055<span></span>
</td>
<td class="nump">86,611<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DeferredTaxAssetsGoodwillAndIntangibleAssets', window );">Intangible and capital assets</a></td>
<td class="nump">98,443<span></span>
</td>
<td class="nump">92,542<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_DeferredTaxAssetsFinancingArrangements', window );">Convertible debt</a></td>
<td class="nump">22,395<span></span>
</td>
<td class="nump">45,681<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_DeferredTaxAssetsInterestExpenseLimitation', window );">Interest expense limitation</a></td>
<td class="nump">0<span></span>
</td>
<td class="nump">6,996<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DeferredTaxAssetsOther', window );">Other</a></td>
<td class="nump">13,402<span></span>
</td>
<td class="nump">15,048<span></span>
</td>
</tr>
<tr class="rou">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DeferredTaxAssetsGross', window );">Total deferred tax assets</a></td>
<td class="nump">668,174<span></span>
</td>
<td class="nump">706,346<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DeferredTaxLiabilitiesAbstract', window );"><strong>Deferred Tax Liabilities [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DeferredTaxLiabilitiesPropertyPlantAndEquipment', window );">Fixed assets</a></td>
<td class="num">(3,611)<span></span>
</td>
<td class="num">(3,303)<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DeferredTaxLiabilitiesOther', window );">Other</a></td>
<td class="num">(5,808)<span></span>
</td>
<td class="num">(5,270)<span></span>
</td>
</tr>
<tr class="rou">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_DeferredTaxAssetsLiabilitiesNetBeforeValuationAllowance', window );">Net deferred tax asset</a></td>
<td class="nump">658,755<span></span>
</td>
<td class="nump">697,773<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DeferredTaxAssetsValuationAllowance', window );">Valuation allowance</a></td>
<td class="num">(658,755)<span></span>
</td>
<td class="num">(697,773)<span></span>
</td>
</tr>
<tr class="rou">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DeferredTaxAssetsLiabilitiesNet', window );">Total net deferred tax assets and liabilities</a></td>
<td class="nump">0<span></span>
</td>
<td class="nump">0<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ValuationAllowancesAndReservesPeriodIncreaseDecrease', window );">Increase in valuation allowance</a></td>
<td class="nump">$ 341,000<span></span>
</td>
<td class="nump">$ 39,000<span></span>
</td>
</tr>
</table>
<div style="display: none;">
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_DeferredTaxAssetsFinancingArrangements">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount before allocation of valuation allowances of deferred tax asset attributable to deductible temporary differences from financing arrangements.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_DeferredTaxAssetsFinancingArrangements</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_DeferredTaxAssetsInterestExpenseLimitation">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount before allocation of valuation allowances of deferred tax asset attributable to deductible temporary differences from a limitation on interest expense.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_DeferredTaxAssetsInterestExpenseLimitation</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_DeferredTaxAssetsLiabilitiesNetBeforeValuationAllowance">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Represents the net amount of deferred tax assets (before reduction for valuation allowance) and liabilities as of the balance sheet date, which result from applying the applicable enacted tax rate to net temporary differences and carryforwards pertaining to assets or liabilities.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_DeferredTaxAssetsLiabilitiesNetBeforeValuationAllowance</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_DeferredTaxAssetsDeferredIncome">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount before allocation of valuation allowances of deferred tax asset attributable to deductible temporary differences from deferred income.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section 50<br> -Paragraph 8<br> -URI http://asc.fasb.org/extlink&amp;oid=121826272&amp;loc=d3e32632-109319<br><br>Reference 2: http://www.xbrl.org/2009/role/commonPracticeRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section 50<br> -Paragraph 6<br> -URI http://asc.fasb.org/extlink&amp;oid=121826272&amp;loc=d3e32621-109319<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_DeferredTaxAssetsDeferredIncome</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_DeferredTaxAssetsGoodwillAndIntangibleAssets">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount before allocation of valuation allowances of deferred tax asset attributable to deductible temporary differences from intangible assets including goodwill.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_DeferredTaxAssetsGoodwillAndIntangibleAssets</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_DeferredTaxAssetsGross">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount before allocation of valuation allowances of deferred tax asset attributable to deductible temporary differences and carryforwards.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section 50<br> -Paragraph 2<br> -Subparagraph (b)<br> -URI http://asc.fasb.org/extlink&amp;oid=121826272&amp;loc=d3e32537-109319<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_DeferredTaxAssetsGross</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_DeferredTaxAssetsGrossAbstract">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_DeferredTaxAssetsGrossAbstract</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:stringItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_DeferredTaxAssetsLiabilitiesNet">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount, after allocation of valuation allowances and deferred tax liability, of deferred tax asset attributable to deductible differences and carryforwards, without jurisdictional netting.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2009/role/commonPracticeRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section 50<br> -Paragraph 2<br> -URI http://asc.fasb.org/extlink&amp;oid=121826272&amp;loc=d3e32537-109319<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_DeferredTaxAssetsLiabilitiesNet</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_DeferredTaxAssetsOperatingLossCarryforwards">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount before allocation of valuation allowances of deferred tax asset attributable to deductible operating loss carryforwards.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section 50<br> -Paragraph 8<br> -URI http://asc.fasb.org/extlink&amp;oid=121826272&amp;loc=d3e32632-109319<br><br>Reference 2: http://www.xbrl.org/2009/role/commonPracticeRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section 50<br> -Paragraph 6<br> -URI http://asc.fasb.org/extlink&amp;oid=121826272&amp;loc=d3e32621-109319<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_DeferredTaxAssetsOperatingLossCarryforwards</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_DeferredTaxAssetsOther">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount, before allocation of valuation allowance, of deferred tax asset attributable to deductible temporary differences, classified as other.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2009/role/commonPracticeRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section 50<br> -Paragraph 6<br> -URI http://asc.fasb.org/extlink&amp;oid=121826272&amp;loc=d3e32621-109319<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section 50<br> -Paragraph 8<br> -URI http://asc.fasb.org/extlink&amp;oid=121826272&amp;loc=d3e32632-109319<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_DeferredTaxAssetsOther</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_DeferredTaxAssetsTaxCreditCarryforwards">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount, before allocation of a valuation allowances, of deferred tax assets attributable to deductible tax credit carryforwards including, but not limited to, research, foreign, general business, alternative minimum tax, and other deductible tax credit carryforwards.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section 50<br> -Paragraph 8<br> -URI http://asc.fasb.org/extlink&amp;oid=121826272&amp;loc=d3e32632-109319<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section 50<br> -Paragraph 3<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=121826272&amp;loc=d3e32559-109319<br><br>Reference 3: http://www.xbrl.org/2009/role/commonPracticeRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section 50<br> -Paragraph 6<br> -URI http://asc.fasb.org/extlink&amp;oid=121826272&amp;loc=d3e32621-109319<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_DeferredTaxAssetsTaxCreditCarryforwards</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_DeferredTaxAssetsTaxDeferredExpenseCompensationAndBenefitsShareBasedCompensationCost">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount before allocation of valuation allowances of deferred tax asset attributable to deductible temporary differences from share-based compensation.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2009/role/commonPracticeRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section 50<br> -Paragraph 6<br> -URI http://asc.fasb.org/extlink&amp;oid=121826272&amp;loc=d3e32621-109319<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section 50<br> -Paragraph 8<br> -URI http://asc.fasb.org/extlink&amp;oid=121826272&amp;loc=d3e32632-109319<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_DeferredTaxAssetsTaxDeferredExpenseCompensationAndBenefitsShareBasedCompensationCost</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_DeferredTaxAssetsValuationAllowance">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of deferred tax assets for which it is more likely than not that a tax benefit will not be realized.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section 50<br> -Paragraph 2<br> -Subparagraph (c)<br> -URI http://asc.fasb.org/extlink&amp;oid=121826272&amp;loc=d3e32537-109319<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_DeferredTaxAssetsValuationAllowance</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_DeferredTaxLiabilitiesAbstract">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_DeferredTaxLiabilitiesAbstract</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:stringItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_DeferredTaxLiabilitiesOther">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of deferred tax liability attributable to taxable temporary differences classified as other.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section 50<br> -Paragraph 8<br> -URI http://asc.fasb.org/extlink&amp;oid=121826272&amp;loc=d3e32632-109319<br><br>Reference 2: http://www.xbrl.org/2009/role/commonPracticeRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section 50<br> -Paragraph 6<br> -URI http://asc.fasb.org/extlink&amp;oid=121826272&amp;loc=d3e32621-109319<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_DeferredTaxLiabilitiesOther</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_DeferredTaxLiabilitiesPropertyPlantAndEquipment">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of deferred tax liability attributable to taxable temporary differences from property, plant, and equipment.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2009/role/commonPracticeRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section 50<br> -Paragraph 6<br> -URI http://asc.fasb.org/extlink&amp;oid=121826272&amp;loc=d3e32621-109319<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section 50<br> -Paragraph 8<br> -URI http://asc.fasb.org/extlink&amp;oid=121826272&amp;loc=d3e32632-109319<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_DeferredTaxLiabilitiesPropertyPlantAndEquipment</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_ValuationAllowancesAndReservesPeriodIncreaseDecrease">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of increase (decrease) in valuation and qualifying accounts and reserves.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2009/role/commonPracticeRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 235<br> -SubTopic 10<br> -Section S99<br> -Paragraph 4<br> -Subparagraph (SX 210.12-09)<br> -URI http://asc.fasb.org/extlink&amp;oid=120395691&amp;loc=d3e24092-122690<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ValuationAllowancesAndReservesPeriodIncreaseDecrease</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
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<span style="display: none;">v3.22.0.1</span><table class="report" border="0" cellspacing="2" id="idm139691013092712">
<tr>
<th class="tl" colspan="1" rowspan="1"><div style="width: 200px;"><strong>Income Taxes, Tax Credit Carryforwards (Details)<br> $ in Millions</strong></div></th>
<th class="th">
<div>Dec. 31, 2021 </div>
<div>USD ($)</div>
</th>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_IncomeTaxAuthorityNameAxis=us-gaap_InternalRevenueServiceIRSMember', window );">Federal [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_OperatingLossCarryforwardsLineItems', window );"><strong>Operating Loss Carryforwards [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_OperatingLossCarryforwards', window );">Net operating loss carryforwards</a></td>
<td class="nump">$ 271.5<span></span>
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</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_IncomeTaxAuthorityNameAxis=us-gaap_InternalRevenueServiceIRSMember', window );">Federal [Member] | Research and Development [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_TaxCreditCarryforwardLineItems', window );"><strong>Tax Credit Carryforwards [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_TaxCreditCarryforwardAmount', window );">Tax credit carryforwards</a></td>
<td class="nump">225.5<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_IncomeTaxAuthorityNameAxis=us-gaap_CaliforniaFranchiseTaxBoardMember', window );">California [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_OperatingLossCarryforwardsLineItems', window );"><strong>Operating Loss Carryforwards [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_OperatingLossCarryforwards', window );">Net operating loss carryforwards</a></td>
<td class="nump">333.8<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_IncomeTaxAuthorityNameAxis=us-gaap_CaliforniaFranchiseTaxBoardMember', window );">California [Member] | Research and Development [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_TaxCreditCarryforwardLineItems', window );"><strong>Tax Credit Carryforwards [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_TaxCreditCarryforwardAmount', window );">Tax credit carryforwards</a></td>
<td class="nump">$ 99.7<span></span>
</td>
</tr>
</table>
<div style="display: none;">
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_OperatingLossCarryforwards">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of operating loss carryforward, before tax effects, available to reduce future taxable income under enacted tax laws.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section 50<br> -Paragraph 3<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=121826272&amp;loc=d3e32559-109319<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_OperatingLossCarryforwards</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_OperatingLossCarryforwardsLineItems">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Line items represent financial concepts included in a table. These concepts are used to disclose reportable information associated with domain members defined in one or many axes to the table.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_OperatingLossCarryforwardsLineItems</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:stringItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
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<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
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</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_TaxCreditCarryforwardAmount">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The amount of the tax credit carryforward, before tax effects, available to reduce future taxable income under enacted tax laws.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section 50<br> -Paragraph 3<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=121826272&amp;loc=d3e32559-109319<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_TaxCreditCarryforwardAmount</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_TaxCreditCarryforwardLineItems">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Line items represent financial concepts included in a table. These concepts are used to disclose reportable information associated with domain members defined in one or many axes to the table.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_TaxCreditCarryforwardLineItems</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:stringItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
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<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_IncomeTaxAuthorityNameAxis=us-gaap_InternalRevenueServiceIRSMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_IncomeTaxAuthorityNameAxis=us-gaap_InternalRevenueServiceIRSMember</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td></td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_TaxCreditCarryforwardAxis=us-gaap_ResearchMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_TaxCreditCarryforwardAxis=us-gaap_ResearchMember</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td></td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_IncomeTaxAuthorityNameAxis=us-gaap_CaliforniaFranchiseTaxBoardMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_IncomeTaxAuthorityNameAxis=us-gaap_CaliforniaFranchiseTaxBoardMember</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>na</td>
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<tr>
<td><strong> Balance Type:</strong></td>
<td></td>
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<tr>
<td><strong> Period Type:</strong></td>
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</div></td></tr>
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</TEXT>
</DOCUMENT>
<DOCUMENT>
<TYPE>XML
<SEQUENCE>100
<FILENAME>R70.htm
<DESCRIPTION>IDEA: XBRL DOCUMENT
<TEXT>
<html>
<head>
<title></title>
<link rel="stylesheet" type="text/css" href="report.css">
<script type="text/javascript" src="Show.js">/* Do Not Remove This Comment */</script><script type="text/javascript">
							function toggleNextSibling (e) {
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</head>
<body>
<span style="display: none;">v3.22.0.1</span><table class="report" border="0" cellspacing="2" id="idm139691012885224">
<tr>
<th class="tl" colspan="1" rowspan="2"><div style="width: 200px;"><strong>Income Taxes, Gross Unrecognized Tax Benefits (Details) - USD ($)<br> $ in Thousands</strong></div></th>
<th class="th" colspan="3">12 Months Ended</th>
</tr>
<tr>
<th class="th"><div>Dec. 31, 2021</div></th>
<th class="th"><div>Dec. 31, 2020</div></th>
<th class="th"><div>Dec. 31, 2019</div></th>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ReconciliationOfUnrecognizedTaxBenefitsExcludingAmountsPertainingToExaminedTaxReturnsRollForward', window );"><strong>Gross Unrecognized Tax Benefits [Roll Forward]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_UnrecognizedTaxBenefits', window );">Beginning balance of unrecognized tax benefits</a></td>
<td class="nump">$ 54,163<span></span>
</td>
<td class="nump">$ 69,784<span></span>
</td>
<td class="nump">$ 68,301<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_UnrecognizedTaxBenefitsDecreasesResultingFromPriorPeriodTaxPositions', window );">Decrease for prior period tax positions</a></td>
<td class="num">(695)<span></span>
</td>
<td class="num">(24,154)<span></span>
</td>
<td class="num">(867)<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_UnrecognizedTaxBenefitsIncreasesResultingFromPriorPeriodTaxPositions', window );">Increase for prior period tax positions</a></td>
<td class="nump">263<span></span>
</td>
<td class="nump">7,023<span></span>
</td>
<td class="nump">736<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_UnrecognizedTaxBenefitsIncreasesResultingFromCurrentPeriodTaxPositions', window );">Increase for current period tax positions</a></td>
<td class="nump">1,354<span></span>
</td>
<td class="nump">1,510<span></span>
</td>
<td class="nump">1,614<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_UnrecognizedTaxBenefits', window );">Ending balance of unrecognized tax benefits</a></td>
<td class="nump">55,085<span></span>
</td>
<td class="nump">54,163<span></span>
</td>
<td class="nump">69,784<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_UnrecognizedTaxBenefitsThatWouldImpactEffectiveTaxRate', window );">Unrecognized tax benefits that could impact effective tax rate, if recognized</a></td>
<td class="nump">6,200<span></span>
</td>
<td class="nump">6,400<span></span>
</td>
<td class="nump">400<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_UnrecognizedTaxBenefitsIncomeTaxPenaltiesAndInterestExpense', window );">Interest and penalties on gross unrecognized tax benefits</a></td>
<td class="nump">$ 500<span></span>
</td>
<td class="nump">$ 300<span></span>
</td>
<td class="nump">$ 0<span></span>
</td>
</tr>
</table>
<div style="display: none;">
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_ReconciliationOfUnrecognizedTaxBenefitsExcludingAmountsPertainingToExaminedTaxReturnsRollForward">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>A roll forward is a reconciliation of a concept from the beginning of a period to the end of a period.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ReconciliationOfUnrecognizedTaxBenefitsExcludingAmountsPertainingToExaminedTaxReturnsRollForward</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:stringItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_UnrecognizedTaxBenefits">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of unrecognized tax benefits.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section 45<br> -Paragraph 10B<br> -URI http://asc.fasb.org/extlink&amp;oid=123427490&amp;loc=SL37586934-109318<br><br>Reference 2: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section 50<br> -Paragraph 15A<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=121826272&amp;loc=SL6600010-109319<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_UnrecognizedTaxBenefits</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_UnrecognizedTaxBenefitsDecreasesResultingFromPriorPeriodTaxPositions">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of decrease in unrecognized tax benefits resulting from tax positions taken in prior period tax returns.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section 50<br> -Paragraph 15A<br> -Subparagraph (a)(1)<br> -URI http://asc.fasb.org/extlink&amp;oid=121826272&amp;loc=SL6600010-109319<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_UnrecognizedTaxBenefitsDecreasesResultingFromPriorPeriodTaxPositions</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_UnrecognizedTaxBenefitsIncomeTaxPenaltiesAndInterestExpense">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of expense for interest on an underpayment of income taxes and penalties related to a tax position claimed or expected to be claimed in the tax return.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section 50<br> -Paragraph 15<br> -Subparagraph (c)<br> -URI http://asc.fasb.org/extlink&amp;oid=121826272&amp;loc=d3e32718-109319<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_UnrecognizedTaxBenefitsIncomeTaxPenaltiesAndInterestExpense</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_UnrecognizedTaxBenefitsIncreasesResultingFromCurrentPeriodTaxPositions">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of increase in unrecognized tax benefits resulting from tax positions that have been or will be taken in current period tax return.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section 50<br> -Paragraph 15A<br> -Subparagraph (a)(2)<br> -URI http://asc.fasb.org/extlink&amp;oid=121826272&amp;loc=SL6600010-109319<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_UnrecognizedTaxBenefitsIncreasesResultingFromCurrentPeriodTaxPositions</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_UnrecognizedTaxBenefitsIncreasesResultingFromPriorPeriodTaxPositions">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of increase in unrecognized tax benefits resulting from tax positions taken in prior period tax returns.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section 50<br> -Paragraph 15A<br> -Subparagraph (a)(1)<br> -URI http://asc.fasb.org/extlink&amp;oid=121826272&amp;loc=SL6600010-109319<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_UnrecognizedTaxBenefitsIncreasesResultingFromPriorPeriodTaxPositions</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_UnrecognizedTaxBenefitsThatWouldImpactEffectiveTaxRate">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The total amount of unrecognized tax benefits that, if recognized, would affect the effective tax rate.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section 50<br> -Paragraph 15A<br> -Subparagraph (b)<br> -URI http://asc.fasb.org/extlink&amp;oid=121826272&amp;loc=SL6600010-109319<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_UnrecognizedTaxBenefitsThatWouldImpactEffectiveTaxRate</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
</div>
</body>
</html>
</TEXT>
</DOCUMENT>
<DOCUMENT>
<TYPE>XML
<SEQUENCE>101
<FILENAME>R71.htm
<DESCRIPTION>IDEA: XBRL DOCUMENT
<TEXT>
<html>
<head>
<title></title>
<link rel="stylesheet" type="text/css" href="report.css">
<script type="text/javascript" src="Show.js">/* Do Not Remove This Comment */</script><script type="text/javascript">
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<span style="display: none;">v3.22.0.1</span><table class="report" border="0" cellspacing="2" id="idm139690996924808">
<tr>
<th class="tl" colspan="1" rowspan="2"><div style="width: 200px;"><strong>Collaborative Arrangements and Licensing Agreements, Biogen (Details)<br> $ in Thousands</strong></div></th>
<th class="th" colspan="3">1 Months Ended</th>
<th class="th" colspan="6">3 Months Ended</th>
<th class="th" colspan="3">12 Months Ended</th>
<th class="th" colspan="1"></th>
</tr>
<tr>
<th class="th">
<div>Dec. 31, 2021 </div>
<div>USD ($) </div>
<div>Medicine </div>
<div>Program</div>
</th>
<th class="th">
<div>Sep. 30, 2013 </div>
<div>USD ($) </div>
<div>PerformanceObligation</div>
</th>
<th class="th">
<div>Dec. 31, 2012 </div>
<div>USD ($) </div>
<div>Program</div>
</th>
<th class="th">
<div>Dec. 31, 2021 </div>
<div>USD ($) </div>
<div>Medicine </div>
<div>Program</div>
</th>
<th class="th">
<div>Jun. 30, 2021 </div>
<div>USD ($)</div>
</th>
<th class="th">
<div>Dec. 31, 2019 </div>
<div>USD ($)</div>
</th>
<th class="th">
<div>Sep. 30, 2019 </div>
<div>USD ($)</div>
</th>
<th class="th">
<div>Jun. 30, 2018 </div>
<div>USD ($)</div>
</th>
<th class="th">
<div>Dec. 31, 2017 </div>
<div>USD ($) </div>
<div>PerformanceObligation</div>
</th>
<th class="th">
<div>Dec. 31, 2021 </div>
<div>USD ($) </div>
<div>Medicine </div>
<div>Program</div>
</th>
<th class="th">
<div>Dec. 31, 2020 </div>
<div>USD ($)</div>
</th>
<th class="th">
<div>Dec. 31, 2019 </div>
<div>USD ($)</div>
</th>
<th class="th">
<div>Apr. 30, 2018 </div>
<div>USD ($) </div>
<div>PerformanceObligation</div>
</th>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CollaborativeArrangementAndLicensingAgreementAbstract', window );"><strong>Collaborative Arrangement and Licensing Agreement [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax', window );">Revenue</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 810,456<span></span>
</td>
<td class="nump">$ 729,264<span></span>
</td>
<td class="nump">$ 1,122,599<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_srt_ProductOrServiceAxis=ions_SpinrazaRoyaltiesMember', window );">SPINRAZA Royalties [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CollaborativeArrangementAndLicensingAgreementAbstract', window );"><strong>Collaborative Arrangement and Licensing Agreement [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax', window );">Revenue</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">267,776<span></span>
</td>
<td class="nump">286,583<span></span>
</td>
<td class="nump">292,992<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_srt_ProductOrServiceAxis=ions_ResearchAndDevelopmentRevenueUnderCollaborativeAgreementsMember', window );">R&amp;D Revenue [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CollaborativeArrangementAndLicensingAgreementAbstract', window );"><strong>Collaborative Arrangement and Licensing Agreement [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax', window );">Revenue</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 468,061<span></span>
</td>
<td class="nump">364,565<span></span>
</td>
<td class="nump">770,149<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_TypeOfArrangementAxis=ions_BiogenCollaborationsMember', window );">Biogen [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CollaborativeArrangementAndLicensingAgreementAbstract', window );"><strong>Collaborative Arrangement and Licensing Agreement [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_NumberOfMedicinesBeingDeveloped', window );">Number of medicines currently being developed | Medicine</a></td>
<td class="nump">9<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">9<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">9<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax', window );">Revenue</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 428,800<span></span>
</td>
<td class="nump">408,600<span></span>
</td>
<td class="nump">$ 473,600<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ContractWithCustomerLiability', window );">Deferred revenue</a></td>
<td class="nump">$ 407,500<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 407,500<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 407,500<span></span>
</td>
<td class="nump">$ 465,800<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_TypeOfArrangementAxis=ions_BiogenCollaborationsMember', window );">Biogen [Member] | Revenue [Member] | Strategic Partner [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CollaborativeArrangementAndLicensingAgreementAbstract', window );"><strong>Collaborative Arrangement and Licensing Agreement [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ConcentrationRiskPercentage1', window );">Concentration percentage</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">53.00%<span></span>
</td>
<td class="nump">56.00%<span></span>
</td>
<td class="nump">42.00%<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_TypeOfArrangementAxis=ions_BiogenCollaborationsMember', window );">Biogen [Member] | Minimum [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CollaborativeArrangementAndLicensingAgreementAbstract', window );"><strong>Collaborative Arrangement and Licensing Agreement [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CumulativePaymentsReceived', window );">Cumulative payments received</a></td>
<td class="nump">3,100,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">3,100,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 3,100,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_TypeOfArrangementAxis=ions_BiogenCollaborationsMember', window );">Biogen [Member] | SPINRAZA Royalties [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CollaborativeArrangementAndLicensingAgreementAbstract', window );"><strong>Collaborative Arrangement and Licensing Agreement [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax', window );">Revenue</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">267,800<span></span>
</td>
<td class="nump">$ 286,600<span></span>
</td>
<td class="nump">$ 293,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_TypeOfArrangementAxis=ions_BiogenCollaborationsMember', window );">Biogen [Member] | R&amp;D Revenue [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CollaborativeArrangementAndLicensingAgreementAbstract', window );"><strong>Collaborative Arrangement and Licensing Agreement [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax', window );">Revenue</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">161,000<span></span>
</td>
<td class="nump">122,000<span></span>
</td>
<td class="nump">$ 180,600<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_TypeOfArrangementAxis=ions_BiogenCollaborationSpinrazaMember', window );">SPINRAZA [Member] | Minimum [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CollaborativeArrangementAndLicensingAgreementAbstract', window );"><strong>Collaborative Arrangement and Licensing Agreement [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CumulativeRevenueFromContractWithCustomerExcludingAssessedTax', window );">Cumulative revenue earned</a></td>
<td class="nump">1,600,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">1,600,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 1,600,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_RoyaltyPercentageReceivedOnNetSalesOfMedicine', window );">Royalty percentage received on net sales of medicine</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">11.00%<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_TypeOfArrangementAxis=ions_BiogenCollaborationSpinrazaMember', window );">SPINRAZA [Member] | Maximum [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CollaborativeArrangementAndLicensingAgreementAbstract', window );"><strong>Collaborative Arrangement and Licensing Agreement [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_RoyaltyPercentageReceivedOnNetSalesOfMedicine', window );">Royalty percentage received on net sales of medicine</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">15.00%<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_TypeOfArrangementAxis=ions_BiogenCollaborationSpinrazaMember', window );">SPINRAZA [Member] | SPINRAZA Royalties [Member] | Maximum [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CollaborativeArrangementAndLicensingAgreementAbstract', window );"><strong>Collaborative Arrangement and Licensing Agreement [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CumulativeRevenueFromContractWithCustomerExcludingAssessedTax', window );">Cumulative revenue earned</a></td>
<td class="nump">1,200,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">1,200,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 1,200,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_TypeOfArrangementAxis=ions_BiogenCollaborationSpinrazaMember', window );">SPINRAZA [Member] | R&amp;D Revenue [Member] | Minimum [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CollaborativeArrangementAndLicensingAgreementAbstract', window );"><strong>Collaborative Arrangement and Licensing Agreement [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CumulativeRevenueFromContractWithCustomerExcludingAssessedTax', window );">Cumulative revenue earned</a></td>
<td class="nump">435,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">435,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 435,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_TypeOfArrangementAxis=ions_BiogenCollaborationNewAntisenseMedicinesForTreatmentOfSmaMember', window );">New Antisense Medicines for the Treatment of SMA [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CollaborativeArrangementAndLicensingAgreementAbstract', window );"><strong>Collaborative Arrangement and Licensing Agreement [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_RoyaltyPercentageReceivedOnNetSalesOfMedicine', window );">Royalty percentage received on net sales of medicine</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">20.00%<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_UpfrontPaymentReceived', window );">Upfront payment received</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 25,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_MaximumAmountOfPaymentsReceivableForLicenseFeesMilestonePaymentsAndOtherPayments', window );">Maximum amount of payments receivable for license fees, milestone payments and other payments</a></td>
<td class="nump">1,200,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">1,200,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 1,200,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_NextPotentialPayment', window );">Next prospective payment</a></td>
<td class="nump">45,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">45,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">45,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_RevenueFromContractWithCustomerNumberOfSeparatePerformanceObligations', window );">Number of separate performance obligations | PerformanceObligation</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">1<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_RevenueFromContractWithCustomerTransactionPrice', window );">Transaction price</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 25,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax', window );">Revenue</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 8,300<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_TypeOfArrangementAxis=ions_BiogenCollaborationNewAntisenseMedicinesForTreatmentOfSmaMember', window );">New Antisense Medicines for the Treatment of SMA [Member] | ION306 [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CollaborativeArrangementAndLicensingAgreementAbstract', window );"><strong>Collaborative Arrangement and Licensing Agreement [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_MaximumAmountOfPaymentsReceivableForDevelopmentCommercializationAndSalesMilestones', window );">Maximum amount of payments receivable for development, commercialization and sales milestones</a></td>
<td class="nump">555,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">555,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">555,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_MaximumAmountOfPaymentsReceivableForDevelopmentMilestones', window );">Maximum amount of payments receivable for development milestones</a></td>
<td class="nump">45,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">45,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">45,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_MaximumAmountOfPaymentsReceivableForRegulatoryMilestones', window );">Maximum amount of payments receivable for regulatory milestones</a></td>
<td class="nump">110,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">110,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">110,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_MaximumAmountOfPaymentsReceivableForSalesMilestones', window );">Maximum amount of payments receivable for sales milestones</a></td>
<td class="nump">400,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">400,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 400,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax', window );">Revenue</a></td>
<td class="nump">60,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">60,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_TypeOfArrangementAxis=ions_BiogenCollaboration2018StrategicNeurologyMember', window );">2018 Strategic Neurology [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CollaborativeArrangementAndLicensingAgreementAbstract', window );"><strong>Collaborative Arrangement and Licensing Agreement [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_RoyaltyPercentageReceivedOnNetSalesOfMedicine', window );">Royalty percentage received on net sales of medicine</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">20.00%<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_UpfrontPaymentReceived', window );">Upfront payment received</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 375,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_NextPotentialPayment', window );">Next prospective payment</a></td>
<td class="nump">7,500<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">7,500<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 7,500<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_RevenueFromContractWithCustomerNumberOfSeparatePerformanceObligations', window );">Number of separate performance obligations | PerformanceObligation</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">1<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_RevenueFromContractWithCustomerTransactionPrice', window );">Transaction price</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 552,000<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_TermOfCollaborationAgreement', window );">Term of collaboration agreement</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">10 years<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_UpfrontPaymentReceivedIncludingPurchaseOfStock', window );">Upfront payment received, including purchase of stock</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">1,000,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ProceedsFromIssuanceOfCommonStock', window );">Proceeds from issuance of common stock</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 625,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_PercentageCashPremiumPaidOnSharesPurchased', window );">Percentage cash premium paid on shares purchased</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">25.00%<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_MaximumAmountOfPaymentsReceivablePerMedicineForMilestonePayments', window );">Maximum amount of payments receivable per medicine for milestone payments</a></td>
<td class="nump">$ 270,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 270,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 270,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_NumberOfProgramsBeingAdvanced', window );">Number of programs being advanced | Program</a></td>
<td class="nump">9<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">9<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">9<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_PremiumPaidOnSharesPurchased', window );">Premium paid on shares purchased</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 177,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CumulativePaymentsIncludedInTransactionPriceForPerformanceObligation', window );">Cumulative payments included in transaction price for performance obligation</a></td>
<td class="nump">$ 616,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 616,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 616,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_MilestonePaymentsAchievedAndIncludedInTransactionPriceForPerformanceObligation', window );">Milestone payments achieved and included in transaction price for performance obligation</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">23,000<span></span>
</td>
<td class="nump">11,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax', window );">Revenue</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">15,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_TypeOfArrangementAxis=ions_BiogenCollaboration2018StrategicNeurologyMember', window );">2018 Strategic Neurology [Member] | Maximum [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CollaborativeArrangementAndLicensingAgreementAbstract', window );"><strong>Collaborative Arrangement and Licensing Agreement [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CumulativePaymentsReceived', window );">Cumulative payments received</a></td>
<td class="nump">1,100,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">1,100,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">1,100,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_TypeOfArrangementAxis=ions_BiogenCollaboration2013StrategicNeurologyMember', window );">2013 Strategic Neurology [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CollaborativeArrangementAndLicensingAgreementAbstract', window );"><strong>Collaborative Arrangement and Licensing Agreement [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_UpfrontPaymentReceived', window );">Upfront payment received</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 100,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_NextPotentialPayment', window );">Next prospective payment</a></td>
<td class="nump">$ 70,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 70,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 70,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_RevenueFromContractWithCustomerNumberOfSeparatePerformanceObligations', window );">Number of separate performance obligations | PerformanceObligation</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">1<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_RevenueFromContractWithCustomerTransactionPrice', window );">Transaction price</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 100,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_NumberOfMedicinesCurrentlyBeingAdvanced', window );">Number of medicines currently being advanced | Medicine</a></td>
<td class="nump">6<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">6<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">6<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax', window );">Revenue</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="num">$ (16,500)<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_TypeOfArrangementAxis=ions_BiogenCollaboration2013StrategicNeurologyMember', window );">2013 Strategic Neurology [Member] | Minimum [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CollaborativeArrangementAndLicensingAgreementAbstract', window );"><strong>Collaborative Arrangement and Licensing Agreement [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CumulativePaymentsReceived', window );">Cumulative payments received</a></td>
<td class="nump">$ 280,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 280,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 280,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_TypeOfArrangementAxis=ions_BiogenCollaboration2013StrategicNeurologyMember', window );">2013 Strategic Neurology [Member] | R&amp;D Revenue [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CollaborativeArrangementAndLicensingAgreementAbstract', window );"><strong>Collaborative Arrangement and Licensing Agreement [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CumulativePaymentsIncludedInTransactionPriceForPerformanceObligation', window );">Cumulative payments included in transaction price for performance obligation</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">145,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_TypeOfArrangementAxis=ions_BiogenCollaboration2013StrategicNeurologyMember', window );">2013 Strategic Neurology [Member] | Medicines for Parkinson's Disease [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CollaborativeArrangementAndLicensingAgreementAbstract', window );"><strong>Collaborative Arrangement and Licensing Agreement [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
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<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CollaborativeArrangementAndLicensingAgreementAbstract', window );"><strong>Collaborative Arrangement and Licensing Agreement [Abstract]</strong></a></td>
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<td class="text">&#160;<span></span>
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<td class="text">&#160;<span></span>
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<td class="text">&#160;<span></span>
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<td class="text">&#160;<span></span>
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<td class="text">&#160;<span></span>
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<td class="text">&#160;<span></span>
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<td class="text">&#160;<span></span>
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<td class="text">&#160;<span></span>
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<td class="text">&#160;<span></span>
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<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_MaximumAmountOfPaymentsReceivablePerProgramForLicenseFeesAndSubstantiveMilestonePayments', window );">Maximum amount of payments receivable per program for license fee and milestone payments</a></td>
<td class="nump">$ 260,000<span></span>
</td>
<td class="text">&#160;<span></span>
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<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 260,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 260,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
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</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_MaximumAmountOfPaymentsReceivablePerProgramForDevelopmentMilestones', window );">Maximum amount of payments receivable per program for development milestones</a></td>
<td class="nump">60,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">60,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">60,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
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<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_MaximumAmountOfPaymentsReceivablePerProgramForRegulatoryMilestones', window );">Maximum amount of payments receivable per program for regulatory milestones</a></td>
<td class="nump">130,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">130,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">130,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
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<td class="text">&#160;<span></span>
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<td class="text">&#160;<span></span>
</td>
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</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
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<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CollaborativeArrangementAndLicensingAgreementAbstract', window );"><strong>Collaborative Arrangement and Licensing Agreement [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
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<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax', window );">Revenue</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 10,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
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<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_TypeOfArrangementAxis=ions_BiogenCollaboration2012NeurologyMember', window );">2012 Neurology [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CollaborativeArrangementAndLicensingAgreementAbstract', window );"><strong>Collaborative Arrangement and Licensing Agreement [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
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<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CumulativePaymentsReceived', window );">Cumulative payments received</a></td>
<td class="nump">155,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">155,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">155,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_UpfrontPaymentReceived', window );">Upfront payment received</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 30,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_NextPotentialPayment', window );">Next prospective payment</a></td>
<td class="nump">25,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">25,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">25,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_MaximumAmountOfPaymentsReceivablePerProgramForLicenseFeesAndSubstantiveMilestonePayments', window );">Maximum amount of payments receivable per program for license fee and milestone payments</a></td>
<td class="nump">210,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">210,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">210,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_MaximumAmountOfPaymentsReceivablePerProgramForDevelopmentMilestones', window );">Maximum amount of payments receivable per program for development milestones</a></td>
<td class="nump">10,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">10,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">10,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_MaximumAmountOfPaymentsReceivablePerProgramForRegulatoryMilestones', window );">Maximum amount of payments receivable per program for regulatory milestones</a></td>
<td class="nump">130,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">130,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">130,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_NumberOfProgramsUnderWhichMedicinesAreToBeDevelopedAndCommercialized', window );">Number of programs under which medicines are to be developed and commercialized | Program</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">3<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax', window );">Revenue</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 6,300<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_TypeOfArrangementAxis=ions_BiogenCollaboration2012NeurologyMember', window );">2012 Neurology [Member] | R&amp;D Revenue [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CollaborativeArrangementAndLicensingAgreementAbstract', window );"><strong>Collaborative Arrangement and Licensing Agreement [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CumulativePaymentsIncludedInTransactionPriceForPerformanceObligation', window );">Cumulative payments included in transaction price for performance obligation</a></td>
<td class="nump">40,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">40,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">40,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_TypeOfArrangementAxis=ions_BiogenCollaboration2012NeurologyMember', window );">2012 Neurology [Member] | IONIS-MAPT [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CollaborativeArrangementAndLicensingAgreementAbstract', window );"><strong>Collaborative Arrangement and Licensing Agreement [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CumulativePaymentsIncludedInTransactionPriceForPerformanceObligation', window );">Cumulative payments included in transaction price for performance obligation</a></td>
<td class="nump">$ 57,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">57,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 57,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_MilestonePaymentsAchievedAndIncludedInTransactionPriceForPerformanceObligation', window );">Milestone payments achieved and included in transaction price for performance obligation</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 19,500<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_TermOfExtensionStudy', window );">Term of extension study</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">1 year<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax', window );">Revenue</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 45,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_TypeOfArrangementAxis=ions_BiogenCollaboration2012NeurologyMember', window );">2012 Neurology [Member] | ION582 [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CollaborativeArrangementAndLicensingAgreementAbstract', window );"><strong>Collaborative Arrangement and Licensing Agreement [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax', window );">Revenue</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 10,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
</table>
<div style="display: none;">
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_CollaborativeArrangementAndLicensingAgreementAbstract">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_CollaborativeArrangementAndLicensingAgreementAbstract</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:stringItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_CumulativePaymentsIncludedInTransactionPriceForPerformanceObligation">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Cumulative payments received since inception of the collaboration agreement included in the transaction price for the performance obligation.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_CumulativePaymentsIncludedInTransactionPriceForPerformanceObligation</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_CumulativePaymentsReceived">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Cumulative amount of payments received under the collaboration agreement as of the end of the reporting period.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_CumulativePaymentsReceived</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_CumulativeRevenueFromContractWithCustomerExcludingAssessedTax">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Cumulative amount, excluding tax collected from customer, of revenue from satisfaction of performance obligation by transferring promised good or service to customer. Tax collected from customer is tax assessed by governmental authority that is both imposed on and concurrent with specific revenue-producing transaction, including, but not limited to, sales, use, value added and excise.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_CumulativeRevenueFromContractWithCustomerExcludingAssessedTax</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_MaximumAmountOfPaymentsReceivableForDevelopmentCommercializationAndSalesMilestones">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The maximum amount of payments receivable for development, commercialization and sales milestones under the collaboration agreement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_MaximumAmountOfPaymentsReceivableForDevelopmentCommercializationAndSalesMilestones</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_MaximumAmountOfPaymentsReceivableForDevelopmentMilestones">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The maximum amount of payments receivable for development milestones under the collaboration agreement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_MaximumAmountOfPaymentsReceivableForDevelopmentMilestones</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_MaximumAmountOfPaymentsReceivableForLicenseFeesMilestonePaymentsAndOtherPayments">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Maximum amount of payments receivable for license fees, milestone payments and other payments under the collaboration agreement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_MaximumAmountOfPaymentsReceivableForLicenseFeesMilestonePaymentsAndOtherPayments</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_MaximumAmountOfPaymentsReceivableForRegulatoryMilestones">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The maximum amount of payments receivable for regulatory milestones under the collaboration agreement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_MaximumAmountOfPaymentsReceivableForRegulatoryMilestones</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_MaximumAmountOfPaymentsReceivableForSalesMilestones">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The maximum amount of payments receivable for sales milestones under the collaboration agreement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_MaximumAmountOfPaymentsReceivableForSalesMilestones</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_MaximumAmountOfPaymentsReceivablePerMedicineForMilestonePayments">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The maximum amount of payments receivable for milestone payments for each medicine that achieves marketing approval under the collaboration agreement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_MaximumAmountOfPaymentsReceivablePerMedicineForMilestonePayments</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_MaximumAmountOfPaymentsReceivablePerProgramForDevelopmentMilestones">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The maximum amount of payments receivable per program for development milestone payments under the collaboration agreement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_MaximumAmountOfPaymentsReceivablePerProgramForDevelopmentMilestones</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_MaximumAmountOfPaymentsReceivablePerProgramForLicenseFeesAndSubstantiveMilestonePayments">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The maximum amount of payments receivable per program for license fees and/or substantive milestone payments under the collaboration agreement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_MaximumAmountOfPaymentsReceivablePerProgramForLicenseFeesAndSubstantiveMilestonePayments</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_MaximumAmountOfPaymentsReceivablePerProgramForRegulatoryMilestones">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The maximum amount of payments receivable per program for regulatory milestone payments under the collaboration agreement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_MaximumAmountOfPaymentsReceivablePerProgramForRegulatoryMilestones</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_MilestonePaymentsAchievedAndIncludedInTransactionPriceForPerformanceObligation">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Milestone payments achieved under the collaboration agreement during the period and included in the transaction price for the performance obligation.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_MilestonePaymentsAchievedAndIncludedInTransactionPriceForPerformanceObligation</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_NextPotentialPayment">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The next potential payment to be earned under the collaboration agreement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_NextPotentialPayment</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_NumberOfMedicinesBeingDeveloped">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The number of medicines currently being developed under the collaboration agreement(s).</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_NumberOfMedicinesBeingDeveloped</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:integerItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_NumberOfMedicinesCurrentlyBeingAdvanced">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The number of medicines currently being advanced under the collaboration agreement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_NumberOfMedicinesCurrentlyBeingAdvanced</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:integerItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_NumberOfProgramsBeingAdvanced">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The number of programs being advanced under the collaboration agreement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_NumberOfProgramsBeingAdvanced</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:integerItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_NumberOfProgramsUnderWhichMedicinesAreToBeDevelopedAndCommercialized">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The number of programs under which medicines are to be developed and commercialized under the collaboration agreement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_NumberOfProgramsUnderWhichMedicinesAreToBeDevelopedAndCommercialized</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:integerItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_PercentageCashPremiumPaidOnSharesPurchased">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The percentage cash premium paid per share of the Company's common stock under the collaboration agreement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_PercentageCashPremiumPaidOnSharesPurchased</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>dtr-types:percentItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_PremiumPaidOnSharesPurchased">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The cash premium paid on the purchase of the Company's common stock under the collaboration agreement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_PremiumPaidOnSharesPurchased</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_RevenueFromContractWithCustomerNumberOfSeparatePerformanceObligations">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The number of separate performance obligations under the collaboration agreement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_RevenueFromContractWithCustomerNumberOfSeparatePerformanceObligations</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:integerItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_RevenueFromContractWithCustomerTransactionPrice">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The amount of consideration the Company earned or is eligible to earn under the collaboration agreement, including any variable consideration.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_RevenueFromContractWithCustomerTransactionPrice</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_RoyaltyPercentageReceivedOnNetSalesOfMedicine">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Royalty percentage received on the net sales of a medicine by a collaboration partner under the collaboration agreement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_RoyaltyPercentageReceivedOnNetSalesOfMedicine</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>dtr-types:percentItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_TermOfCollaborationAgreement">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Term of the collaboration agreement, in 'PnYnMnDTnHnMnS' format, for example, 'P1Y5M13D' represents the reported fact of one year, five months, and thirteen days.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_TermOfCollaborationAgreement</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:durationItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_TermOfExtensionStudy">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Term of long-term open label extension study, in which patients participating in double blind placebo controlled trials of new medications are invited, on completion of the initial trial, to take the study drug for some further period, for example, 'P1Y5M13D' represents reported fact of one year, five months, and thirteen days.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_TermOfExtensionStudy</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:durationItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_UpfrontPaymentReceived">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The amount of upfront payments received during the period under the collaboration agreement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_UpfrontPaymentReceived</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_UpfrontPaymentReceivedIncludingPurchaseOfStock">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The total amount of the upfront payment received, including the purchase of shares of the Company's stock, under the collaboration agreement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_UpfrontPaymentReceivedIncludingPurchaseOfStock</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_ConcentrationRiskPercentage1">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>For an entity that discloses a concentration risk in relation to quantitative amount, which serves as the "benchmark" (or denominator) in the equation, this concept represents the concentration percentage derived from the division.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 280<br> -SubTopic 10<br> -Section 50<br> -Paragraph 42<br> -URI http://asc.fasb.org/extlink&amp;oid=123359005&amp;loc=d3e9054-108599<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 275<br> -SubTopic 10<br> -Section 50<br> -Paragraph 18<br> -URI http://asc.fasb.org/extlink&amp;oid=99393423&amp;loc=d3e6351-108592<br><br>Reference 3: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 825<br> -SubTopic 10<br> -Section 50<br> -Paragraph 20<br> -URI http://asc.fasb.org/extlink&amp;oid=123594938&amp;loc=d3e13531-108611<br><br>Reference 4: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 825<br> -SubTopic 10<br> -Section 50<br> -Paragraph 21<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=123594938&amp;loc=d3e13537-108611<br><br>Reference 5: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 275<br> -SubTopic 10<br> -Section 50<br> -Paragraph 20<br> -URI http://asc.fasb.org/extlink&amp;oid=99393423&amp;loc=d3e6404-108592<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ConcentrationRiskPercentage1</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>dtr-types:percentItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_ContractWithCustomerLiability">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of obligation to transfer good or service to customer for which consideration has been received or is receivable.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 606<br> -SubTopic 10<br> -Section 45<br> -Paragraph 1<br> -URI http://asc.fasb.org/extlink&amp;oid=123360276&amp;loc=SL49130531-203044<br><br>Reference 2: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 606<br> -SubTopic 10<br> -Section 50<br> -Paragraph 8<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=123351226&amp;loc=SL49130549-203045<br><br>Reference 3: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 606<br> -SubTopic 10<br> -Section 45<br> -Paragraph 2<br> -URI http://asc.fasb.org/extlink&amp;oid=123360276&amp;loc=SL49130532-203044<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ContractWithCustomerLiability</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_ProceedsFromIssuanceOfCommonStock">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The cash inflow from the additional capital contribution to the entity.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 230<br> -SubTopic 10<br> -Section 45<br> -Paragraph 14<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=123570139&amp;loc=d3e3255-108585<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ProceedsFromIssuanceOfCommonStock</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount, excluding tax collected from customer, of revenue from satisfaction of performance obligation by transferring promised good or service to customer. Tax collected from customer is tax assessed by governmental authority that is both imposed on and concurrent with specific revenue-producing transaction, including, but not limited to, sales, use, value added and excise.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 280<br> -SubTopic 10<br> -Section 50<br> -Paragraph 30<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=123359005&amp;loc=d3e8906-108599<br><br>Reference 2: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 280<br> -SubTopic 10<br> -Section 50<br> -Paragraph 40<br> -URI http://asc.fasb.org/extlink&amp;oid=123359005&amp;loc=d3e9031-108599<br><br>Reference 3: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 280<br> -SubTopic 10<br> -Section 50<br> -Paragraph 41<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=123359005&amp;loc=d3e9038-108599<br><br>Reference 4: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 280<br> -SubTopic 10<br> -Section 50<br> -Paragraph 32<br> -Subparagraph (b)<br> -URI http://asc.fasb.org/extlink&amp;oid=123359005&amp;loc=d3e8933-108599<br><br>Reference 5: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 280<br> -SubTopic 10<br> -Section 50<br> -Paragraph 32<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=123359005&amp;loc=d3e8933-108599<br><br>Reference 6: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 606<br> -SubTopic 10<br> -Section 50<br> -Paragraph 4<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=123351226&amp;loc=SL49130543-203045<br><br>Reference 7: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 280<br> -SubTopic 10<br> -Section 50<br> -Paragraph 22<br> -Subparagraph (b)<br> -URI http://asc.fasb.org/extlink&amp;oid=123359005&amp;loc=d3e8736-108599<br><br>Reference 8: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 280<br> -SubTopic 10<br> -Section 50<br> -Paragraph 22<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=123359005&amp;loc=d3e8736-108599<br><br>Reference 9: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 280<br> -SubTopic 10<br> -Section 50<br> -Paragraph 42<br> -URI http://asc.fasb.org/extlink&amp;oid=123359005&amp;loc=d3e9054-108599<br><br>Reference 10: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 606<br> -SubTopic 10<br> -Section 50<br> -Paragraph 5<br> -URI http://asc.fasb.org/extlink&amp;oid=123351226&amp;loc=SL49130545-203045<br><br>Reference 11: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 924<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SAB Topic 11.L)<br> -URI http://asc.fasb.org/extlink&amp;oid=6472922&amp;loc=d3e499488-122856<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
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<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_srt_ProductOrServiceAxis=ions_SpinrazaRoyaltiesMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">srt_ProductOrServiceAxis=ions_SpinrazaRoyaltiesMember</td>
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<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>na</td>
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<tr>
<td><strong> Balance Type:</strong></td>
<td></td>
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</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_srt_ProductOrServiceAxis=ions_ResearchAndDevelopmentRevenueUnderCollaborativeAgreementsMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">srt_ProductOrServiceAxis=ions_ResearchAndDevelopmentRevenueUnderCollaborativeAgreementsMember</td>
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<td></td>
</tr>
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<td><strong> Data Type:</strong></td>
<td>na</td>
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<tr>
<td><strong> Balance Type:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td></td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_TypeOfArrangementAxis=ions_BiogenCollaborationsMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_TypeOfArrangementAxis=ions_BiogenCollaborationsMember</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td></td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_ConcentrationRiskByBenchmarkAxis=us-gaap_RevenueFromContractWithCustomerMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ConcentrationRiskByBenchmarkAxis=us-gaap_RevenueFromContractWithCustomerMember</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td></td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_ConcentrationRiskByTypeAxis=us-gaap_CustomerConcentrationRiskMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ConcentrationRiskByTypeAxis=us-gaap_CustomerConcentrationRiskMember</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td></td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_srt_RangeAxis=srt_MinimumMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">srt_RangeAxis=srt_MinimumMember</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td></td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_TypeOfArrangementAxis=ions_BiogenCollaborationSpinrazaMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_TypeOfArrangementAxis=ions_BiogenCollaborationSpinrazaMember</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td></td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_srt_RangeAxis=srt_MaximumMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">srt_RangeAxis=srt_MaximumMember</td>
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<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td></td>
</tr>
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<td><strong> Data Type:</strong></td>
<td>na</td>
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<td><strong> Balance Type:</strong></td>
<td></td>
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<tr>
<td><strong> Period Type:</strong></td>
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</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_TypeOfArrangementAxis=ions_BiogenCollaborationNewAntisenseMedicinesForTreatmentOfSmaMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_TypeOfArrangementAxis=ions_BiogenCollaborationNewAntisenseMedicinesForTreatmentOfSmaMember</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>na</td>
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<tr>
<td><strong> Balance Type:</strong></td>
<td></td>
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<tr>
<td><strong> Period Type:</strong></td>
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</div></td></tr>
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<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_srt_ProductOrServiceAxis=ions_Ion306Member">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">srt_ProductOrServiceAxis=ions_Ion306Member</td>
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<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
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</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_TypeOfArrangementAxis=ions_BiogenCollaboration2018StrategicNeurologyMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_TypeOfArrangementAxis=ions_BiogenCollaboration2018StrategicNeurologyMember</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td></td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_TypeOfArrangementAxis=ions_BiogenCollaboration2013StrategicNeurologyMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_TypeOfArrangementAxis=ions_BiogenCollaboration2013StrategicNeurologyMember</td>
</tr>
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<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
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<tr>
<td><strong> Data Type:</strong></td>
<td>na</td>
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<tr>
<td><strong> Balance Type:</strong></td>
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<tr>
<td><strong> Period Type:</strong></td>
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</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_srt_ProductOrServiceAxis=ions_MedicinesForParkinsonsDiseaseMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">srt_ProductOrServiceAxis=ions_MedicinesForParkinsonsDiseaseMember</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td></td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_srt_ProductOrServiceAxis=ions_MedicinesForAmyotrophicLateralSclerosisMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">srt_ProductOrServiceAxis=ions_MedicinesForAmyotrophicLateralSclerosisMember</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td></td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_srt_ProductOrServiceAxis=ions_MedicinesForMultipleSystemAtrophyMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">srt_ProductOrServiceAxis=ions_MedicinesForMultipleSystemAtrophyMember</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td></td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_srt_ProductOrServiceAxis=ions_MedicinesForUndisclosedTargetsMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">srt_ProductOrServiceAxis=ions_MedicinesForUndisclosedTargetsMember</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td></td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_srt_ProductOrServiceAxis=ions_AntisenseMoleculeMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">srt_ProductOrServiceAxis=ions_AntisenseMoleculeMember</td>
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<tr>
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<td><strong> Balance Type:</strong></td>
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<span style="display: none;">v3.22.0.1</span><table class="report" border="0" cellspacing="2" id="idm139691009007496">
<tr>
<th class="tl" colspan="1" rowspan="2"><div style="width: 200px;"><strong>Collaborative Arrangements and Licensing Agreements, AstraZeneca (Details)<br> $ in Thousands</strong></div></th>
<th class="th" colspan="3">1 Months Ended</th>
<th class="th" colspan="2">3 Months Ended</th>
<th class="th" colspan="3">12 Months Ended</th>
</tr>
<tr>
<th class="th">
<div>Dec. 31, 2021 </div>
<div>USD ($) </div>
<div>Component </div>
<div>Agreement </div>
<div>PerformanceObligation </div>
<div>Medicine</div>
</th>
<th class="th">
<div>Jul. 31, 2015 </div>
<div>USD ($) </div>
<div>PerformanceObligation</div>
</th>
<th class="th">
<div>Dec. 31, 2012 </div>
<div>USD ($)</div>
</th>
<th class="th">
<div>Dec. 31, 2021 </div>
<div>USD ($) </div>
<div>Component </div>
<div>Agreement </div>
<div>PerformanceObligation </div>
<div>Medicine</div>
</th>
<th class="th">
<div>Jun. 30, 2020 </div>
<div>USD ($)</div>
</th>
<th class="th">
<div>Dec. 31, 2021 </div>
<div>USD ($) </div>
<div>Component </div>
<div>Agreement </div>
<div>PerformanceObligation </div>
<div>Medicine</div>
</th>
<th class="th">
<div>Dec. 31, 2020 </div>
<div>USD ($)</div>
</th>
<th class="th">
<div>Dec. 31, 2019 </div>
<div>USD ($)</div>
</th>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CollaborativeArrangementAndLicensingAgreementAbstract', window );"><strong>Collaborative Arrangement and Licensing Agreement [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax', window );">Revenue</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 810,456<span></span>
</td>
<td class="nump">$ 729,264<span></span>
</td>
<td class="nump">$ 1,122,599<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_srt_ProductOrServiceAxis=ions_ResearchAndDevelopmentRevenueUnderCollaborativeAgreementsMember', window );">R&amp;D Revenue [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CollaborativeArrangementAndLicensingAgreementAbstract', window );"><strong>Collaborative Arrangement and Licensing Agreement [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax', window );">Revenue</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">468,061<span></span>
</td>
<td class="nump">364,565<span></span>
</td>
<td class="nump">$ 770,149<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_TypeOfArrangementAxis=ions_AstrazenecaCollaborationsMember', window );">AstraZeneca [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CollaborativeArrangementAndLicensingAgreementAbstract', window );"><strong>Collaborative Arrangement and Licensing Agreement [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ContractWithCustomerLiability', window );">Deferred revenue</a></td>
<td class="nump">$ 0<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 0<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 0<span></span>
</td>
<td class="nump">$ 10,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_TypeOfArrangementAxis=ions_AstrazenecaCollaborationsMember', window );">AstraZeneca [Member] | Revenue [Member] | Strategic Partner [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CollaborativeArrangementAndLicensingAgreementAbstract', window );"><strong>Collaborative Arrangement and Licensing Agreement [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ConcentrationRiskPercentage1', window );">Concentration percentage</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">31.00%<span></span>
</td>
<td class="nump">12.00%<span></span>
</td>
<td class="nump">3.00%<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_TypeOfArrangementAxis=ions_AstrazenecaCollaborationsMember', window );">AstraZeneca [Member] | R&amp;D Revenue [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CollaborativeArrangementAndLicensingAgreementAbstract', window );"><strong>Collaborative Arrangement and Licensing Agreement [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax', window );">Revenue</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 254,600<span></span>
</td>
<td class="nump">$ 88,000<span></span>
</td>
<td class="nump">$ 28,100<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_TypeOfArrangementAxis=ions_AstrazenecaCollaborationEplontersenMember', window );">Eplontersen Collaboration [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CollaborativeArrangementAndLicensingAgreementAbstract', window );"><strong>Collaborative Arrangement and Licensing Agreement [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_UpfrontPaymentReceived', window );">Upfront payment received</a></td>
<td class="nump">200,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_MaximumAmountOfPaymentsReceivableForDevelopmentAndRegulatoryMilestones', window );">Maximum amount of payments receivable for development and regulatory milestones</a></td>
<td class="nump">485,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">485,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">485,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_MaximumAmountOfPaymentsReceivableForSalesRelatedMilestones', window );">Maximum amount of payments receivable for sales-related milestones</a></td>
<td class="nump">$ 2,900,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 2,900,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 2,900,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_RoyaltyPercentageReceivedOnSalesOfMedicineInUnitedStates', window );">Royalty percentage received on sales of medicine in U.S.</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">20.00%<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_NumberOfMaterialComponents', window );">Number of material components | Component</a></td>
<td class="nump">4<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">4<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">4<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_PercentageOfCostsAssociatedWithOngoingGlobalPhase3DevelopmentProgramPaidByCollaborationPartner', window );">Percentage of costs associated with ongoing global Phase 3 development program paid by AstraZeneca</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">55.00%<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_RevenueFromContractWithCustomerNumberOfSeparatePerformanceObligations', window );">Number of separate performance obligations | PerformanceObligation</a></td>
<td class="nump">1<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">1<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">1<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_RevenueFromContractWithCustomerTransactionPrice', window );">Transaction price</a></td>
<td class="nump">$ 200,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 200,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 200,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_NextPotentialPayment', window );">Next prospective payment</a></td>
<td class="nump">50,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">50,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">50,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax', window );">Revenue</a></td>
<td class="nump">200,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_TypeOfArrangementAxis=ions_AstraZenecaCollaborationsResearchAndDevelopmentMember', window );">Research and Development Collaborations [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CollaborativeArrangementAndLicensingAgreementAbstract', window );"><strong>Collaborative Arrangement and Licensing Agreement [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CumulativePaymentsReceived', window );">Cumulative payments received</a></td>
<td class="nump">$ 386,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 386,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 386,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_NumberOfCollaborationAgreements', window );">Number of collaboration agreements | Agreement</a></td>
<td class="nump">2<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">2<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">2<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_NumberOfMedicinesBeingDeveloped', window );">Number of medicines currently being developed | Medicine</a></td>
<td class="nump">6<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">6<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">6<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_TypeOfArrangementAxis=ions_AstrazenecaCollaborationCardiovascularRenalAndMetabolicDiseasesMember', window );">Cardiovascular, Renal and Metabolic Diseases Collaboration [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CollaborativeArrangementAndLicensingAgreementAbstract', window );"><strong>Collaborative Arrangement and Licensing Agreement [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_NumberOfLicensedMedicines', window );">Number of licensed medicines | Medicine</a></td>
<td class="nump">5<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">5<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">5<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_UpfrontPaymentReceived', window );">Upfront payment received</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 65,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_NumberOfCollaborationAgreements', window );">Number of collaboration agreements | Agreement</a></td>
<td class="nump">1<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">1<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">1<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_MinimumAmountOfPaymentsReceivableForLicenseFeesAndMilestonePayments', window );">Minimum amount of payments receivable for license fees and milestones</a></td>
<td class="nump">$ 5,500,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 5,500,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 5,500,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_MaximumAmountOfPaymentsReceivableForDevelopmentMilestones', window );">Maximum amount of payments receivable for development milestones</a></td>
<td class="nump">1,100,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">1,100,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">1,100,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_MaximumAmountOfPaymentsReceivableForRegulatoryMilestones', window );">Maximum amount of payments receivable for regulatory milestones</a></td>
<td class="nump">2,900,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">2,900,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">2,900,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_MaximumAmountOfPaymentsReceivableForCommercializationMilestones', window );">Maximum amount of payments receivable for commercialization milestones</a></td>
<td class="nump">1,500,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">1,500,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">1,500,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_RevenueFromContractWithCustomerNumberOfSeparatePerformanceObligations', window );">Number of separate performance obligations | PerformanceObligation</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">1<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_RevenueFromContractWithCustomerTransactionPrice', window );">Transaction price</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 65,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_NextPotentialPayment', window );">Next prospective payment</a></td>
<td class="nump">10,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">10,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">10,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax', window );">Revenue</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">10,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">10,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_TypeOfArrangementAxis=ions_AstrazenecaCollaborationCardiovascularRenalAndMetabolicDiseasesMember', window );">Cardiovascular, Renal and Metabolic Diseases Collaboration [Member] | Minimum [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CollaborativeArrangementAndLicensingAgreementAbstract', window );"><strong>Collaborative Arrangement and Licensing Agreement [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CumulativePaymentsReceived', window );">Cumulative payments received</a></td>
<td class="nump">282,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">282,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">282,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_TypeOfArrangementAxis=ions_AstrazenecaCollaborationCardiovascularRenalAndMetabolicDiseasesMember', window );">Cardiovascular, Renal and Metabolic Diseases Collaboration [Member] | Target for Metabolic Disease [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CollaborativeArrangementAndLicensingAgreementAbstract', window );"><strong>Collaborative Arrangement and Licensing Agreement [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax', window );">Revenue</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">30,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_TypeOfArrangementAxis=ions_AstrazenecaCollaborationCardiovascularRenalAndMetabolicDiseasesMember', window );">Cardiovascular, Renal and Metabolic Diseases Collaboration [Member] | R&amp;D Revenue [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CollaborativeArrangementAndLicensingAgreementAbstract', window );"><strong>Collaborative Arrangement and Licensing Agreement [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CumulativePaymentsIncludedInTransactionPriceForPerformanceObligation', window );">Cumulative payments included in transaction price for performance obligation</a></td>
<td class="nump">$ 90,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 90,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 90,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_TypeOfArrangementAxis=ions_AstrazenecaCollaborationOncologyMember', window );">Oncology Collaboration [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CollaborativeArrangementAndLicensingAgreementAbstract', window );"><strong>Collaborative Arrangement and Licensing Agreement [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_UpfrontPaymentReceived', window );">Upfront payment received</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 31,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_NumberOfCollaborationAgreements', window );">Number of collaboration agreements | Agreement</a></td>
<td class="nump">1<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">1<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">1<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_MaximumAmountOfPaymentsReceivableForLicenseFeesAndMilestones', window );">Maximum amount of payments receivable for license fees and milestones</a></td>
<td class="nump">$ 160,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 160,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 160,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_MaximumAmountOfPaymentsReceivableForDevelopmentMilestones', window );">Maximum amount of payments receivable for development milestones</a></td>
<td class="nump">42,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">42,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">42,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_MaximumAmountOfPaymentsReceivableForRegulatoryMilestones', window );">Maximum amount of payments receivable for regulatory milestones</a></td>
<td class="nump">105,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">105,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">105,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_NextPotentialPayment', window );">Next prospective payment</a></td>
<td class="nump">12,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">12,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">12,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_TypeOfArrangementAxis=ions_AstrazenecaCollaborationOncologyMember', window );">Oncology Collaboration [Member] | Minimum [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CollaborativeArrangementAndLicensingAgreementAbstract', window );"><strong>Collaborative Arrangement and Licensing Agreement [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CumulativePaymentsReceived', window );">Cumulative payments received</a></td>
<td class="nump">$ 141,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 141,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 141,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_TypeOfArrangementAxis=ions_AstrazenecaCollaborationOncologyMember', window );">Oncology Collaboration [Member] | ION736 [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CollaborativeArrangementAndLicensingAgreementAbstract', window );"><strong>Collaborative Arrangement and Licensing Agreement [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax', window );">Revenue</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 13,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 13,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
</table>
<div style="display: none;">
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_CollaborativeArrangementAndLicensingAgreementAbstract">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_CollaborativeArrangementAndLicensingAgreementAbstract</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:stringItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_CumulativePaymentsIncludedInTransactionPriceForPerformanceObligation">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Cumulative payments received since inception of the collaboration agreement included in the transaction price for the performance obligation.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_CumulativePaymentsIncludedInTransactionPriceForPerformanceObligation</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_CumulativePaymentsReceived">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Cumulative amount of payments received under the collaboration agreement as of the end of the reporting period.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_CumulativePaymentsReceived</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_MaximumAmountOfPaymentsReceivableForCommercializationMilestones">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The maximum amount of payments receivable for commercialization milestones under the collaboration agreement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_MaximumAmountOfPaymentsReceivableForCommercializationMilestones</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_MaximumAmountOfPaymentsReceivableForDevelopmentAndRegulatoryMilestones">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The maximum amount of payments receivable for development and regulatory milestones under the collaboration agreement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_MaximumAmountOfPaymentsReceivableForDevelopmentAndRegulatoryMilestones</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_MaximumAmountOfPaymentsReceivableForDevelopmentMilestones">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The maximum amount of payments receivable for development milestones under the collaboration agreement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_MaximumAmountOfPaymentsReceivableForDevelopmentMilestones</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_MaximumAmountOfPaymentsReceivableForLicenseFeesAndMilestones">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Maximum amount of payments receivable for license fees and milestone payments under the collaboration agreement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_MaximumAmountOfPaymentsReceivableForLicenseFeesAndMilestones</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_MaximumAmountOfPaymentsReceivableForRegulatoryMilestones">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The maximum amount of payments receivable for regulatory milestones under the collaboration agreement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_MaximumAmountOfPaymentsReceivableForRegulatoryMilestones</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_MaximumAmountOfPaymentsReceivableForSalesRelatedMilestones">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The maximum amount of payments receivable for sales-related milestones under the collaboration agreement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_MaximumAmountOfPaymentsReceivableForSalesRelatedMilestones</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_MinimumAmountOfPaymentsReceivableForLicenseFeesAndMilestonePayments">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The minimum amount of payments receivable for license fees and milestone payments under the collaboration agreement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_MinimumAmountOfPaymentsReceivableForLicenseFeesAndMilestonePayments</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_NextPotentialPayment">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The next potential payment to be earned under the collaboration agreement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_NextPotentialPayment</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_NumberOfCollaborationAgreements">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The number of collaboration agreements with the collaboration partner.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_NumberOfCollaborationAgreements</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:integerItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_NumberOfLicensedMedicines">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The number of medicines that have been licensed under the collaboration agreement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_NumberOfLicensedMedicines</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:integerItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_NumberOfMaterialComponents">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The number of material components identified in the collaboration agreement under Accounting Standards Codification (ASC) 808, Collaborative Arrangements.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_NumberOfMaterialComponents</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:integerItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_NumberOfMedicinesBeingDeveloped">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The number of medicines currently being developed under the collaboration agreement(s).</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_NumberOfMedicinesBeingDeveloped</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:integerItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_PercentageOfCostsAssociatedWithOngoingGlobalPhase3DevelopmentProgramPaidByCollaborationPartner">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Percentage of costs associated with the ongoing global Phase 3 development program paid by a collaboration partner under the collaboration agreement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_PercentageOfCostsAssociatedWithOngoingGlobalPhase3DevelopmentProgramPaidByCollaborationPartner</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>dtr-types:percentItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_RevenueFromContractWithCustomerNumberOfSeparatePerformanceObligations">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The number of separate performance obligations under the collaboration agreement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_RevenueFromContractWithCustomerNumberOfSeparatePerformanceObligations</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:integerItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_RevenueFromContractWithCustomerTransactionPrice">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The amount of consideration the Company earned or is eligible to earn under the collaboration agreement, including any variable consideration.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_RevenueFromContractWithCustomerTransactionPrice</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_RoyaltyPercentageReceivedOnSalesOfMedicineInUnitedStates">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Royalty percentage received on sales of a medicine in the United States by a collaboration partner under the collaboration agreement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_RoyaltyPercentageReceivedOnSalesOfMedicineInUnitedStates</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>dtr-types:percentItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_UpfrontPaymentReceived">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The amount of upfront payments received during the period under the collaboration agreement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_UpfrontPaymentReceived</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_ConcentrationRiskPercentage1">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>For an entity that discloses a concentration risk in relation to quantitative amount, which serves as the "benchmark" (or denominator) in the equation, this concept represents the concentration percentage derived from the division.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 280<br> -SubTopic 10<br> -Section 50<br> -Paragraph 42<br> -URI http://asc.fasb.org/extlink&amp;oid=123359005&amp;loc=d3e9054-108599<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 275<br> -SubTopic 10<br> -Section 50<br> -Paragraph 18<br> -URI http://asc.fasb.org/extlink&amp;oid=99393423&amp;loc=d3e6351-108592<br><br>Reference 3: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 825<br> -SubTopic 10<br> -Section 50<br> -Paragraph 20<br> -URI http://asc.fasb.org/extlink&amp;oid=123594938&amp;loc=d3e13531-108611<br><br>Reference 4: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 825<br> -SubTopic 10<br> -Section 50<br> -Paragraph 21<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=123594938&amp;loc=d3e13537-108611<br><br>Reference 5: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 275<br> -SubTopic 10<br> -Section 50<br> -Paragraph 20<br> -URI http://asc.fasb.org/extlink&amp;oid=99393423&amp;loc=d3e6404-108592<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ConcentrationRiskPercentage1</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>dtr-types:percentItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_ContractWithCustomerLiability">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of obligation to transfer good or service to customer for which consideration has been received or is receivable.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 606<br> -SubTopic 10<br> -Section 45<br> -Paragraph 1<br> -URI http://asc.fasb.org/extlink&amp;oid=123360276&amp;loc=SL49130531-203044<br><br>Reference 2: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 606<br> -SubTopic 10<br> -Section 50<br> -Paragraph 8<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=123351226&amp;loc=SL49130549-203045<br><br>Reference 3: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 606<br> -SubTopic 10<br> -Section 45<br> -Paragraph 2<br> -URI http://asc.fasb.org/extlink&amp;oid=123360276&amp;loc=SL49130532-203044<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ContractWithCustomerLiability</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount, excluding tax collected from customer, of revenue from satisfaction of performance obligation by transferring promised good or service to customer. Tax collected from customer is tax assessed by governmental authority that is both imposed on and concurrent with specific revenue-producing transaction, including, but not limited to, sales, use, value added and excise.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 280<br> -SubTopic 10<br> -Section 50<br> -Paragraph 30<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=123359005&amp;loc=d3e8906-108599<br><br>Reference 2: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 280<br> -SubTopic 10<br> -Section 50<br> -Paragraph 40<br> -URI http://asc.fasb.org/extlink&amp;oid=123359005&amp;loc=d3e9031-108599<br><br>Reference 3: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 280<br> -SubTopic 10<br> -Section 50<br> -Paragraph 41<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=123359005&amp;loc=d3e9038-108599<br><br>Reference 4: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 280<br> -SubTopic 10<br> -Section 50<br> -Paragraph 32<br> -Subparagraph (b)<br> -URI http://asc.fasb.org/extlink&amp;oid=123359005&amp;loc=d3e8933-108599<br><br>Reference 5: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 280<br> -SubTopic 10<br> -Section 50<br> -Paragraph 32<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=123359005&amp;loc=d3e8933-108599<br><br>Reference 6: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 606<br> -SubTopic 10<br> -Section 50<br> -Paragraph 4<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=123351226&amp;loc=SL49130543-203045<br><br>Reference 7: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 280<br> -SubTopic 10<br> -Section 50<br> -Paragraph 22<br> -Subparagraph (b)<br> -URI http://asc.fasb.org/extlink&amp;oid=123359005&amp;loc=d3e8736-108599<br><br>Reference 8: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 280<br> -SubTopic 10<br> -Section 50<br> -Paragraph 22<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=123359005&amp;loc=d3e8736-108599<br><br>Reference 9: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 280<br> -SubTopic 10<br> -Section 50<br> -Paragraph 42<br> -URI http://asc.fasb.org/extlink&amp;oid=123359005&amp;loc=d3e9054-108599<br><br>Reference 10: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 606<br> -SubTopic 10<br> -Section 50<br> -Paragraph 5<br> -URI http://asc.fasb.org/extlink&amp;oid=123351226&amp;loc=SL49130545-203045<br><br>Reference 11: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 924<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SAB Topic 11.L)<br> -URI http://asc.fasb.org/extlink&amp;oid=6472922&amp;loc=d3e499488-122856<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
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</tr>
<tr>
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</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_srt_ProductOrServiceAxis=ions_ResearchAndDevelopmentRevenueUnderCollaborativeAgreementsMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">srt_ProductOrServiceAxis=ions_ResearchAndDevelopmentRevenueUnderCollaborativeAgreementsMember</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td></td>
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<td><strong> Data Type:</strong></td>
<td>na</td>
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<tr>
<td><strong> Balance Type:</strong></td>
<td></td>
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<tr>
<td><strong> Period Type:</strong></td>
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</table></div>
</div></td></tr>
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<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_TypeOfArrangementAxis=ions_AstrazenecaCollaborationsMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_TypeOfArrangementAxis=ions_AstrazenecaCollaborationsMember</td>
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<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
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<td><strong> Data Type:</strong></td>
<td>na</td>
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<td><strong> Balance Type:</strong></td>
<td></td>
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<tr>
<td><strong> Period Type:</strong></td>
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<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_ConcentrationRiskByBenchmarkAxis=us-gaap_RevenueFromContractWithCustomerMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ConcentrationRiskByBenchmarkAxis=us-gaap_RevenueFromContractWithCustomerMember</td>
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<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
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<td><strong> Data Type:</strong></td>
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<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ConcentrationRiskByTypeAxis=us-gaap_CustomerConcentrationRiskMember</td>
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<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_TypeOfArrangementAxis=ions_AstrazenecaCollaborationEplontersenMember</td>
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<td><strong> Data Type:</strong></td>
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<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_TypeOfArrangementAxis=ions_AstraZenecaCollaborationsResearchAndDevelopmentMember</td>
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<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_TypeOfArrangementAxis=ions_AstrazenecaCollaborationCardiovascularRenalAndMetabolicDiseasesMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_TypeOfArrangementAxis=ions_AstrazenecaCollaborationCardiovascularRenalAndMetabolicDiseasesMember</td>
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<td><strong> Data Type:</strong></td>
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<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">srt_RangeAxis=srt_MinimumMember</td>
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<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_srt_ProductOrServiceAxis=ions_TargetForMetabolicDiseaseMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
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<tr>
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<th class="tl" colspan="1" rowspan="2"><div style="width: 200px;"><strong>Collaborative Arrangements and Licensing Agreements, Bayer (Details)<br> $ in Thousands</strong></div></th>
<th class="th" colspan="2">1 Months Ended</th>
<th class="th" colspan="2">3 Months Ended</th>
<th class="th" colspan="3">12 Months Ended</th>
</tr>
<tr>
<th class="th">
<div>Feb. 28, 2017 </div>
<div>USD ($) </div>
<div>PerformanceObligation</div>
</th>
<th class="th">
<div>May 31, 2015 </div>
<div>USD ($) </div>
<div>PerformanceObligation</div>
</th>
<th class="th">
<div>Dec. 31, 2019 </div>
<div>USD ($)</div>
</th>
<th class="th">
<div>Jun. 30, 2015 </div>
<div>USD ($)</div>
</th>
<th class="th">
<div>Dec. 31, 2021 </div>
<div>USD ($)</div>
</th>
<th class="th">
<div>Dec. 31, 2020 </div>
<div>USD ($)</div>
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<th class="th">
<div>Dec. 31, 2019 </div>
<div>USD ($)</div>
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<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
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<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
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<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
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<td class="text">&#160;<span></span>
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<td class="nump">$ 810,456<span></span>
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<td class="nump">$ 729,264<span></span>
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<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
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<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CollaborativeArrangementAndLicensingAgreementAbstract', window );"><strong>Collaborative Arrangement and Licensing Agreement [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
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<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax', window );">Revenue</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">468,061<span></span>
</td>
<td class="nump">364,565<span></span>
</td>
<td class="nump">$ 770,149<span></span>
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<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_TypeOfArrangementAxis=ions_BayerCollaborationsMember', window );">Bayer [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CollaborativeArrangementAndLicensingAgreementAbstract', window );"><strong>Collaborative Arrangement and Licensing Agreement [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax', window );">Revenue</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 10,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ContractWithCustomerLiability', window );">Deferred revenue</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text"> <span></span>
</td>
<td class="nump">$ 0<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_TypeOfArrangementAxis=ions_BayerCollaborationsMember', window );">Bayer [Member] | Revenue [Member] | Strategic Partner [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CollaborativeArrangementAndLicensingAgreementAbstract', window );"><strong>Collaborative Arrangement and Licensing Agreement [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ConcentrationRiskPercentage1', window );">Concentration percentage</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">0.00%<span></span>
</td>
<td class="nump">0.00%<span></span>
</td>
<td class="nump">1.00%<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_TypeOfArrangementAxis=ions_BayerCollaborationsMember', window );">Bayer [Member] | R&amp;D Revenue [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CollaborativeArrangementAndLicensingAgreementAbstract', window );"><strong>Collaborative Arrangement and Licensing Agreement [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax', window );">Revenue</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 1,100<span></span>
</td>
<td class="nump">$ 3,200<span></span>
</td>
<td class="nump">$ 14,300<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_TypeOfArrangementAxis=ions_BayerCollaborationIonisFxiMember', window );">Bayer [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CollaborativeArrangementAndLicensingAgreementAbstract', window );"><strong>Collaborative Arrangement and Licensing Agreement [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_UpfrontPaymentReceived', window );">Upfront payment received</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 100,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 100,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_MaximumAmountOfPaymentsReceivableForLicenseFeesAndMilestones', window );">Maximum amount of payments receivable for license fees and milestones</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">385,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_MaximumAmountOfPaymentsReceivableForDevelopmentMilestones', window );">Maximum amount of payments receivable for development milestones</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">125,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_MaximumAmountOfPaymentsReceivableForSalesMilestones', window );">Maximum amount of payments receivable for sales milestones</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 110,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_RoyaltyPercentageReceivedOnGrossMarginsOfMedicinesUnderCollaborationAgreement', window );">Royalty percentage received on gross margins of both medicines combined</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">20.00%<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_NextPotentialPayment', window );">Next prospective payment</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 20,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_RevenueFromContractWithCustomerNumberOfSeparatePerformanceObligations', window );">Number of separate performance obligations | PerformanceObligation</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">3<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_TypeOfArrangementAxis=ions_BayerCollaborationIonisFxiMember', window );">Bayer [Member] | Minimum [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CollaborativeArrangementAndLicensingAgreementAbstract', window );"><strong>Collaborative Arrangement and Licensing Agreement [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CumulativePaymentsReceived', window );">Cumulative payments received</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 191,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_TypeOfArrangementAxis=ions_BayerCollaborationIonisFxiMember', window );">Bayer [Member] | R&amp;D Services for Fesomersen [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CollaborativeArrangementAndLicensingAgreementAbstract', window );"><strong>Collaborative Arrangement and Licensing Agreement [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_RevenueFromContractWithCustomerTransactionPrice', window );">Transaction price</a></td>
<td class="nump">$ 10,100<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_TypeOfArrangementAxis=ions_BayerCollaborationIonisFxiAmendmentMember', window );">Bayer [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CollaborativeArrangementAndLicensingAgreementAbstract', window );"><strong>Collaborative Arrangement and Licensing Agreement [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_UpfrontPaymentReceived', window );">Upfront payment received</a></td>
<td class="nump">75,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_PaymentReceivedForAdvancingPrograms', window );">Payment received for advancing programs</a></td>
<td class="nump">$ 75,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_RevenueFromContractWithCustomerNumberOfSeparatePerformanceObligations', window );">Number of separate performance obligations | PerformanceObligation</a></td>
<td class="nump">3<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_RevenueFromContractWithCustomerNumberOfNewPerformanceObligations', window );">Number of new performance obligations | PerformanceObligation</a></td>
<td class="nump">2<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_RevenueFromContractWithCustomerTransactionPrice', window );">Transaction price</a></td>
<td class="nump">$ 75,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_TypeOfArrangementAxis=ions_BayerCollaborationIonisFxiAmendmentMember', window );">Bayer [Member] | Fesomersen [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CollaborativeArrangementAndLicensingAgreementAbstract', window );"><strong>Collaborative Arrangement and Licensing Agreement [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_RevenueFromContractWithCustomerNumberOfNewPerformanceObligations', window );">Number of new performance obligations | PerformanceObligation</a></td>
<td class="nump">1<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_RevenueFromContractWithCustomerTransactionPrice', window );">Transaction price</a></td>
<td class="nump">$ 64,900<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_TypeOfArrangementAxis=ions_BayerCollaborationIonisFxiAmendmentMember', window );">Bayer [Member] | R&amp;D Services for Fesomersen [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CollaborativeArrangementAndLicensingAgreementAbstract', window );"><strong>Collaborative Arrangement and Licensing Agreement [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_RevenueFromContractWithCustomerNumberOfNewPerformanceObligations', window );">Number of new performance obligations | PerformanceObligation</a></td>
<td class="nump">1<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
</table>
<div style="display: none;">
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_CollaborativeArrangementAndLicensingAgreementAbstract">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_CollaborativeArrangementAndLicensingAgreementAbstract</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:stringItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_CumulativePaymentsReceived">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Cumulative amount of payments received under the collaboration agreement as of the end of the reporting period.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_CumulativePaymentsReceived</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_MaximumAmountOfPaymentsReceivableForDevelopmentMilestones">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The maximum amount of payments receivable for development milestones under the collaboration agreement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_MaximumAmountOfPaymentsReceivableForDevelopmentMilestones</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_MaximumAmountOfPaymentsReceivableForLicenseFeesAndMilestones">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Maximum amount of payments receivable for license fees and milestone payments under the collaboration agreement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_MaximumAmountOfPaymentsReceivableForLicenseFeesAndMilestones</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_MaximumAmountOfPaymentsReceivableForSalesMilestones">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The maximum amount of payments receivable for sales milestones under the collaboration agreement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_MaximumAmountOfPaymentsReceivableForSalesMilestones</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_NextPotentialPayment">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The next potential payment to be earned under the collaboration agreement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_NextPotentialPayment</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_PaymentReceivedForAdvancingPrograms">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The amount of payments received during the period for advancing programs under the collaboration agreement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_PaymentReceivedForAdvancingPrograms</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_RevenueFromContractWithCustomerNumberOfNewPerformanceObligations">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The number of new performance obligations identified under the collaboration agreement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_RevenueFromContractWithCustomerNumberOfNewPerformanceObligations</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:integerItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_RevenueFromContractWithCustomerNumberOfSeparatePerformanceObligations">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The number of separate performance obligations under the collaboration agreement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_RevenueFromContractWithCustomerNumberOfSeparatePerformanceObligations</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:integerItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_RevenueFromContractWithCustomerTransactionPrice">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The amount of consideration the Company earned or is eligible to earn under the collaboration agreement, including any variable consideration.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_RevenueFromContractWithCustomerTransactionPrice</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_RoyaltyPercentageReceivedOnGrossMarginsOfMedicinesUnderCollaborationAgreement">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The royalty percentage received on gross margins of medicines under the collaborative arrangement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_RoyaltyPercentageReceivedOnGrossMarginsOfMedicinesUnderCollaborationAgreement</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>dtr-types:percentItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_UpfrontPaymentReceived">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The amount of upfront payments received during the period under the collaboration agreement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_UpfrontPaymentReceived</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_ConcentrationRiskPercentage1">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>For an entity that discloses a concentration risk in relation to quantitative amount, which serves as the "benchmark" (or denominator) in the equation, this concept represents the concentration percentage derived from the division.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 280<br> -SubTopic 10<br> -Section 50<br> -Paragraph 42<br> -URI http://asc.fasb.org/extlink&amp;oid=123359005&amp;loc=d3e9054-108599<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 275<br> -SubTopic 10<br> -Section 50<br> -Paragraph 18<br> -URI http://asc.fasb.org/extlink&amp;oid=99393423&amp;loc=d3e6351-108592<br><br>Reference 3: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 825<br> -SubTopic 10<br> -Section 50<br> -Paragraph 20<br> -URI http://asc.fasb.org/extlink&amp;oid=123594938&amp;loc=d3e13531-108611<br><br>Reference 4: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 825<br> -SubTopic 10<br> -Section 50<br> -Paragraph 21<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=123594938&amp;loc=d3e13537-108611<br><br>Reference 5: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 275<br> -SubTopic 10<br> -Section 50<br> -Paragraph 20<br> -URI http://asc.fasb.org/extlink&amp;oid=99393423&amp;loc=d3e6404-108592<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ConcentrationRiskPercentage1</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>dtr-types:percentItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_ContractWithCustomerLiability">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of obligation to transfer good or service to customer for which consideration has been received or is receivable.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 606<br> -SubTopic 10<br> -Section 45<br> -Paragraph 1<br> -URI http://asc.fasb.org/extlink&amp;oid=123360276&amp;loc=SL49130531-203044<br><br>Reference 2: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 606<br> -SubTopic 10<br> -Section 50<br> -Paragraph 8<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=123351226&amp;loc=SL49130549-203045<br><br>Reference 3: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 606<br> -SubTopic 10<br> -Section 45<br> -Paragraph 2<br> -URI http://asc.fasb.org/extlink&amp;oid=123360276&amp;loc=SL49130532-203044<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ContractWithCustomerLiability</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount, excluding tax collected from customer, of revenue from satisfaction of performance obligation by transferring promised good or service to customer. Tax collected from customer is tax assessed by governmental authority that is both imposed on and concurrent with specific revenue-producing transaction, including, but not limited to, sales, use, value added and excise.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 280<br> -SubTopic 10<br> -Section 50<br> -Paragraph 30<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=123359005&amp;loc=d3e8906-108599<br><br>Reference 2: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 280<br> -SubTopic 10<br> -Section 50<br> -Paragraph 40<br> -URI http://asc.fasb.org/extlink&amp;oid=123359005&amp;loc=d3e9031-108599<br><br>Reference 3: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 280<br> -SubTopic 10<br> -Section 50<br> -Paragraph 41<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=123359005&amp;loc=d3e9038-108599<br><br>Reference 4: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 280<br> -SubTopic 10<br> -Section 50<br> -Paragraph 32<br> -Subparagraph (b)<br> -URI http://asc.fasb.org/extlink&amp;oid=123359005&amp;loc=d3e8933-108599<br><br>Reference 5: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 280<br> -SubTopic 10<br> -Section 50<br> -Paragraph 32<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=123359005&amp;loc=d3e8933-108599<br><br>Reference 6: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 606<br> -SubTopic 10<br> -Section 50<br> -Paragraph 4<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=123351226&amp;loc=SL49130543-203045<br><br>Reference 7: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 280<br> -SubTopic 10<br> -Section 50<br> -Paragraph 22<br> -Subparagraph (b)<br> -URI http://asc.fasb.org/extlink&amp;oid=123359005&amp;loc=d3e8736-108599<br><br>Reference 8: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 280<br> -SubTopic 10<br> -Section 50<br> -Paragraph 22<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=123359005&amp;loc=d3e8736-108599<br><br>Reference 9: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 280<br> -SubTopic 10<br> -Section 50<br> -Paragraph 42<br> -URI http://asc.fasb.org/extlink&amp;oid=123359005&amp;loc=d3e9054-108599<br><br>Reference 10: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 606<br> -SubTopic 10<br> -Section 50<br> -Paragraph 5<br> -URI http://asc.fasb.org/extlink&amp;oid=123351226&amp;loc=SL49130545-203045<br><br>Reference 11: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 924<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SAB Topic 11.L)<br> -URI http://asc.fasb.org/extlink&amp;oid=6472922&amp;loc=d3e499488-122856<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_srt_ProductOrServiceAxis=ions_ResearchAndDevelopmentRevenueUnderCollaborativeAgreementsMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">srt_ProductOrServiceAxis=ions_ResearchAndDevelopmentRevenueUnderCollaborativeAgreementsMember</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td></td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_TypeOfArrangementAxis=ions_BayerCollaborationsMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_TypeOfArrangementAxis=ions_BayerCollaborationsMember</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td></td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_ConcentrationRiskByBenchmarkAxis=us-gaap_RevenueFromContractWithCustomerMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ConcentrationRiskByBenchmarkAxis=us-gaap_RevenueFromContractWithCustomerMember</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td></td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_ConcentrationRiskByTypeAxis=us-gaap_CustomerConcentrationRiskMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ConcentrationRiskByTypeAxis=us-gaap_CustomerConcentrationRiskMember</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td></td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_TypeOfArrangementAxis=ions_BayerCollaborationIonisFxiMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_TypeOfArrangementAxis=ions_BayerCollaborationIonisFxiMember</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td></td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_srt_RangeAxis=srt_MinimumMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">srt_RangeAxis=srt_MinimumMember</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td></td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_srt_ProductOrServiceAxis=ions_ResearchAndDevelopmentServicesForFesomersenMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">srt_ProductOrServiceAxis=ions_ResearchAndDevelopmentServicesForFesomersenMember</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td></td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_TypeOfArrangementAxis=ions_BayerCollaborationIonisFxiAmendmentMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_TypeOfArrangementAxis=ions_BayerCollaborationIonisFxiAmendmentMember</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td></td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_srt_ProductOrServiceAxis=ions_FesomersenMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">srt_ProductOrServiceAxis=ions_FesomersenMember</td>
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<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td></td>
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<tr>
<td><strong> Data Type:</strong></td>
<td>na</td>
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<tr>
<td><strong> Balance Type:</strong></td>
<td></td>
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<tr>
<td><strong> Period Type:</strong></td>
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<span style="display: none;">v3.22.0.1</span><table class="report" border="0" cellspacing="2" id="idm139691007241768">
<tr>
<th class="tl" colspan="1" rowspan="2"><div style="width: 200px;"><strong>Collaborative Arrangements and Licensing Agreements, GSK (Details)<br> $ in Thousands</strong></div></th>
<th class="th" colspan="1">1 Months Ended</th>
<th class="th" colspan="1">3 Months Ended</th>
<th class="th" colspan="3">12 Months Ended</th>
</tr>
<tr>
<th class="th">
<div>Mar. 31, 2010 </div>
<div>USD ($)</div>
</th>
<th class="th">
<div>Sep. 30, 2019 </div>
<div>USD ($)</div>
</th>
<th class="th">
<div>Dec. 31, 2021 </div>
<div>USD ($) </div>
<div>Medicine</div>
</th>
<th class="th">
<div>Dec. 31, 2020 </div>
<div>USD ($)</div>
</th>
<th class="th">
<div>Dec. 31, 2019 </div>
<div>USD ($)</div>
</th>
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<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CollaborativeArrangementAndLicensingAgreementAbstract', window );"><strong>Collaborative Arrangement and Licensing Agreement [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax', window );">Revenue</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 810,456<span></span>
</td>
<td class="nump">$ 729,264<span></span>
</td>
<td class="nump">$ 1,122,599<span></span>
</td>
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<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_srt_ProductOrServiceAxis=ions_ResearchAndDevelopmentRevenueUnderCollaborativeAgreementsMember', window );">R&amp;D Revenue [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CollaborativeArrangementAndLicensingAgreementAbstract', window );"><strong>Collaborative Arrangement and Licensing Agreement [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax', window );">Revenue</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 468,061<span></span>
</td>
<td class="nump">364,565<span></span>
</td>
<td class="nump">$ 770,149<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_TypeOfArrangementAxis=ions_GlaxoSmithKlineCollaborationMember', window );">GSK [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CollaborativeArrangementAndLicensingAgreementAbstract', window );"><strong>Collaborative Arrangement and Licensing Agreement [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_UpfrontPaymentReceived', window );">Upfront payment received</a></td>
<td class="nump">$ 35,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_NumberOfMedicinesBeingDeveloped', window );">Number of medicines currently being developed | Medicine</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">2<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_MinimumAmountOfPaymentsReceivableForLicenseFeesAndMilestonePayments', window );">Minimum amount of payments receivable for license fees and milestones</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 260,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_MaximumAmountOfPaymentsReceivableForDevelopmentMilestones', window );">Maximum amount of payments receivable for development milestones</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">47,500<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_MaximumAmountOfPaymentsReceivableForRegulatoryMilestones', window );">Maximum amount of payments receivable for regulatory milestones</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">120,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_MaximumAmountOfPaymentsReceivableForSalesMilestones', window );">Maximum amount of payments receivable for sales milestones</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">70,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_NextPotentialPayment', window );">Next prospective payment</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">15,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax', window );">Revenue</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 25,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ContractWithCustomerLiability', window );">Deferred revenue</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 0<span></span>
</td>
<td class="nump">$ 0<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_TypeOfArrangementAxis=ions_GlaxoSmithKlineCollaborationMember', window );">GSK [Member] | Revenue [Member] | Strategic Partner [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CollaborativeArrangementAndLicensingAgreementAbstract', window );"><strong>Collaborative Arrangement and Licensing Agreement [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ConcentrationRiskPercentage1', window );">Concentration percentage</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">0.00%<span></span>
</td>
<td class="nump">0.00%<span></span>
</td>
<td class="nump">2.00%<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_TypeOfArrangementAxis=ions_GlaxoSmithKlineCollaborationMember', window );">GSK [Member] | Minimum [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CollaborativeArrangementAndLicensingAgreementAbstract', window );"><strong>Collaborative Arrangement and Licensing Agreement [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CumulativePaymentsReceived', window );">Cumulative payments received</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 190,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_TypeOfArrangementAxis=ions_GlaxoSmithKlineCollaborationMember', window );">GSK [Member] | R&amp;D Revenue [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CollaborativeArrangementAndLicensingAgreementAbstract', window );"><strong>Collaborative Arrangement and Licensing Agreement [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax', window );">Revenue</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 0<span></span>
</td>
<td class="nump">$ 200<span></span>
</td>
<td class="nump">$ 25,400<span></span>
</td>
</tr>
</table>
<div style="display: none;">
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_CollaborativeArrangementAndLicensingAgreementAbstract">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_CollaborativeArrangementAndLicensingAgreementAbstract</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:stringItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_CumulativePaymentsReceived">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Cumulative amount of payments received under the collaboration agreement as of the end of the reporting period.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_CumulativePaymentsReceived</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_MaximumAmountOfPaymentsReceivableForDevelopmentMilestones">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The maximum amount of payments receivable for development milestones under the collaboration agreement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_MaximumAmountOfPaymentsReceivableForDevelopmentMilestones</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_MaximumAmountOfPaymentsReceivableForRegulatoryMilestones">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The maximum amount of payments receivable for regulatory milestones under the collaboration agreement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_MaximumAmountOfPaymentsReceivableForRegulatoryMilestones</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_MaximumAmountOfPaymentsReceivableForSalesMilestones">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The maximum amount of payments receivable for sales milestones under the collaboration agreement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_MaximumAmountOfPaymentsReceivableForSalesMilestones</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_MinimumAmountOfPaymentsReceivableForLicenseFeesAndMilestonePayments">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The minimum amount of payments receivable for license fees and milestone payments under the collaboration agreement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_MinimumAmountOfPaymentsReceivableForLicenseFeesAndMilestonePayments</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_NextPotentialPayment">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The next potential payment to be earned under the collaboration agreement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_NextPotentialPayment</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_NumberOfMedicinesBeingDeveloped">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The number of medicines currently being developed under the collaboration agreement(s).</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_NumberOfMedicinesBeingDeveloped</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:integerItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_UpfrontPaymentReceived">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The amount of upfront payments received during the period under the collaboration agreement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_UpfrontPaymentReceived</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_ConcentrationRiskPercentage1">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>For an entity that discloses a concentration risk in relation to quantitative amount, which serves as the "benchmark" (or denominator) in the equation, this concept represents the concentration percentage derived from the division.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 280<br> -SubTopic 10<br> -Section 50<br> -Paragraph 42<br> -URI http://asc.fasb.org/extlink&amp;oid=123359005&amp;loc=d3e9054-108599<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 275<br> -SubTopic 10<br> -Section 50<br> -Paragraph 18<br> -URI http://asc.fasb.org/extlink&amp;oid=99393423&amp;loc=d3e6351-108592<br><br>Reference 3: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 825<br> -SubTopic 10<br> -Section 50<br> -Paragraph 20<br> -URI http://asc.fasb.org/extlink&amp;oid=123594938&amp;loc=d3e13531-108611<br><br>Reference 4: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 825<br> -SubTopic 10<br> -Section 50<br> -Paragraph 21<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=123594938&amp;loc=d3e13537-108611<br><br>Reference 5: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 275<br> -SubTopic 10<br> -Section 50<br> -Paragraph 20<br> -URI http://asc.fasb.org/extlink&amp;oid=99393423&amp;loc=d3e6404-108592<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ConcentrationRiskPercentage1</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
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<tr>
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<td>dtr-types:percentItemType</td>
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<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
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<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
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<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_ContractWithCustomerLiability">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of obligation to transfer good or service to customer for which consideration has been received or is receivable.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 606<br> -SubTopic 10<br> -Section 45<br> -Paragraph 1<br> -URI http://asc.fasb.org/extlink&amp;oid=123360276&amp;loc=SL49130531-203044<br><br>Reference 2: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 606<br> -SubTopic 10<br> -Section 50<br> -Paragraph 8<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=123351226&amp;loc=SL49130549-203045<br><br>Reference 3: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 606<br> -SubTopic 10<br> -Section 45<br> -Paragraph 2<br> -URI http://asc.fasb.org/extlink&amp;oid=123360276&amp;loc=SL49130532-203044<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ContractWithCustomerLiability</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
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<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
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<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
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<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount, excluding tax collected from customer, of revenue from satisfaction of performance obligation by transferring promised good or service to customer. Tax collected from customer is tax assessed by governmental authority that is both imposed on and concurrent with specific revenue-producing transaction, including, but not limited to, sales, use, value added and excise.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 280<br> -SubTopic 10<br> -Section 50<br> -Paragraph 30<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=123359005&amp;loc=d3e8906-108599<br><br>Reference 2: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 280<br> -SubTopic 10<br> -Section 50<br> -Paragraph 40<br> -URI http://asc.fasb.org/extlink&amp;oid=123359005&amp;loc=d3e9031-108599<br><br>Reference 3: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 280<br> -SubTopic 10<br> -Section 50<br> -Paragraph 41<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=123359005&amp;loc=d3e9038-108599<br><br>Reference 4: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 280<br> -SubTopic 10<br> -Section 50<br> -Paragraph 32<br> -Subparagraph (b)<br> -URI http://asc.fasb.org/extlink&amp;oid=123359005&amp;loc=d3e8933-108599<br><br>Reference 5: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 280<br> -SubTopic 10<br> -Section 50<br> -Paragraph 32<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=123359005&amp;loc=d3e8933-108599<br><br>Reference 6: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 606<br> -SubTopic 10<br> -Section 50<br> -Paragraph 4<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=123351226&amp;loc=SL49130543-203045<br><br>Reference 7: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 280<br> -SubTopic 10<br> -Section 50<br> -Paragraph 22<br> -Subparagraph (b)<br> -URI http://asc.fasb.org/extlink&amp;oid=123359005&amp;loc=d3e8736-108599<br><br>Reference 8: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 280<br> -SubTopic 10<br> -Section 50<br> -Paragraph 22<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=123359005&amp;loc=d3e8736-108599<br><br>Reference 9: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 280<br> -SubTopic 10<br> -Section 50<br> -Paragraph 42<br> -URI http://asc.fasb.org/extlink&amp;oid=123359005&amp;loc=d3e9054-108599<br><br>Reference 10: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 606<br> -SubTopic 10<br> -Section 50<br> -Paragraph 5<br> -URI http://asc.fasb.org/extlink&amp;oid=123351226&amp;loc=SL49130545-203045<br><br>Reference 11: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 924<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SAB Topic 11.L)<br> -URI http://asc.fasb.org/extlink&amp;oid=6472922&amp;loc=d3e499488-122856<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax</td>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
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<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
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<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
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<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ConcentrationRiskByBenchmarkAxis=us-gaap_RevenueFromContractWithCustomerMember</td>
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<span style="display: none;">v3.22.0.1</span><table class="report" border="0" cellspacing="2" id="idm139691008697944">
<tr>
<th class="tl" colspan="1" rowspan="2"><div style="width: 200px;"><strong>Collaborative Arrangements and Licensing Agreements, Novartis (Details)<br> $ in Thousands, shares in Millions</strong></div></th>
<th class="th" colspan="3">3 Months Ended</th>
<th class="th" colspan="3">12 Months Ended</th>
<th class="th" colspan="1"></th>
</tr>
<tr>
<th class="th">
<div>Sep. 30, 2021 </div>
<div>USD ($)</div>
</th>
<th class="th">
<div>Mar. 31, 2019 </div>
<div>USD ($)</div>
</th>
<th class="th">
<div>Mar. 31, 2017 </div>
<div>USD ($) </div>
<div>PerformanceObligation </div>
<div>shares</div>
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<th class="th">
<div>Dec. 31, 2021 </div>
<div>USD ($)</div>
</th>
<th class="th">
<div>Dec. 31, 2020 </div>
<div>USD ($)</div>
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<th class="th">
<div>Dec. 31, 2019 </div>
<div>USD ($)</div>
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<td class="text">&#160;<span></span>
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<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
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<td class="text">&#160;<span></span>
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<td class="text">&#160;<span></span>
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<td class="text">&#160;<span></span>
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<td class="nump">$ 729,264<span></span>
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<td class="text">&#160;<span></span>
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<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
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<td class="text">&#160;<span></span>
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<td class="text">&#160;<span></span>
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<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CollaborativeArrangementAndLicensingAgreementAbstract', window );"><strong>Collaborative Arrangement and Licensing Agreement [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
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<td class="text">&#160;<span></span>
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<td class="text">&#160;<span></span>
</td>
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<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax', window );">Revenue</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">19,119<span></span>
</td>
<td class="nump">8,117<span></span>
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<td class="nump">17,205<span></span>
</td>
<td class="text">&#160;<span></span>
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<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_srt_ProductOrServiceAxis=ions_ResearchAndDevelopmentRevenueUnderCollaborativeAgreementsMember', window );">R&amp;D Revenue [Member]</a></td>
<td class="text">&#160;<span></span>
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<td class="text">&#160;<span></span>
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<td class="text">&#160;<span></span>
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<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
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<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CollaborativeArrangementAndLicensingAgreementAbstract', window );"><strong>Collaborative Arrangement and Licensing Agreement [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
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<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax', window );">Revenue</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">468,061<span></span>
</td>
<td class="nump">364,565<span></span>
</td>
<td class="nump">$ 770,149<span></span>
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<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_TypeOfArrangementAxis=ions_NovartisCollaborationMember', window );">Novartis [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CollaborativeArrangementAndLicensingAgreementAbstract', window );"><strong>Collaborative Arrangement and Licensing Agreement [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_UpfrontPaymentReceived', window );">Upfront payment received</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 75,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_MaximumAmountOfPaymentsReceivableForMilestones', window );">Maximum amount of payments receivable for milestones</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">675,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_MaximumAmountOfPaymentsReceivableForDevelopmentMilestones', window );">Maximum amount of payments receivable for development milestones</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">25,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_MaximumAmountOfPaymentsReceivableForRegulatoryMilestones', window );">Maximum amount of payments receivable for regulatory milestones</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">290,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_MaximumAmountOfPaymentsReceivableForSalesMilestones', window );">Maximum amount of payments receivable for sales milestones</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">360,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CumulativePaymentsReceived', window );">Cumulative payments received</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">425,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_NextPotentialPayment', window );">Next prospective payment</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">75,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_StockIssuedDuringPeriodSharesNewIssues', window );">Shares issued (in shares) | shares</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">1.6<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_ProceedsFromSaleOfCommonStockIncludingPremiumPaid', window );">Proceeds from sale of common stock</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 100,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_RevenueFromContractWithCustomerNumberOfSeparatePerformanceObligations', window );">Number of separate performance obligations | PerformanceObligation</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">4<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_RevenueFromContractWithCustomerTransactionPrice', window );">Transaction price</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 108,400<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_PremiumReceivedOnSharesIssued', window );">Premium received on shares issued</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">28,400<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_PotentialPremiumReceivedIfCommonStockIsPurchasedInFuture', window );">Potential premium received if common stock is purchased in the future</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">5,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ContractWithCustomerLiability', window );">Deferred revenue</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 0<span></span>
</td>
<td class="nump">$ 0<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_TypeOfArrangementAxis=ions_NovartisCollaborationMember', window );">Novartis [Member] | Revenue [Member] | Strategic Partner [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CollaborativeArrangementAndLicensingAgreementAbstract', window );"><strong>Collaborative Arrangement and Licensing Agreement [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ConcentrationRiskPercentage1', window );">Concentration percentage</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">3.00%<span></span>
</td>
<td class="nump">0.00%<span></span>
</td>
<td class="nump">17.00%<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_TypeOfArrangementAxis=ions_NovartisCollaborationMember', window );">Novartis [Member] | Licensing and Other Royalties [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CollaborativeArrangementAndLicensingAgreementAbstract', window );"><strong>Collaborative Arrangement and Licensing Agreement [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax', window );">Revenue</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 150,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_TypeOfArrangementAxis=ions_NovartisCollaborationMember', window );">Novartis [Member] | R&amp;D Services for Pelacarsen [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CollaborativeArrangementAndLicensingAgreementAbstract', window );"><strong>Collaborative Arrangement and Licensing Agreement [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_RevenueFromContractWithCustomerTransactionPrice', window );">Transaction price</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">64,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_TypeOfArrangementAxis=ions_NovartisCollaborationMember', window );">Novartis [Member] | R&amp;D Services for Olezarsen [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CollaborativeArrangementAndLicensingAgreementAbstract', window );"><strong>Collaborative Arrangement and Licensing Agreement [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_RevenueFromContractWithCustomerTransactionPrice', window );">Transaction price</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">40,100<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_TypeOfArrangementAxis=ions_NovartisCollaborationMember', window );">Novartis [Member] | Pelacarsen API [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CollaborativeArrangementAndLicensingAgreementAbstract', window );"><strong>Collaborative Arrangement and Licensing Agreement [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_RoyaltyPercentageReceivedOnSalesOfMedicine', window );">Royalty percentage received on sales of medicine</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">20.00%<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_PercentageEnrollmentInPhase3Study', window );">Percentage enrollment in Lp(a) HORIZON Phase 3 cardiovascular outcome study</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">50.00%<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_RevenueFromContractWithCustomerTransactionPrice', window );">Transaction price</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">1,500<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax', window );">Revenue</a></td>
<td class="nump">$ 25,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_TypeOfArrangementAxis=ions_NovartisCollaborationMember', window );">Novartis [Member] | Olezarsen API [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CollaborativeArrangementAndLicensingAgreementAbstract', window );"><strong>Collaborative Arrangement and Licensing Agreement [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_RevenueFromContractWithCustomerTransactionPrice', window );">Transaction price</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 2,800<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_TypeOfArrangementAxis=ions_NovartisCollaborationMember', window );">Novartis [Member] | R&amp;D Revenue [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CollaborativeArrangementAndLicensingAgreementAbstract', window );"><strong>Collaborative Arrangement and Licensing Agreement [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax', window );">Revenue</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 25,500<span></span>
</td>
<td class="nump">$ 1,000<span></span>
</td>
<td class="nump">$ 187,400<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
</table>
<div style="display: none;">
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_CollaborativeArrangementAndLicensingAgreementAbstract">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_CollaborativeArrangementAndLicensingAgreementAbstract</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:stringItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_CumulativePaymentsReceived">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Cumulative amount of payments received under the collaboration agreement as of the end of the reporting period.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_CumulativePaymentsReceived</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_MaximumAmountOfPaymentsReceivableForDevelopmentMilestones">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The maximum amount of payments receivable for development milestones under the collaboration agreement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_MaximumAmountOfPaymentsReceivableForDevelopmentMilestones</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_MaximumAmountOfPaymentsReceivableForMilestones">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The maximum amount of payments receivable for milestones under the collaboration agreement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_MaximumAmountOfPaymentsReceivableForMilestones</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_MaximumAmountOfPaymentsReceivableForRegulatoryMilestones">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The maximum amount of payments receivable for regulatory milestones under the collaboration agreement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_MaximumAmountOfPaymentsReceivableForRegulatoryMilestones</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_MaximumAmountOfPaymentsReceivableForSalesMilestones">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The maximum amount of payments receivable for sales milestones under the collaboration agreement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_MaximumAmountOfPaymentsReceivableForSalesMilestones</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_NextPotentialPayment">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The next potential payment to be earned under the collaboration agreement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_NextPotentialPayment</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_PercentageEnrollmentInPhase3Study">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Percentage enrollment in the Lp(a) HORIZON Phase 3 cardiovascular outcome study of pelacarsen.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_PercentageEnrollmentInPhase3Study</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>dtr-types:percentItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_PotentialPremiumReceivedIfCommonStockIsPurchasedInFuture">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The potential premium received if common stock is purchased in the future under a Stock Purchase Agreement (SPA) in conjunction with the collaboration agreement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_PotentialPremiumReceivedIfCommonStockIsPurchasedInFuture</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_PremiumReceivedOnSharesIssued">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The total amount of the premium received over the trading price of common stock at the time of purchase.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_PremiumReceivedOnSharesIssued</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_ProceedsFromSaleOfCommonStockIncludingPremiumPaid">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The cash inflow from the sale of common stock, including the premium paid for the purchase of common stock.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_ProceedsFromSaleOfCommonStockIncludingPremiumPaid</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_RevenueFromContractWithCustomerNumberOfSeparatePerformanceObligations">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The number of separate performance obligations under the collaboration agreement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_RevenueFromContractWithCustomerNumberOfSeparatePerformanceObligations</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:integerItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_RevenueFromContractWithCustomerTransactionPrice">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The amount of consideration the Company earned or is eligible to earn under the collaboration agreement, including any variable consideration.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_RevenueFromContractWithCustomerTransactionPrice</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_RoyaltyPercentageReceivedOnSalesOfMedicine">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Royalty percentage received on the sales of a medicine by a collaboration partner under the collaboration agreement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_RoyaltyPercentageReceivedOnSalesOfMedicine</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>dtr-types:percentItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_UpfrontPaymentReceived">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The amount of upfront payments received during the period under the collaboration agreement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_UpfrontPaymentReceived</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_ConcentrationRiskPercentage1">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>For an entity that discloses a concentration risk in relation to quantitative amount, which serves as the "benchmark" (or denominator) in the equation, this concept represents the concentration percentage derived from the division.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 280<br> -SubTopic 10<br> -Section 50<br> -Paragraph 42<br> -URI http://asc.fasb.org/extlink&amp;oid=123359005&amp;loc=d3e9054-108599<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 275<br> -SubTopic 10<br> -Section 50<br> -Paragraph 18<br> -URI http://asc.fasb.org/extlink&amp;oid=99393423&amp;loc=d3e6351-108592<br><br>Reference 3: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 825<br> -SubTopic 10<br> -Section 50<br> -Paragraph 20<br> -URI http://asc.fasb.org/extlink&amp;oid=123594938&amp;loc=d3e13531-108611<br><br>Reference 4: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 825<br> -SubTopic 10<br> -Section 50<br> -Paragraph 21<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=123594938&amp;loc=d3e13537-108611<br><br>Reference 5: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 275<br> -SubTopic 10<br> -Section 50<br> -Paragraph 20<br> -URI http://asc.fasb.org/extlink&amp;oid=99393423&amp;loc=d3e6404-108592<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ConcentrationRiskPercentage1</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>dtr-types:percentItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_ContractWithCustomerLiability">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of obligation to transfer good or service to customer for which consideration has been received or is receivable.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 606<br> -SubTopic 10<br> -Section 45<br> -Paragraph 1<br> -URI http://asc.fasb.org/extlink&amp;oid=123360276&amp;loc=SL49130531-203044<br><br>Reference 2: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 606<br> -SubTopic 10<br> -Section 50<br> -Paragraph 8<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=123351226&amp;loc=SL49130549-203045<br><br>Reference 3: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 606<br> -SubTopic 10<br> -Section 45<br> -Paragraph 2<br> -URI http://asc.fasb.org/extlink&amp;oid=123360276&amp;loc=SL49130532-203044<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ContractWithCustomerLiability</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount, excluding tax collected from customer, of revenue from satisfaction of performance obligation by transferring promised good or service to customer. Tax collected from customer is tax assessed by governmental authority that is both imposed on and concurrent with specific revenue-producing transaction, including, but not limited to, sales, use, value added and excise.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 280<br> -SubTopic 10<br> -Section 50<br> -Paragraph 30<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=123359005&amp;loc=d3e8906-108599<br><br>Reference 2: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 280<br> -SubTopic 10<br> -Section 50<br> -Paragraph 40<br> -URI http://asc.fasb.org/extlink&amp;oid=123359005&amp;loc=d3e9031-108599<br><br>Reference 3: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 280<br> -SubTopic 10<br> -Section 50<br> -Paragraph 41<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=123359005&amp;loc=d3e9038-108599<br><br>Reference 4: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 280<br> -SubTopic 10<br> -Section 50<br> -Paragraph 32<br> -Subparagraph (b)<br> -URI http://asc.fasb.org/extlink&amp;oid=123359005&amp;loc=d3e8933-108599<br><br>Reference 5: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 280<br> -SubTopic 10<br> -Section 50<br> -Paragraph 32<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=123359005&amp;loc=d3e8933-108599<br><br>Reference 6: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 606<br> -SubTopic 10<br> -Section 50<br> -Paragraph 4<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=123351226&amp;loc=SL49130543-203045<br><br>Reference 7: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 280<br> -SubTopic 10<br> -Section 50<br> -Paragraph 22<br> -Subparagraph (b)<br> -URI http://asc.fasb.org/extlink&amp;oid=123359005&amp;loc=d3e8736-108599<br><br>Reference 8: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 280<br> -SubTopic 10<br> -Section 50<br> -Paragraph 22<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=123359005&amp;loc=d3e8736-108599<br><br>Reference 9: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 280<br> -SubTopic 10<br> -Section 50<br> -Paragraph 42<br> -URI http://asc.fasb.org/extlink&amp;oid=123359005&amp;loc=d3e9054-108599<br><br>Reference 10: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 606<br> -SubTopic 10<br> -Section 50<br> -Paragraph 5<br> -URI http://asc.fasb.org/extlink&amp;oid=123351226&amp;loc=SL49130545-203045<br><br>Reference 11: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 924<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SAB Topic 11.L)<br> -URI http://asc.fasb.org/extlink&amp;oid=6472922&amp;loc=d3e499488-122856<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_StockIssuedDuringPeriodSharesNewIssues">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Number of new stock issued during the period.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 210<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.5-02(29))<br> -URI http://asc.fasb.org/extlink&amp;oid=120391452&amp;loc=d3e13212-122682<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 505<br> -SubTopic 10<br> -Section 50<br> -Paragraph 2<br> -URI http://asc.fasb.org/extlink&amp;oid=123467817&amp;loc=d3e21463-112644<br><br>Reference 3: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 505<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.3-04)<br> -URI http://asc.fasb.org/extlink&amp;oid=120397183&amp;loc=d3e187085-122770<br><br>Reference 4: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 210<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.5-02(28))<br> -URI http://asc.fasb.org/extlink&amp;oid=120391452&amp;loc=d3e13212-122682<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_StockIssuedDuringPeriodSharesNewIssues</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:sharesItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_srt_ProductOrServiceAxis=ions_LicensingAndOtherRoyaltiesMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">srt_ProductOrServiceAxis=ions_LicensingAndOtherRoyaltiesMember</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td></td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_srt_ProductOrServiceAxis=ions_ResearchAndDevelopmentRevenueUnderCollaborativeAgreementsMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">srt_ProductOrServiceAxis=ions_ResearchAndDevelopmentRevenueUnderCollaborativeAgreementsMember</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td></td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_TypeOfArrangementAxis=ions_NovartisCollaborationMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_TypeOfArrangementAxis=ions_NovartisCollaborationMember</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td></td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_ConcentrationRiskByBenchmarkAxis=us-gaap_RevenueFromContractWithCustomerMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ConcentrationRiskByBenchmarkAxis=us-gaap_RevenueFromContractWithCustomerMember</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td></td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_ConcentrationRiskByTypeAxis=us-gaap_CustomerConcentrationRiskMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ConcentrationRiskByTypeAxis=us-gaap_CustomerConcentrationRiskMember</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td></td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_srt_ProductOrServiceAxis=ions_ResearchAndDevelopmentServicesForPelacarsenMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">srt_ProductOrServiceAxis=ions_ResearchAndDevelopmentServicesForPelacarsenMember</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td></td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_srt_ProductOrServiceAxis=ions_ResearchAndDevelopmentServicesForOlezarsenMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">srt_ProductOrServiceAxis=ions_ResearchAndDevelopmentServicesForOlezarsenMember</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td></td>
</tr>
</table></div>
</div></td></tr>
</table>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">srt_ProductOrServiceAxis=ions_PelacarsenActivePharmaceuticalIngredientMember</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td></td>
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<tr>
<td><strong> Data Type:</strong></td>
<td>na</td>
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<tr>
<td><strong> Balance Type:</strong></td>
<td></td>
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<tr>
<td><strong> Period Type:</strong></td>
<td></td>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
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<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">srt_ProductOrServiceAxis=ions_OlezarsenActivePharmaceuticalIngredientMember</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td></td>
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<tr>
<td><strong> Data Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td></td>
</tr>
</table></div>
</div></td></tr>
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<DOCUMENT>
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<FILENAME>R76.htm
<DESCRIPTION>IDEA: XBRL DOCUMENT
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<span style="display: none;">v3.22.0.1</span><table class="report" border="0" cellspacing="2" id="idm139691007652696">
<tr>
<th class="tl" colspan="1" rowspan="2"><div style="width: 200px;"><strong>Collaborative Arrangements and Licensing Agreements, Roche (Details)<br> $ in Thousands</strong></div></th>
<th class="th" colspan="1">1 Months Ended</th>
<th class="th" colspan="2">3 Months Ended</th>
<th class="th" colspan="4">12 Months Ended</th>
<th class="th" colspan="1"></th>
</tr>
<tr>
<th class="th">
<div>Apr. 30, 2013 </div>
<div>USD ($) </div>
<div>PerformanceObligation</div>
</th>
<th class="th">
<div>Dec. 31, 2020 </div>
<div>USD ($)</div>
</th>
<th class="th">
<div>Dec. 31, 2018 </div>
<div>USD ($)</div>
</th>
<th class="th">
<div>Dec. 31, 2021 </div>
<div>USD ($) </div>
<div>Indication</div>
</th>
<th class="th">
<div>Dec. 31, 2020 </div>
<div>USD ($)</div>
</th>
<th class="th">
<div>Dec. 31, 2019 </div>
<div>USD ($)</div>
</th>
<th class="th">
<div>Dec. 31, 2017 </div>
<div>USD ($)</div>
</th>
<th class="th">
<div>Oct. 31, 2018 </div>
<div>USD ($) </div>
<div>PerformanceObligation</div>
</th>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CollaborativeArrangementAndLicensingAgreementAbstract', window );"><strong>Collaborative Arrangement and Licensing Agreement [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax', window );">Revenue</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 810,456<span></span>
</td>
<td class="nump">$ 729,264<span></span>
</td>
<td class="nump">$ 1,122,599<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_srt_ProductOrServiceAxis=ions_ResearchAndDevelopmentRevenueUnderCollaborativeAgreementsMember', window );">R&amp;D Revenue [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CollaborativeArrangementAndLicensingAgreementAbstract', window );"><strong>Collaborative Arrangement and Licensing Agreement [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax', window );">Revenue</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">468,061<span></span>
</td>
<td class="nump">364,565<span></span>
</td>
<td class="nump">$ 770,149<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_TypeOfArrangementAxis=ions_RocheCollaborationMember', window );">Roche [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CollaborativeArrangementAndLicensingAgreementAbstract', window );"><strong>Collaborative Arrangement and Licensing Agreement [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ContractWithCustomerLiability', window );">Deferred revenue</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 47,200<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 31,600<span></span>
</td>
<td class="nump">$ 47,200<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_TypeOfArrangementAxis=ions_RocheCollaborationMember', window );">Roche [Member] | Revenue [Member] | Strategic Partner [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CollaborativeArrangementAndLicensingAgreementAbstract', window );"><strong>Collaborative Arrangement and Licensing Agreement [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ConcentrationRiskPercentage1', window );">Concentration percentage</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">2.00%<span></span>
</td>
<td class="nump">1.00%<span></span>
</td>
<td class="nump">5.00%<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_TypeOfArrangementAxis=ions_RocheCollaborationMember', window );">Roche [Member] | R&amp;D Revenue [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CollaborativeArrangementAndLicensingAgreementAbstract', window );"><strong>Collaborative Arrangement and Licensing Agreement [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax', window );">Revenue</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 17,200<span></span>
</td>
<td class="nump">$ 5,900<span></span>
</td>
<td class="nump">$ 57,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_TypeOfArrangementAxis=ions_RocheCollaborationHuntingtonsDiseaseMember', window );">Huntington's Disease [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CollaborativeArrangementAndLicensingAgreementAbstract', window );"><strong>Collaborative Arrangement and Licensing Agreement [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_UpfrontPaymentReceived', window );">Upfront payment received</a></td>
<td class="nump">$ 30,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_MilestonePaymentsReceived', window );">Milestone payment received</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 3,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_MaximumAmountOfPaymentsReceivableForLicenseFeesAndMilestones', window );">Maximum amount of payments receivable for license fees and milestones</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">365,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_MaximumAmountOfPaymentsReceivableForDevelopmentMilestones', window );">Maximum amount of payments receivable for development milestones</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">70,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_MaximumAmountOfPaymentsReceivableForRegulatoryMilestones', window );">Maximum amount of payments receivable for regulatory milestones</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">170,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_MaximumAmountOfPaymentsReceivableForSalesMilestones', window );">Maximum amount of payments receivable for sales milestones</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">80,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_MaximumAmountOfPaymentReceivableForEachAdditionalMedicineDeveloped', window );">Maximum amount of payment receivable for each additional medicine developed</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">136,500<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CumulativePaymentsReceived', window );">Cumulative payments received</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">150,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_NextPotentialPayment', window );">Next prospective payment</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">15,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_RevenueFromContractWithCustomerNumberOfSeparatePerformanceObligations', window );">Number of separate performance obligations | PerformanceObligation</a></td>
<td class="nump">1<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_RevenueFromContractWithCustomerTransactionPrice', window );">Transaction price</a></td>
<td class="nump">$ 30,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax', window );">Revenue</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 35,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_TypeOfArrangementAxis=ions_RocheCollaborationIonisFbLForComplementMediatedDiseasesMember', window );">IONIS-FB-L for Complement-Mediated Diseases [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CollaborativeArrangementAndLicensingAgreementAbstract', window );"><strong>Collaborative Arrangement and Licensing Agreement [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_UpfrontPaymentReceived', window );">Upfront payment received</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 75,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_MinimumAmountOfPaymentsReceivableForLicenseFeesAndMilestonePayments', window );">Minimum amount of payments receivable for license fees and milestones</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">680,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CumulativePaymentsReceived', window );">Cumulative payments received</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">75,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_NextPotentialPayment', window );">Next prospective payment</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 20,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_RevenueFromContractWithCustomerNumberOfSeparatePerformanceObligations', window );">Number of separate performance obligations | PerformanceObligation</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">1<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_RevenueFromContractWithCustomerTransactionPrice', window );">Transaction price</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 75,000<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_NumberOfDiseaseIndications', window );">Number of disease indications | Indication</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">2<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_RoyaltyPercentageReceivedOnNetSalesOfMedicine', window );">Royalty percentage received on net sales of medicine</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">20.00%<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax', window );">Revenue</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="num">$ (9,200)<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_TypeOfArrangementAxis=ions_RocheCollaborationIonisFbLForComplementMediatedDiseasesMember', window );">IONIS-FB-L for Complement-Mediated Diseases [Member] | GA [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CollaborativeArrangementAndLicensingAgreementAbstract', window );"><strong>Collaborative Arrangement and Licensing Agreement [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_NumberOfDiseaseIndications', window );">Number of disease indications | Indication</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">1<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_TypeOfArrangementAxis=ions_RocheCollaborationIonisFbLForComplementMediatedDiseasesMember', window );">IONIS-FB-L for Complement-Mediated Diseases [Member] | IgA Nephropathy [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CollaborativeArrangementAndLicensingAgreementAbstract', window );"><strong>Collaborative Arrangement and Licensing Agreement [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_NumberOfDiseaseIndications', window );">Number of disease indications | Indication</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">1<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
</table>
<div style="display: none;">
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_CollaborativeArrangementAndLicensingAgreementAbstract">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_CollaborativeArrangementAndLicensingAgreementAbstract</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:stringItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_CumulativePaymentsReceived">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Cumulative amount of payments received under the collaboration agreement as of the end of the reporting period.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_CumulativePaymentsReceived</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_MaximumAmountOfPaymentReceivableForEachAdditionalMedicineDeveloped">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The maximum amount of payments receivable for each additional medicine developed under the collaboration agreement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_MaximumAmountOfPaymentReceivableForEachAdditionalMedicineDeveloped</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_MaximumAmountOfPaymentsReceivableForDevelopmentMilestones">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The maximum amount of payments receivable for development milestones under the collaboration agreement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_MaximumAmountOfPaymentsReceivableForDevelopmentMilestones</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_MaximumAmountOfPaymentsReceivableForLicenseFeesAndMilestones">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Maximum amount of payments receivable for license fees and milestone payments under the collaboration agreement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_MaximumAmountOfPaymentsReceivableForLicenseFeesAndMilestones</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_MaximumAmountOfPaymentsReceivableForRegulatoryMilestones">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The maximum amount of payments receivable for regulatory milestones under the collaboration agreement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_MaximumAmountOfPaymentsReceivableForRegulatoryMilestones</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_MaximumAmountOfPaymentsReceivableForSalesMilestones">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The maximum amount of payments receivable for sales milestones under the collaboration agreement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_MaximumAmountOfPaymentsReceivableForSalesMilestones</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_MilestonePaymentsReceived">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The amount of milestone payments received during the period under the collaboration agreement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_MilestonePaymentsReceived</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_MinimumAmountOfPaymentsReceivableForLicenseFeesAndMilestonePayments">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The minimum amount of payments receivable for license fees and milestone payments under the collaboration agreement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_MinimumAmountOfPaymentsReceivableForLicenseFeesAndMilestonePayments</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_NextPotentialPayment">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The next potential payment to be earned under the collaboration agreement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_NextPotentialPayment</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_NumberOfDiseaseIndications">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Number of disease indications for which studies are currently being conducted under the collaboration agreement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_NumberOfDiseaseIndications</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:integerItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_RevenueFromContractWithCustomerNumberOfSeparatePerformanceObligations">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The number of separate performance obligations under the collaboration agreement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_RevenueFromContractWithCustomerNumberOfSeparatePerformanceObligations</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:integerItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_RevenueFromContractWithCustomerTransactionPrice">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The amount of consideration the Company earned or is eligible to earn under the collaboration agreement, including any variable consideration.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_RevenueFromContractWithCustomerTransactionPrice</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_RoyaltyPercentageReceivedOnNetSalesOfMedicine">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Royalty percentage received on the net sales of a medicine by a collaboration partner under the collaboration agreement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_RoyaltyPercentageReceivedOnNetSalesOfMedicine</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>dtr-types:percentItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_UpfrontPaymentReceived">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The amount of upfront payments received during the period under the collaboration agreement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_UpfrontPaymentReceived</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_ConcentrationRiskPercentage1">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>For an entity that discloses a concentration risk in relation to quantitative amount, which serves as the "benchmark" (or denominator) in the equation, this concept represents the concentration percentage derived from the division.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 280<br> -SubTopic 10<br> -Section 50<br> -Paragraph 42<br> -URI http://asc.fasb.org/extlink&amp;oid=123359005&amp;loc=d3e9054-108599<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 275<br> -SubTopic 10<br> -Section 50<br> -Paragraph 18<br> -URI http://asc.fasb.org/extlink&amp;oid=99393423&amp;loc=d3e6351-108592<br><br>Reference 3: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 825<br> -SubTopic 10<br> -Section 50<br> -Paragraph 20<br> -URI http://asc.fasb.org/extlink&amp;oid=123594938&amp;loc=d3e13531-108611<br><br>Reference 4: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 825<br> -SubTopic 10<br> -Section 50<br> -Paragraph 21<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=123594938&amp;loc=d3e13537-108611<br><br>Reference 5: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 275<br> -SubTopic 10<br> -Section 50<br> -Paragraph 20<br> -URI http://asc.fasb.org/extlink&amp;oid=99393423&amp;loc=d3e6404-108592<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ConcentrationRiskPercentage1</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>dtr-types:percentItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_ContractWithCustomerLiability">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of obligation to transfer good or service to customer for which consideration has been received or is receivable.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 606<br> -SubTopic 10<br> -Section 45<br> -Paragraph 1<br> -URI http://asc.fasb.org/extlink&amp;oid=123360276&amp;loc=SL49130531-203044<br><br>Reference 2: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 606<br> -SubTopic 10<br> -Section 50<br> -Paragraph 8<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=123351226&amp;loc=SL49130549-203045<br><br>Reference 3: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 606<br> -SubTopic 10<br> -Section 45<br> -Paragraph 2<br> -URI http://asc.fasb.org/extlink&amp;oid=123360276&amp;loc=SL49130532-203044<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ContractWithCustomerLiability</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount, excluding tax collected from customer, of revenue from satisfaction of performance obligation by transferring promised good or service to customer. Tax collected from customer is tax assessed by governmental authority that is both imposed on and concurrent with specific revenue-producing transaction, including, but not limited to, sales, use, value added and excise.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 280<br> -SubTopic 10<br> -Section 50<br> -Paragraph 30<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=123359005&amp;loc=d3e8906-108599<br><br>Reference 2: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 280<br> -SubTopic 10<br> -Section 50<br> -Paragraph 40<br> -URI http://asc.fasb.org/extlink&amp;oid=123359005&amp;loc=d3e9031-108599<br><br>Reference 3: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 280<br> -SubTopic 10<br> -Section 50<br> -Paragraph 41<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=123359005&amp;loc=d3e9038-108599<br><br>Reference 4: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 280<br> -SubTopic 10<br> -Section 50<br> -Paragraph 32<br> -Subparagraph (b)<br> -URI http://asc.fasb.org/extlink&amp;oid=123359005&amp;loc=d3e8933-108599<br><br>Reference 5: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 280<br> -SubTopic 10<br> -Section 50<br> -Paragraph 32<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=123359005&amp;loc=d3e8933-108599<br><br>Reference 6: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 606<br> -SubTopic 10<br> -Section 50<br> -Paragraph 4<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=123351226&amp;loc=SL49130543-203045<br><br>Reference 7: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 280<br> -SubTopic 10<br> -Section 50<br> -Paragraph 22<br> -Subparagraph (b)<br> -URI http://asc.fasb.org/extlink&amp;oid=123359005&amp;loc=d3e8736-108599<br><br>Reference 8: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 280<br> -SubTopic 10<br> -Section 50<br> -Paragraph 22<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=123359005&amp;loc=d3e8736-108599<br><br>Reference 9: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 280<br> -SubTopic 10<br> -Section 50<br> -Paragraph 42<br> -URI http://asc.fasb.org/extlink&amp;oid=123359005&amp;loc=d3e9054-108599<br><br>Reference 10: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 606<br> -SubTopic 10<br> -Section 50<br> -Paragraph 5<br> -URI http://asc.fasb.org/extlink&amp;oid=123351226&amp;loc=SL49130545-203045<br><br>Reference 11: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 924<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SAB Topic 11.L)<br> -URI http://asc.fasb.org/extlink&amp;oid=6472922&amp;loc=d3e499488-122856<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_srt_ProductOrServiceAxis=ions_ResearchAndDevelopmentRevenueUnderCollaborativeAgreementsMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">srt_ProductOrServiceAxis=ions_ResearchAndDevelopmentRevenueUnderCollaborativeAgreementsMember</td>
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<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
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<td><strong> Data Type:</strong></td>
<td>na</td>
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<tr>
<td><strong> Balance Type:</strong></td>
<td></td>
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<tr>
<td><strong> Period Type:</strong></td>
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<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_TypeOfArrangementAxis=ions_RocheCollaborationMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_TypeOfArrangementAxis=ions_RocheCollaborationMember</td>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ConcentrationRiskByBenchmarkAxis=us-gaap_RevenueFromContractWithCustomerMember</td>
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<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ConcentrationRiskByTypeAxis=us-gaap_CustomerConcentrationRiskMember</td>
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<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_TypeOfArrangementAxis=ions_RocheCollaborationHuntingtonsDiseaseMember</td>
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<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
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<td></td>
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<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_TypeOfArrangementAxis=ions_RocheCollaborationIonisFbLForComplementMediatedDiseasesMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_TypeOfArrangementAxis=ions_RocheCollaborationIonisFbLForComplementMediatedDiseasesMember</td>
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<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">srt_ProductOrServiceAxis=ions_GeographicAtrophyMember</td>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
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<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">srt_ProductOrServiceAxis=ions_ImmunoglobulinANephropathyMember</td>
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<html>
<head>
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<th class="tl" colspan="1" rowspan="2"><div style="width: 200px;"><strong>Collaborative Arrangements and Licensing Agreements, PTC Therapeutics (Details)<br></strong></div></th>
<th class="th" colspan="1">12 Months Ended</th>
</tr>
<tr><th class="th"><div>Dec. 31, 2021</div></th></tr>
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<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_TypeOfArrangementAxis=ions_PtcTherapeuticsCollaborationMember', window );">PTC Therapeutics [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
</tr>
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<td class="text">&#160;<span></span>
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<tr class="re">
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<td class="nump">20.00%<span></span>
</td>
</tr>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Royalty percentage received on the net sales of each medicine from the collaboration partner under the collaboration agreement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
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<td><strong> Name:</strong></td>
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<TEXT>
<html>
<head>
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<link rel="stylesheet" type="text/css" href="report.css">
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<span style="display: none;">v3.22.0.1</span><table class="report" border="0" cellspacing="2" id="idm139691003286456">
<tr>
<th class="tl" colspan="1" rowspan="2"><div style="width: 200px;"><strong>Collaborative Arrangements and Licensing Agreements, Bicycle License Agreement (Details) - USD ($)<br> $ in Millions</strong></div></th>
<th class="th" colspan="1">1 Months Ended</th>
<th class="th" colspan="3">12 Months Ended</th>
</tr>
<tr>
<th class="th"><div>Jul. 31, 2021</div></th>
<th class="th"><div>Dec. 31, 2021</div></th>
<th class="th"><div>Dec. 31, 2020</div></th>
<th class="th"><div>Dec. 31, 2019</div></th>
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<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ResearchAndDevelopmentExpense', window );">R&amp;D expense</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 638.2<span></span>
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<td class="nump">$ 531.0<span></span>
</td>
<td class="nump">$ 461.5<span></span>
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</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_TypeOfArrangementAxis=ions_BicycleCollaborationMember', window );">Bicycle License Agreement [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CollaborativeArrangementAndLicensingAgreementAbstract', window );"><strong>Collaborative Arrangement and Licensing Agreement [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
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<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_PaymentsMadeUnderCollaborationAgreement', window );">Payment of license fee</a></td>
<td class="nump">$ 42.0<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
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<td class="text">&#160;<span></span>
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<td class="text">1 year<span></span>
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<td class="text">&#160;<span></span>
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<td class="text">&#160;<span></span>
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<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 7.2<span></span>
</td>
<td class="text">&#160;<span></span>
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<td class="text">&#160;<span></span>
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<tr class="ro">
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<td class="text">&#160;<span></span>
</td>
<td class="nump">34.8<span></span>
</td>
<td class="text">&#160;<span></span>
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<td class="text">&#160;<span></span>
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<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CumulativePaymentsMade', window );">Cumulative payments made</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 46.6<span></span>
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<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
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<div style="display: none;">
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_CollaborativeArrangementAndLicensingAgreementAbstract</td>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Cumulative amount of payments made under the collaboration agreement as of the end of the reporting period.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
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<td style="white-space:nowrap;">ions_CumulativePaymentsMade</td>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Acquisition of investment in equity security measured at fair value with change in fair value recognized in net income (FV-NI).</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Period after completion of initial public offering by an equity investee and restriction to sell equity holding in the investee, in 'PnYnMnDTnHnMnS' format, for example, 'P1Y5M13D' represents reported fact of one year, five months, and thirteen days.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Represents the cash outflow for payments made under the collaboration agreement for the reimbursement of support received in connection with the Company's Huntington's disease program.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The aggregate costs incurred (1) in a planned search or critical investigation aimed at discovery of new knowledge with the hope that such knowledge will be useful in developing a new product or service, a new process or technique, or in bringing about a significant improvement to an existing product or process; or (2) to translate research findings or other knowledge into a plan or design for a new product or process or for a significant improvement to an existing product or process whether intended for sale or the entity's use, during the reporting period charged to research and development projects, including the costs of developing computer software up to the point in time of achieving technological feasibility, and costs allocated in accounting for a business combination to in-process projects deemed to have no alternative future use.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2009/role/commonPracticeRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 912<br> -SubTopic 730<br> -Section 25<br> -Paragraph 1<br> -URI http://asc.fasb.org/extlink&amp;oid=6472174&amp;loc=d3e58812-109433<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 985<br> -SubTopic 20<br> -Section 50<br> -Paragraph 1<br> -URI http://asc.fasb.org/extlink&amp;oid=6501960&amp;loc=d3e128462-111756<br><br>Reference 3: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 730<br> -SubTopic 10<br> -Section 50<br> -Paragraph 1<br> -URI http://asc.fasb.org/extlink&amp;oid=6420194&amp;loc=d3e21568-108373<br></p></div>
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<span style="display: none;">v3.22.0.1</span><table class="report" border="0" cellspacing="2" id="idm139690996898136">
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<th class="tl" colspan="1" rowspan="2"><div style="width: 200px;"><strong>Collaborative Arrangements and Licensing Agreements, Alnylam Pharmaceuticals, Inc. (Details) - USD ($)<br> $ in Thousands</strong></div></th>
<th class="th" colspan="1">3 Months Ended</th>
<th class="th" colspan="3">12 Months Ended</th>
</tr>
<tr>
<th class="th"><div>Dec. 31, 2020</div></th>
<th class="th"><div>Dec. 31, 2021</div></th>
<th class="th"><div>Dec. 31, 2020</div></th>
<th class="th"><div>Dec. 31, 2019</div></th>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CollaborativeArrangementAndLicensingAgreementAbstract', window );"><strong>Collaborative Arrangement and Licensing Agreement [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax', window );">Revenue</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 810,456<span></span>
</td>
<td class="nump">$ 729,264<span></span>
</td>
<td class="nump">$ 1,122,599<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_srt_ProductOrServiceAxis=ions_ResearchAndDevelopmentRevenueUnderCollaborativeAgreementsMember', window );">R&amp;D Revenue [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CollaborativeArrangementAndLicensingAgreementAbstract', window );"><strong>Collaborative Arrangement and Licensing Agreement [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
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<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax', window );">Revenue</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">468,061<span></span>
</td>
<td class="nump">364,565<span></span>
</td>
<td class="nump">$ 770,149<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_TypeOfArrangementAxis=ions_AlnylamCollaborationMember', window );">Alnylam [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CollaborativeArrangementAndLicensingAgreementAbstract', window );"><strong>Collaborative Arrangement and Licensing Agreement [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_LitigationSettlementAmountAwardedFromOtherParty', window );">Award from arbitration panel</a></td>
<td class="nump">$ 41,200<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax', window );">Revenue</a></td>
<td class="nump">41,200<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ContractWithCustomerLiability', window );">Deferred revenue</a></td>
<td class="nump">$ 0<span></span>
</td>
<td class="nump">$ 0<span></span>
</td>
<td class="nump">$ 0<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_TypeOfArrangementAxis=ions_AlnylamCollaborationMember', window );">Alnylam [Member] | Revenue [Member] | Strategic Partner [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CollaborativeArrangementAndLicensingAgreementAbstract', window );"><strong>Collaborative Arrangement and Licensing Agreement [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ConcentrationRiskPercentage1', window );">Concentration percentage</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">0.00%<span></span>
</td>
<td class="nump">7.00%<span></span>
</td>
<td class="nump">2.00%<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_TypeOfArrangementAxis=ions_AlnylamCollaborationMember', window );">Alnylam [Member] | R&amp;D Revenue [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CollaborativeArrangementAndLicensingAgreementAbstract', window );"><strong>Collaborative Arrangement and Licensing Agreement [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax', window );">Revenue</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 0<span></span>
</td>
<td class="nump">$ 47,900<span></span>
</td>
<td class="nump">$ 24,100<span></span>
</td>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>For an entity that discloses a concentration risk in relation to quantitative amount, which serves as the "benchmark" (or denominator) in the equation, this concept represents the concentration percentage derived from the division.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 280<br> -SubTopic 10<br> -Section 50<br> -Paragraph 42<br> -URI http://asc.fasb.org/extlink&amp;oid=123359005&amp;loc=d3e9054-108599<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 275<br> -SubTopic 10<br> -Section 50<br> -Paragraph 18<br> -URI http://asc.fasb.org/extlink&amp;oid=99393423&amp;loc=d3e6351-108592<br><br>Reference 3: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 825<br> -SubTopic 10<br> -Section 50<br> -Paragraph 20<br> -URI http://asc.fasb.org/extlink&amp;oid=123594938&amp;loc=d3e13531-108611<br><br>Reference 4: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 825<br> -SubTopic 10<br> -Section 50<br> -Paragraph 21<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=123594938&amp;loc=d3e13537-108611<br><br>Reference 5: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 275<br> -SubTopic 10<br> -Section 50<br> -Paragraph 20<br> -URI http://asc.fasb.org/extlink&amp;oid=99393423&amp;loc=d3e6404-108592<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
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<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ConcentrationRiskPercentage1</td>
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<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of obligation to transfer good or service to customer for which consideration has been received or is receivable.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 606<br> -SubTopic 10<br> -Section 45<br> -Paragraph 1<br> -URI http://asc.fasb.org/extlink&amp;oid=123360276&amp;loc=SL49130531-203044<br><br>Reference 2: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 606<br> -SubTopic 10<br> -Section 50<br> -Paragraph 8<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=123351226&amp;loc=SL49130549-203045<br><br>Reference 3: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 606<br> -SubTopic 10<br> -Section 45<br> -Paragraph 2<br> -URI http://asc.fasb.org/extlink&amp;oid=123360276&amp;loc=SL49130532-203044<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ContractWithCustomerLiability</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_LitigationSettlementAmountAwardedFromOtherParty">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount awarded from other party in judgment or settlement of litigation.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_LitigationSettlementAmountAwardedFromOtherParty</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount, excluding tax collected from customer, of revenue from satisfaction of performance obligation by transferring promised good or service to customer. Tax collected from customer is tax assessed by governmental authority that is both imposed on and concurrent with specific revenue-producing transaction, including, but not limited to, sales, use, value added and excise.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 280<br> -SubTopic 10<br> -Section 50<br> -Paragraph 30<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=123359005&amp;loc=d3e8906-108599<br><br>Reference 2: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 280<br> -SubTopic 10<br> -Section 50<br> -Paragraph 40<br> -URI http://asc.fasb.org/extlink&amp;oid=123359005&amp;loc=d3e9031-108599<br><br>Reference 3: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 280<br> -SubTopic 10<br> -Section 50<br> -Paragraph 41<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=123359005&amp;loc=d3e9038-108599<br><br>Reference 4: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 280<br> -SubTopic 10<br> -Section 50<br> -Paragraph 32<br> -Subparagraph (b)<br> -URI http://asc.fasb.org/extlink&amp;oid=123359005&amp;loc=d3e8933-108599<br><br>Reference 5: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 280<br> -SubTopic 10<br> -Section 50<br> -Paragraph 32<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=123359005&amp;loc=d3e8933-108599<br><br>Reference 6: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 606<br> -SubTopic 10<br> -Section 50<br> -Paragraph 4<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=123351226&amp;loc=SL49130543-203045<br><br>Reference 7: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 280<br> -SubTopic 10<br> -Section 50<br> -Paragraph 22<br> -Subparagraph (b)<br> -URI http://asc.fasb.org/extlink&amp;oid=123359005&amp;loc=d3e8736-108599<br><br>Reference 8: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 280<br> -SubTopic 10<br> -Section 50<br> -Paragraph 22<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=123359005&amp;loc=d3e8736-108599<br><br>Reference 9: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 280<br> -SubTopic 10<br> -Section 50<br> -Paragraph 42<br> -URI http://asc.fasb.org/extlink&amp;oid=123359005&amp;loc=d3e9054-108599<br><br>Reference 10: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 606<br> -SubTopic 10<br> -Section 50<br> -Paragraph 5<br> -URI http://asc.fasb.org/extlink&amp;oid=123351226&amp;loc=SL49130545-203045<br><br>Reference 11: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 924<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SAB Topic 11.L)<br> -URI http://asc.fasb.org/extlink&amp;oid=6472922&amp;loc=d3e499488-122856<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_srt_ProductOrServiceAxis=ions_ResearchAndDevelopmentRevenueUnderCollaborativeAgreementsMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">srt_ProductOrServiceAxis=ions_ResearchAndDevelopmentRevenueUnderCollaborativeAgreementsMember</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td></td>
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<tr>
<td><strong> Data Type:</strong></td>
<td>na</td>
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<td><strong> Balance Type:</strong></td>
<td></td>
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<tr>
<td><strong> Period Type:</strong></td>
<td></td>
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</table></div>
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<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_TypeOfArrangementAxis=ions_AlnylamCollaborationMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_TypeOfArrangementAxis=ions_AlnylamCollaborationMember</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td></td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_ConcentrationRiskByBenchmarkAxis=us-gaap_RevenueFromContractWithCustomerMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ConcentrationRiskByBenchmarkAxis=us-gaap_RevenueFromContractWithCustomerMember</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td></td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_ConcentrationRiskByTypeAxis=us-gaap_CustomerConcentrationRiskMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ConcentrationRiskByTypeAxis=us-gaap_CustomerConcentrationRiskMember</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td></td>
</tr>
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<span style="display: none;">v3.22.0.1</span><table class="report" border="0" cellspacing="2" id="idm139691009292088">
<tr>
<th class="tl" colspan="1" rowspan="2"><div style="width: 200px;"><strong>Akcea Merger (Details) - USD ($)<br> $ / shares in Units, shares in Millions, $ in Millions</strong></div></th>
<th class="th" colspan="1">1 Months Ended</th>
<th class="th" colspan="1">3 Months Ended</th>
<th class="th" colspan="2">12 Months Ended</th>
<th class="th" colspan="1">24 Months Ended</th>
<th class="th" colspan="1"></th>
</tr>
<tr>
<th class="th"><div>Oct. 31, 2020</div></th>
<th class="th"><div>Dec. 31, 2020</div></th>
<th class="th"><div>Dec. 31, 2021</div></th>
<th class="th"><div>Dec. 31, 2020</div></th>
<th class="th"><div>Dec. 31, 2021</div></th>
<th class="th"><div>Sep. 30, 2020</div></th>
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<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RestructuringCostAndReserveAxis=ions_AkceaMergerMember', window );">Akcea Merger [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RestructuringCostsAbstract', window );"><strong>Severance and Retention Costs [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
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<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RestructuringReserve', window );">Beginning balance</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 14.7<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RestructuringCharges', window );">Amount expensed during the year</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">13.5<span></span>
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<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
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<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RestructuringReserveAccrualAdjustment1', window );">Reserve adjustments during the year</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="num">(1.8)<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rou">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_RestructuringReserveRestructuringChargesNetOfReserveAdjustments', window );">Net amount expensed during the year</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">11.7<span></span>
</td>
<td class="nump">$ 15.3<span></span>
</td>
<td class="nump">$ 27.0<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
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<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_PaymentsForRestructuring', window );">Amounts paid during the year</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="num">(26.4)<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RestructuringReserve', window );">Ending balance</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 14.7<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">14.7<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RestructuringCostAndReserveAxis=ions_AkceaMergerMember', window );">Akcea Merger [Member] | Accrued Compensation [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RestructuringCostsAbstract', window );"><strong>Severance and Retention Costs [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RestructuringReserve', window );">Ending balance</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">0.0<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 0.0<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RestructuringCostAndReserveAxis=ions_AkceaMergerMember', window );">Akcea Merger [Member] | R&amp;D Expenses [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RestructuringCostsAbstract', window );"><strong>Severance and Retention Costs [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rou">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_RestructuringReserveRestructuringChargesNetOfReserveAdjustments', window );">Net amount expensed during the year</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">5.1<span></span>
</td>
<td class="nump">3.9<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RestructuringCostAndReserveAxis=ions_AkceaMergerMember', window );">Akcea Merger [Member] | SG&amp;A Expenses [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RestructuringCostsAbstract', window );"><strong>Severance and Retention Costs [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="reu">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_RestructuringReserveRestructuringChargesNetOfReserveAdjustments', window );">Net amount expensed during the year</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 6.6<span></span>
</td>
<td class="nump">11.4<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_srt_OwnershipAxis=ions_AkceaTherapeuticsIncMember', window );">Akcea [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ConsolidationLessThanWhollyOwnedSubsidiaryParentOwnershipInterestChangesNetAbstract', window );"><strong>Akcea Merger [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_MinorityInterestOwnershipPercentageByParent', window );">Percentage ownership</a></td>
<td class="nump">100.00%<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">100.00%<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">100.00%<span></span>
</td>
<td class="nump">76.00%<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_ConsolidationLessThanWhollyOwnedSubsidiaryParentOwnershipInterestChangesPurchaseOfInterestByParentShares', window );">Shares purchased (in shares)</a></td>
<td class="nump">24.8<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_ConsolidationLessThanWhollyOwnedSubsidiaryParentOwnershipInterestChangesPurchaseOfInterestByParentPricePerShare', window );">Purchase price per share (in dollars per share)</a></td>
<td class="nump">$ 18.15<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ConsolidationLessThanWhollyOwnedSubsidiaryParentOwnershipInterestChangesPurchaseOfInterestByParent', window );">Purchase price</a></td>
<td class="nump">$ 450.6<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_BusinessAcquisitionCostOfAcquiredEntityTransactionCosts', window );">Direct transaction costs</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 40.6<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 40.6<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CashPurchasePriceOfEquityAwards', window );">Cash purchase price of equity awards (in dollars per share)</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 18.15<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_PaymentsForCancelledEquityAwards', window );">Payments for cancelled equity awards</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 53.4<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_EmployeeServiceShareBasedCompensationNonvestedAwardsTotalCompensationCostNotYetRecognizedShareBasedAwardsOtherThanOptions', window );">Unrecognized compensation cost related to non-vested units</a></td>
<td class="nump">$ 59.3<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
</table>
<div style="display: none;">
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_CashPurchasePriceOfEquityAwards">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Cash purchase price for each equity award held, including stock options and restricted stock units (RSUs).</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_CashPurchasePriceOfEquityAwards</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>dtr-types:perShareItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_ConsolidationLessThanWhollyOwnedSubsidiaryParentOwnershipInterestChangesPurchaseOfInterestByParentPricePerShare">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Per share amount paid for the shares of the subsidiary purchased by the parent during the period, thereby effecting a change in total (consolidated) equity attributable to the parent.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_ConsolidationLessThanWhollyOwnedSubsidiaryParentOwnershipInterestChangesPurchaseOfInterestByParentPricePerShare</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>dtr-types:perShareItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_ConsolidationLessThanWhollyOwnedSubsidiaryParentOwnershipInterestChangesPurchaseOfInterestByParentShares">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Number of shares of the subsidiary purchased by the parent during the period, thereby effecting a change in total (consolidated) equity attributable to the parent.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_ConsolidationLessThanWhollyOwnedSubsidiaryParentOwnershipInterestChangesPurchaseOfInterestByParentShares</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:sharesItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_PaymentsForCancelledEquityAwards">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The aggregate amount paid by the entity to cancel subsidiary's outstanding equity awards.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_PaymentsForCancelledEquityAwards</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_RestructuringReserveRestructuringChargesNetOfReserveAdjustments">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of expenses associated with exit or disposal activities pursuant to an authorized plan, net of adjustments to a previously accrued restructuring liability. Excludes expenses related to a discontinued operation or an asset retirement obligation.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_RestructuringReserveRestructuringChargesNetOfReserveAdjustments</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_BusinessAcquisitionCostOfAcquiredEntityTransactionCosts">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of direct costs of the business combination including legal, accounting, and other costs incurred to consummate the business acquisition.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_BusinessAcquisitionCostOfAcquiredEntityTransactionCosts</td>
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<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_ConsolidationLessThanWhollyOwnedSubsidiaryParentOwnershipInterestChangesNetAbstract">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ConsolidationLessThanWhollyOwnedSubsidiaryParentOwnershipInterestChangesNetAbstract</td>
</tr>
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<td><strong> Data Type:</strong></td>
<td>xbrli:stringItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_ConsolidationLessThanWhollyOwnedSubsidiaryParentOwnershipInterestChangesPurchaseOfInterestByParent">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Represents the purchase by the parent of an additional equity interest in a subsidiary during the period, thereby effecting a change in total (consolidated) equity attributable to the parent. The purchase of the additional equity interest represented by this element increases the parent's controlling interest in the subsidiary.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 505<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -URI http://asc.fasb.org/extlink&amp;oid=120397183&amp;loc=d3e187085-122770<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 810<br> -SubTopic 10<br> -Section 50<br> -Paragraph 1A<br> -Subparagraph (d)<br> -URI http://asc.fasb.org/extlink&amp;oid=109239629&amp;loc=SL4573702-111684<br><br>Reference 3: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 810<br> -SubTopic 10<br> -Section 55<br> -Paragraph 4M<br> -URI http://asc.fasb.org/extlink&amp;oid=120409616&amp;loc=SL4591554-111686<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ConsolidationLessThanWhollyOwnedSubsidiaryParentOwnershipInterestChangesPurchaseOfInterestByParent</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_EmployeeServiceShareBasedCompensationNonvestedAwardsTotalCompensationCostNotYetRecognizedShareBasedAwardsOtherThanOptions">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of cost to be recognized for nonvested award under share-based payment arrangement. Excludes share and unit options.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 718<br> -SubTopic 10<br> -Section 50<br> -Paragraph 2<br> -Subparagraph (i)<br> -URI http://asc.fasb.org/extlink&amp;oid=120381028&amp;loc=d3e5070-113901<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_EmployeeServiceShareBasedCompensationNonvestedAwardsTotalCompensationCostNotYetRecognizedShareBasedAwardsOtherThanOptions</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
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<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The parent entity's interest in net assets of the subsidiary, expressed as a percentage.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_MinorityInterestOwnershipPercentageByParent</td>
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<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
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<tr>
<td><strong> Data Type:</strong></td>
<td>dtr-types:percentItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
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<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
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</table></div>
</div></td></tr>
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<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_PaymentsForRestructuring">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of cash payments made as the result of exit or disposal activities. Excludes payments associated with a discontinued operation or an asset retirement obligation.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 420<br> -SubTopic 10<br> -Section 50<br> -Paragraph 1<br> -Subparagraph (b)(2)<br> -URI http://asc.fasb.org/extlink&amp;oid=6394359&amp;loc=d3e17939-110869<br><br>Reference 2: http://www.xbrl.org/2009/role/commonPracticeRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 230<br> -SubTopic 10<br> -Section 45<br> -Paragraph 17<br> -Subparagraph (f)<br> -URI http://asc.fasb.org/extlink&amp;oid=123570139&amp;loc=d3e3367-108585<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_PaymentsForRestructuring</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_RestructuringCharges">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of expenses associated with exit or disposal activities pursuant to an authorized plan. Excludes expenses related to a discontinued operation or an asset retirement obligation.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2009/role/commonPracticeRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 420<br> -SubTopic 10<br> -Section 45<br> -Paragraph 3<br> -URI http://asc.fasb.org/extlink&amp;oid=109237686&amp;loc=d3e17752-110868<br><br>Reference 2: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 420<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SAB Topic 5.P.3)<br> -URI http://asc.fasb.org/extlink&amp;oid=115931487&amp;loc=d3e140864-122747<br><br>Reference 3: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 230<br> -SubTopic 10<br> -Section 45<br> -Paragraph 28<br> -Subparagraph (b)<br> -URI http://asc.fasb.org/extlink&amp;oid=123570139&amp;loc=d3e3602-108585<br><br>Reference 4: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 420<br> -SubTopic 10<br> -Section S99<br> -Paragraph 2<br> -Subparagraph (SAB Topic 5.P.4(b)(1))<br> -URI http://asc.fasb.org/extlink&amp;oid=115931487&amp;loc=d3e140904-122747<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_RestructuringCharges</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_RestructuringCostsAbstract">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_RestructuringCostsAbstract</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
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<td><strong> Data Type:</strong></td>
<td>xbrli:stringItemType</td>
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<td><strong> Balance Type:</strong></td>
<td>na</td>
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<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_RestructuringReserve">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Carrying amount (including both current and noncurrent portions of the accrual) as of the balance sheet date pertaining to a specified type of cost associated with exit from or disposal of business activities or restructuring pursuant to a duly authorized plan.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 420<br> -SubTopic 10<br> -Section 50<br> -Paragraph 1<br> -Subparagraph (b)(2)<br> -URI http://asc.fasb.org/extlink&amp;oid=6394359&amp;loc=d3e17939-110869<br><br>Reference 2: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 420<br> -SubTopic 10<br> -Section S99<br> -Paragraph 2<br> -Subparagraph (SAB TOPIC 5.P.4(b)(2))<br> -URI http://asc.fasb.org/extlink&amp;oid=115931487&amp;loc=d3e140904-122747<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_RestructuringReserve</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
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<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
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<td><strong> Balance Type:</strong></td>
<td>credit</td>
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<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
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</div></td></tr>
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<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_RestructuringReserveAccrualAdjustment1">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of expense (reversal of expense) which increases (decreases) the restructuring reserve from an adjustment to a previously accrued restructuring liability.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 420<br> -SubTopic 10<br> -Section S99<br> -Paragraph 2<br> -Subparagraph (SAB Topic 5.P.4(b)(2))<br> -URI http://asc.fasb.org/extlink&amp;oid=115931487&amp;loc=d3e140904-122747<br><br>Reference 2: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 420<br> -SubTopic 10<br> -Section 50<br> -Paragraph 1<br> -Subparagraph (b)(2)<br> -URI http://asc.fasb.org/extlink&amp;oid=6394359&amp;loc=d3e17939-110869<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_RestructuringReserveAccrualAdjustment1</td>
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<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
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<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
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<td><strong> Balance Type:</strong></td>
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<td><strong> Period Type:</strong></td>
<td>duration</td>
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</table></div>
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<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_RestructuringCostAndReserveAxis=ions_AkceaMergerMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_RestructuringCostAndReserveAxis=ions_AkceaMergerMember</td>
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<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
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<td><strong> Data Type:</strong></td>
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<td><strong> Balance Type:</strong></td>
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<tr>
<td><strong> Period Type:</strong></td>
<td></td>
</tr>
</table></div>
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</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_BalanceSheetLocationAxis=ions_EmployeeRelatedLiabilitiesCurrentMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_BalanceSheetLocationAxis=ions_EmployeeRelatedLiabilitiesCurrentMember</td>
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<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
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<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_IncomeStatementLocationAxis=ions_ResearchDevelopmentAndPatentExpensesMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
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<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_IncomeStatementLocationAxis=us-gaap_SellingGeneralAndAdministrativeExpensesMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_IncomeStatementLocationAxis=us-gaap_SellingGeneralAndAdministrativeExpensesMember</td>
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<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
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<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_srt_OwnershipAxis=ions_AkceaTherapeuticsIncMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
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<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">srt_OwnershipAxis=ions_AkceaTherapeuticsIncMember</td>
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<span style="display: none;">v3.22.0.1</span><table class="report" border="0" cellspacing="2" id="idm139691003691304">
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<th class="tl" colspan="1" rowspan="2"><div style="width: 200px;"><strong>Severance and Retention Costs related to our Restructured Operations, Restructured European Operations (Details) - Restructured European Operations [Member] - USD ($)<br> $ in Millions</strong></div></th>
<th class="th" colspan="2">12 Months Ended</th>
<th class="th" colspan="1">24 Months Ended</th>
</tr>
<tr>
<th class="th"><div>Dec. 31, 2021</div></th>
<th class="th"><div>Dec. 31, 2020</div></th>
<th class="th"><div>Dec. 31, 2021</div></th>
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<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RestructuringCostsAbstract', window );"><strong>Severance and Retention Costs related to our Restructured European Operations [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
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<td class="text">&#160;<span></span>
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<td class="nump">$ 12.4<span></span>
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<td class="text">&#160;<span></span>
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<td class="text">&#160;<span></span>
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</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RestructuringCharges', window );">Amount expensed during the year</a></td>
<td class="nump">2.6<span></span>
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<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
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<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RestructuringReserveAccrualAdjustment1', window );">Reserve adjustments during the year</a></td>
<td class="num">(0.9)<span></span>
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<td class="text">&#160;<span></span>
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<td class="text">&#160;<span></span>
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<tr class="reu">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_RestructuringReserveRestructuringChargesNetOfReserveAdjustments', window );">Net amount expensed during the year</a></td>
<td class="nump">1.7<span></span>
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<td class="nump">$ 12.5<span></span>
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<td class="nump">$ 14.2<span></span>
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<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_PaymentsForRestructuring', window );">Amounts paid during the year</a></td>
<td class="num">(14.1)<span></span>
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<td class="text">&#160;<span></span>
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<td class="text">&#160;<span></span>
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<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RestructuringReserve', window );">Ending balance</a></td>
<td class="nump">0.0<span></span>
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<td class="nump">12.4<span></span>
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<td class="nump">$ 0.0<span></span>
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<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RestructuringCostAndReserveAxis=ions_UpdatedEuropeanDistributionModelEmployeeSeveranceAndRetentionMember', window );">R&amp;D Expenses [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RestructuringCostsAbstract', window );"><strong>Severance and Retention Costs related to our Restructured European Operations [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
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<tr class="rou">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_RestructuringReserveRestructuringChargesNetOfReserveAdjustments', window );">Net amount expensed during the year</a></td>
<td class="nump">0.6<span></span>
</td>
<td class="nump">4.2<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RestructuringCostAndReserveAxis=ions_UpdatedEuropeanDistributionModelEmployeeSeveranceAndRetentionMember', window );">SG&amp;A Expenses [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RestructuringCostsAbstract', window );"><strong>Severance and Retention Costs related to our Restructured European Operations [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="reu">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_RestructuringReserveRestructuringChargesNetOfReserveAdjustments', window );">Net amount expensed during the year</a></td>
<td class="nump">$ 1.1<span></span>
</td>
<td class="nump">$ 8.3<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
</table>
<div style="display: none;">
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<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of expenses associated with exit or disposal activities pursuant to an authorized plan, net of adjustments to a previously accrued restructuring liability. Excludes expenses related to a discontinued operation or an asset retirement obligation.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_RestructuringReserveRestructuringChargesNetOfReserveAdjustments</td>
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<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
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<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
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<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
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<tr>
<td><strong> Period Type:</strong></td>
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<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of cash payments made as the result of exit or disposal activities. Excludes payments associated with a discontinued operation or an asset retirement obligation.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 420<br> -SubTopic 10<br> -Section 50<br> -Paragraph 1<br> -Subparagraph (b)(2)<br> -URI http://asc.fasb.org/extlink&amp;oid=6394359&amp;loc=d3e17939-110869<br><br>Reference 2: http://www.xbrl.org/2009/role/commonPracticeRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 230<br> -SubTopic 10<br> -Section 45<br> -Paragraph 17<br> -Subparagraph (f)<br> -URI http://asc.fasb.org/extlink&amp;oid=123570139&amp;loc=d3e3367-108585<br></p></div>
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<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_PaymentsForRestructuring</td>
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<td><strong> Balance Type:</strong></td>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of expenses associated with exit or disposal activities pursuant to an authorized plan. Excludes expenses related to a discontinued operation or an asset retirement obligation.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2009/role/commonPracticeRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 420<br> -SubTopic 10<br> -Section 45<br> -Paragraph 3<br> -URI http://asc.fasb.org/extlink&amp;oid=109237686&amp;loc=d3e17752-110868<br><br>Reference 2: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 420<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SAB Topic 5.P.3)<br> -URI http://asc.fasb.org/extlink&amp;oid=115931487&amp;loc=d3e140864-122747<br><br>Reference 3: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 230<br> -SubTopic 10<br> -Section 45<br> -Paragraph 28<br> -Subparagraph (b)<br> -URI http://asc.fasb.org/extlink&amp;oid=123570139&amp;loc=d3e3602-108585<br><br>Reference 4: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 420<br> -SubTopic 10<br> -Section S99<br> -Paragraph 2<br> -Subparagraph (SAB Topic 5.P.4(b)(1))<br> -URI http://asc.fasb.org/extlink&amp;oid=115931487&amp;loc=d3e140904-122747<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_RestructuringCharges</td>
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<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
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<td><strong> Data Type:</strong></td>
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<td><strong> Balance Type:</strong></td>
<td>debit</td>
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<td><strong> Period Type:</strong></td>
<td>duration</td>
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<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_RestructuringCostsAbstract</td>
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<td><strong> Period Type:</strong></td>
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<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Carrying amount (including both current and noncurrent portions of the accrual) as of the balance sheet date pertaining to a specified type of cost associated with exit from or disposal of business activities or restructuring pursuant to a duly authorized plan.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 420<br> -SubTopic 10<br> -Section 50<br> -Paragraph 1<br> -Subparagraph (b)(2)<br> -URI http://asc.fasb.org/extlink&amp;oid=6394359&amp;loc=d3e17939-110869<br><br>Reference 2: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 420<br> -SubTopic 10<br> -Section S99<br> -Paragraph 2<br> -Subparagraph (SAB TOPIC 5.P.4(b)(2))<br> -URI http://asc.fasb.org/extlink&amp;oid=115931487&amp;loc=d3e140904-122747<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of expense (reversal of expense) which increases (decreases) the restructuring reserve from an adjustment to a previously accrued restructuring liability.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 420<br> -SubTopic 10<br> -Section S99<br> -Paragraph 2<br> -Subparagraph (SAB Topic 5.P.4(b)(2))<br> -URI http://asc.fasb.org/extlink&amp;oid=115931487&amp;loc=d3e140904-122747<br><br>Reference 2: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 420<br> -SubTopic 10<br> -Section 50<br> -Paragraph 1<br> -Subparagraph (b)(2)<br> -URI http://asc.fasb.org/extlink&amp;oid=6394359&amp;loc=d3e17939-110869<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_RestructuringReserveAccrualAdjustment1</td>
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<td><strong> Period Type:</strong></td>
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<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_RestructuringCostAndReserveAxis=ions_UpdatedEuropeanDistributionModelEmployeeSeveranceAndRetentionMember</td>
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<td><strong> Balance Type:</strong></td>
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<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
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<td><strong> Name:</strong></td>
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<td><strong> Balance Type:</strong></td>
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<td><strong> Period Type:</strong></td>
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<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
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<th class="tl" colspan="1" rowspan="2"><div style="width: 200px;"><strong>Severance and Retention Costs related to our Restructured Operations, Restructured North American TEGSEDI Operations (Details) - Restructured North American TEGSEDI Operations [Member]<br> $ in Millions</strong></div></th>
<th class="th" colspan="1">12 Months Ended</th>
</tr>
<tr><th class="th">
<div>Dec. 31, 2021 </div>
<div>USD ($)</div>
</th></tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RestructuringCostsAbstract', window );"><strong>Severance and Retention Costs [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
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<td class="nump">$ 0.0<span></span>
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<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RestructuringCharges', window );">Net amount expensed during the year</a></td>
<td class="nump">9.4<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_PaymentsForRestructuring', window );">Amounts paid during the year</a></td>
<td class="num">(9.4)<span></span>
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<td class="nump">0.0<span></span>
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<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RestructuringCostAndReserveAxis=ions_RestructuredNorthAmericanTegsediOperationsMember', window );">R&amp;D Expenses [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
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<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RestructuringCostsAbstract', window );"><strong>Severance and Retention Costs [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
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<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RestructuringCharges', window );">Net amount expensed during the year</a></td>
<td class="nump">2.3<span></span>
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<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RestructuringCostAndReserveAxis=ions_RestructuredNorthAmericanTegsediOperationsMember', window );">SG&amp;A Expenses [Member]</a></td>
<td class="text">&#160;<span></span>
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<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RestructuringCostsAbstract', window );"><strong>Severance and Retention Costs [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RestructuringCharges', window );">Net amount expensed during the year</a></td>
<td class="nump">$ 7.1<span></span>
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<div style="display: none;">
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_PaymentsForRestructuring">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of cash payments made as the result of exit or disposal activities. Excludes payments associated with a discontinued operation or an asset retirement obligation.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 420<br> -SubTopic 10<br> -Section 50<br> -Paragraph 1<br> -Subparagraph (b)(2)<br> -URI http://asc.fasb.org/extlink&amp;oid=6394359&amp;loc=d3e17939-110869<br><br>Reference 2: http://www.xbrl.org/2009/role/commonPracticeRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 230<br> -SubTopic 10<br> -Section 45<br> -Paragraph 17<br> -Subparagraph (f)<br> -URI http://asc.fasb.org/extlink&amp;oid=123570139&amp;loc=d3e3367-108585<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_PaymentsForRestructuring</td>
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<tr>
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<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
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<td><strong> Balance Type:</strong></td>
<td>credit</td>
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<td><strong> Period Type:</strong></td>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of expenses associated with exit or disposal activities pursuant to an authorized plan. Excludes expenses related to a discontinued operation or an asset retirement obligation.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2009/role/commonPracticeRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 420<br> -SubTopic 10<br> -Section 45<br> -Paragraph 3<br> -URI http://asc.fasb.org/extlink&amp;oid=109237686&amp;loc=d3e17752-110868<br><br>Reference 2: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 420<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SAB Topic 5.P.3)<br> -URI http://asc.fasb.org/extlink&amp;oid=115931487&amp;loc=d3e140864-122747<br><br>Reference 3: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 230<br> -SubTopic 10<br> -Section 45<br> -Paragraph 28<br> -Subparagraph (b)<br> -URI http://asc.fasb.org/extlink&amp;oid=123570139&amp;loc=d3e3602-108585<br><br>Reference 4: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 420<br> -SubTopic 10<br> -Section S99<br> -Paragraph 2<br> -Subparagraph (SAB Topic 5.P.4(b)(1))<br> -URI http://asc.fasb.org/extlink&amp;oid=115931487&amp;loc=d3e140904-122747<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_RestructuringCostsAbstract</td>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Carrying amount (including both current and noncurrent portions of the accrual) as of the balance sheet date pertaining to a specified type of cost associated with exit from or disposal of business activities or restructuring pursuant to a duly authorized plan.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 420<br> -SubTopic 10<br> -Section 50<br> -Paragraph 1<br> -Subparagraph (b)(2)<br> -URI http://asc.fasb.org/extlink&amp;oid=6394359&amp;loc=d3e17939-110869<br><br>Reference 2: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 420<br> -SubTopic 10<br> -Section S99<br> -Paragraph 2<br> -Subparagraph (SAB TOPIC 5.P.4(b)(2))<br> -URI http://asc.fasb.org/extlink&amp;oid=115931487&amp;loc=d3e140904-122747<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
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<span style="display: none;">v3.22.0.1</span><table class="report" border="0" cellspacing="2" id="idm139691013540728">
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<th class="tl" colspan="1" rowspan="2"><div style="width: 200px;"><strong>Employment Benefits (Details) - USD ($)<br></strong></div></th>
<th class="th" colspan="3">12 Months Ended</th>
</tr>
<tr>
<th class="th"><div>Dec. 31, 2021</div></th>
<th class="th"><div>Dec. 31, 2020</div></th>
<th class="th"><div>Dec. 31, 2019</div></th>
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<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_GeneralDiscussionOfPensionAndOtherPostretirementBenefitsAbstract', window );"><strong>Employee Benefits [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
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<td class="text">&#160;<span></span>
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<td class="text">&#160;<span></span>
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<td class="nump">$ 5,500,000<span></span>
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<td class="nump">$ 5,700,000<span></span>
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<td class="nump">$ 6,400,000<span></span>
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<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_srt_RangeAxis=srt_MinimumMember', window );">Minimum [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
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<td class="text">&#160;<span></span>
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<td class="text">&#160;<span></span>
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<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
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<td class="nump">20,500<span></span>
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<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
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<td class="text">&#160;<span></span>
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<td class="text">&#160;<span></span>
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<td class="text">&#160;<span></span>
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<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_GeneralDiscussionOfPensionAndOtherPostretirementBenefitsAbstract', window );"><strong>Employee Benefits [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
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<td class="text">&#160;<span></span>
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<td class="text">&#160;<span></span>
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<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DefinedContributionPlanMaximumAnnualContributionsPerEmployeeAmount', window );">Employee contribution limit per calendar year</a></td>
<td class="nump">$ 27,000<span></span>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of cost for defined contribution plan.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 715<br> -SubTopic 70<br> -Section 50<br> -Paragraph 1<br> -URI http://asc.fasb.org/extlink&amp;oid=49170846&amp;loc=d3e28014-114942<br></p></div>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Maximum amount the employee may contribute to a defined contribution plan.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
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<span style="display: none;">v3.22.0.1</span><table class="report" border="0" cellspacing="2" id="idm139691017213368">
<tr>
<th class="tl" colspan="1" rowspan="1"><div style="width: 200px;"><strong>Legal Proceedings (Details)<br></strong></div></th>
<th class="th">
<div>Aug. 05, 2021 </div>
<div>Plaintiff</div>
</th>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_srt_LitigationCaseAxis=ions_JohnMakrisEtAlVIonisPharmaceuticalsIncEtAlMember', window );">John Makris, et al. v. Ionis Pharmaceuticals, Inc., et al. [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_LossContingencyClaimsQuantitiesAbstract', window );"><strong>Legal Procedings [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_LossContingencyNumberOfPlaintiffs', window );">Number of plaintiffs</a></td>
<td class="nump">4<span></span>
</td>
</tr>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
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<td style="white-space:nowrap;">us-gaap_LossContingencyClaimsQuantitiesAbstract</td>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Number of plaintiffs that have filed claims pertaining to a loss contingency.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
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<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">srt_LitigationCaseAxis=ions_JohnMakrisEtAlVIonisPharmaceuticalsIncEtAlMember</td>
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<span style="display: none;">v3.22.0.1</span><table class="report" border="0" cellspacing="2" id="idm139690999548824">
<tr>
<th class="tl" colspan="1" rowspan="2"><div style="width: 200px;"><strong>Fourth Quarter Financial Data (Unaudited) (Details) - USD ($)<br> $ / shares in Units, shares in Thousands, $ in Thousands</strong></div></th>
<th class="th" colspan="1">1 Months Ended</th>
<th class="th" colspan="1">2 Months Ended</th>
<th class="th" colspan="4">3 Months Ended</th>
<th class="th" colspan="3">12 Months Ended</th>
<th class="th" colspan="1"></th>
<th class="th" colspan="1"></th>
<th class="th" colspan="1"></th>
<th class="th" colspan="1"></th>
</tr>
<tr>
<th class="th"><div>Oct. 31, 2020</div></th>
<th class="th"><div>Dec. 31, 2020</div></th>
<th class="th" colspan="2"><div>Dec. 31, 2021</div></th>
<th class="th" colspan="2"><div>Dec. 31, 2020</div></th>
<th class="th"><div>Dec. 31, 2021</div></th>
<th class="th"><div>Dec. 31, 2020</div></th>
<th class="th"><div>Dec. 31, 2019</div></th>
<th class="th"><div>Nov. 30, 2021</div></th>
<th class="th"><div>Apr. 30, 2021</div></th>
<th class="th"><div>Dec. 31, 2016</div></th>
<th class="th"><div>Nov. 30, 2014</div></th>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_SelectedQuarterlyFinancialInformationAbstract', window );"><strong>Fourth Quarter Financial Data (Unaudited) [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_Revenues', window );">Revenue</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 440,006<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">$ 290,281<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_CostsAndExpenses', window );">Operating expenses</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">219,403<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">312,945<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">$ 840,642<span></span>
</td>
<td class="nump">$ 901,346<span></span>
</td>
<td class="nump">$ 756,716<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rou">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_OperatingIncomeLoss', window );">Income (loss) from operations</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">220,603<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="num">(22,664)<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="num">(30,186)<span></span>
</td>
<td class="num">(172,082)<span></span>
</td>
<td class="nump">365,883<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ProfitLoss', window );">Net income (loss)</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">224,613<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="num">(355,687)<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="num">(28,597)<span></span>
</td>
<td class="num">(479,743)<span></span>
</td>
<td class="nump">287,259<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_NetIncomeLoss', window );">Net income (loss) attributable to Ionis Pharmaceuticals, Inc. common stockholders</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 224,613<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="num">$ (354,532)<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="num">$ (28,597)<span></span>
</td>
<td class="num">$ (444,263)<span></span>
</td>
<td class="nump">$ 278,143<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_EarningsPerShareBasic', window );">Basic net income (loss) per share (in dollars per share)</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 1.59<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"><sup>[1],[2]</sup></td>
<td class="num">$ (2.54)<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"><sup>[1],[2]</sup></td>
<td class="num">$ (0.20)<span></span>
</td>
<td class="num">$ (3.18)<span></span>
</td>
<td class="nump">$ 2.00<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_EarningsPerShareDiluted', window );">Diluted net income (loss) per share (in dollars per share)</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 1.41<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"><sup>[1],[3]</sup></td>
<td class="num">$ (2.54)<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"><sup>[1]</sup></td>
<td class="num">$ (0.20)<span></span>
</td>
<td class="num">$ (3.18)<span></span>
</td>
<td class="nump">$ 1.90<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_NetIncomeLossAvailableToCommonStockholdersDilutedAbstract', window );"><strong>Income (Numerator) [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_NetIncomeLossAvailableToCommonStockholdersBasic', window );">Income (loss) available to Ionis common stockholders</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 224,612<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="num">$ (356,008)<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="num">$ (444,464)<span></span>
</td>
<td class="nump">$ 280,560<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="reu">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_NetIncomeLossAvailableToCommonStockholdersDiluted', window );">Net income available to Ionis common shareholders</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 226,210<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 290,947<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_WeightedAverageNumberOfSharesOutstandingDilutedDisclosureItemsAbstract', window );"><strong>Shares (Denominator) [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_WeightedAverageNumberOfSharesOutstandingBasic', window );">Shares used in computing basic net income (loss) per share (in shares)</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">141,205<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">139,956<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">141,021<span></span>
</td>
<td class="nump">139,612<span></span>
</td>
<td class="nump">139,998<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_WeightedAverageNumberDilutedSharesOutstandingAdjustmentAbstract', window );"><strong>Effect of Diluted Securities [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_IncrementalCommonSharesAttributableToEmployeeStockPurchasePlan', window );">Shares issuable related to our ESPP (in shares)</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">34<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">18<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rou">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_WeightedAverageNumberOfDilutedSharesOutstanding', window );">Shares used in computing diluted net income per share (in shares)</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">160,340<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">141,021<span></span>
</td>
<td class="nump">139,612<span></span>
</td>
<td class="nump">153,164<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DebtInstrumentAxis=ions_ConvertibleSeniorNotes0PercentMember', window );">0 Percent Convertible Senior Notes [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_SelectedQuarterlyFinancialInformationAbstract', window );"><strong>Fourth Quarter Financial Data (Unaudited) [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DebtInstrumentInterestRateStatedPercentage', window );">Interest rate on convertible senior notes</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">0.00%<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">0.00%<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">0.00%<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">0.00%<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_NetIncomeLossAvailableToCommonStockholdersDilutedAbstract', window );"><strong>Income (Numerator) [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DilutiveSecuritiesEffectOnBasicEarningsPerShareOther', window );">Shares issuable related to our convertible notes</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 777<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_WeightedAverageNumberDilutedSharesOutstandingAdjustmentAbstract', window );"><strong>Effect of Diluted Securities [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_IncrementalCommonSharesAttributableToConversionOfDebtSecurities', window );">Shares issuable related to our convertible notes (in shares)</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">10,936<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DebtInstrumentAxis=ions_ConvertibleSeniorNotes0125PercentMember', window );">0.125 Percent Convertible Senior Notes [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_SelectedQuarterlyFinancialInformationAbstract', window );"><strong>Fourth Quarter Financial Data (Unaudited) [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DebtInstrumentInterestRateStatedPercentage', window );">Interest rate on convertible senior notes</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">0.125%<span></span>
</td>
<td class="nump">0.125%<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">0.125%<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">0.125%<span></span>
</td>
<td class="nump">0.125%<span></span>
</td>
<td class="nump">0.125%<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_NetIncomeLossAvailableToCommonStockholdersDilutedAbstract', window );"><strong>Income (Numerator) [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DilutiveSecuritiesEffectOnBasicEarningsPerShareOther', window );">Shares issuable related to our convertible notes</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 716<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 860<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_WeightedAverageNumberDilutedSharesOutstandingAdjustmentAbstract', window );"><strong>Effect of Diluted Securities [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_IncrementalCommonSharesAttributableToConversionOfDebtSecurities', window );">Shares issuable related to our convertible notes (in shares)</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">6,590<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">217<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DebtInstrumentAxis=ions_ConvertibleSeniorNotes1PercentMember', window );">1 Percent Convertible Senior Notes [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_SelectedQuarterlyFinancialInformationAbstract', window );"><strong>Fourth Quarter Financial Data (Unaudited) [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DebtInstrumentInterestRateStatedPercentage', window );">Interest rate on convertible senior notes</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">1.00%<span></span>
</td>
<td class="nump">1.00%<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">1.00%<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">1.00%<span></span>
</td>
<td class="nump">1.00%<span></span>
</td>
<td class="nump">1.00%<span></span>
</td>
<td class="nump">1.00%<span></span>
</td>
<td class="nump">1.00%<span></span>
</td>
<td class="nump">1.00%<span></span>
</td>
<td class="nump">1.00%<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_NetIncomeLossAvailableToCommonStockholdersDilutedAbstract', window );"><strong>Income (Numerator) [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DilutiveSecuritiesEffectOnBasicEarningsPerShareOther', window );">Shares issuable related to our convertible notes</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 105<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 9,527<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_WeightedAverageNumberDilutedSharesOutstandingAdjustmentAbstract', window );"><strong>Effect of Diluted Securities [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_IncrementalCommonSharesAttributableToConversionOfDebtSecurities', window );">Shares issuable related to our convertible notes (in shares)</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">464<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">10,075<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AwardTypeAxis=us-gaap_EmployeeStockOptionMember', window );">Stock Options [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_WeightedAverageNumberDilutedSharesOutstandingAdjustmentAbstract', window );"><strong>Effect of Diluted Securities [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_IncrementalCommonSharesAttributableToShareBasedPaymentArrangements', window );">Shares issuable related to stock-based compensation (in shares)</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">46<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">2,090<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AwardTypeAxis=us-gaap_RestrictedStockMember', window );">Restricted Stock Awards [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_WeightedAverageNumberDilutedSharesOutstandingAdjustmentAbstract', window );"><strong>Effect of Diluted Securities [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_IncrementalCommonSharesAttributableToShareBasedPaymentArrangements', window );">Shares issuable related to stock-based compensation (in shares)</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">1,065<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">766<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_StatementBusinessSegmentsAxis=ions_IonisCoreMember', window );">Ionis [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_SelectedQuarterlyFinancialInformationAbstract', window );"><strong>Fourth Quarter Financial Data (Unaudited) [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_NetIncomeLoss', window );">Net income (loss) attributable to Ionis Pharmaceuticals, Inc. common stockholders</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="num">$ (266,418)<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="num">$ (246,702)<span></span>
</td>
<td class="nump">$ 246,487<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_srt_OwnershipAxis=ions_AkceaTherapeuticsIncMember', window );">Akcea [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_SelectedQuarterlyFinancialInformationAbstract', window );"><strong>Fourth Quarter Financial Data (Unaudited) [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_NetIncomeLoss', window );">Net income (loss) attributable to Ionis Pharmaceuticals, Inc. common stockholders</a></td>
<td class="num">$ (3,603)<span></span>
</td>
<td class="num">$ (85,987)<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="num">$ (89,590)<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_EarningsPerShareBasic', window );">Basic net income (loss) per share (in dollars per share)</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="num">$ (0.05)<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_WeightedAverageNumberOfSharesOwnedInSubsidiary', window );">Weighted average shares owned in Akcea (in shares)</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">77,095<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr><td colspan="14"></td></tr>
<tr><td colspan="14"><table class="outerFootnotes" width="100%">
<tr class="outerFootnote">
<td style="vertical-align: top; width: 12pt;" valign="top">[1]</td>
<td style="vertical-align: top;" valign="top"><span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">We </span>compute net income (loss) per share independently for each quarter during <span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;">the year.</span></td>
</tr>
<tr class="outerFootnote">
<td style="vertical-align: top; width: 12pt;" valign="top">[2]</td>
<td style="vertical-align: top;" valign="top">As discussed in Note 1, Organization and Significant Accounting Policies, we compute basic net income (loss) per share by dividing the total net income (loss)
            attributable to our common stockholders by our weighted-average number of common shares outstanding during the period. Our basic net income per share for the fourth quarter of 2021 was $1.59.Our basic net loss per share calculation for the fourth quarter of 2020 considered our net loss for Ionis on a stand-alone
    basis plus our share of Akcea&#8217;s net loss for the period. To calculate the portion of Akcea&#8217;s net loss attributable to our ownership, we multiplied Akcea&#8217;s loss per share by the weighted average shares we owned in Akcea during the period. As a result of
    this calculation, our total net loss available to Ionis common stockholders for the calculation of net loss per share is different than net loss attributable to Ionis Pharmaceuticals, Inc. common stockholders in the consolidated statements of
    operations.</td>
</tr>
<tr class="outerFootnote">
<td style="vertical-align: top; width: 12pt;" valign="top">[3]</td>
<td style="vertical-align: top;" valign="top">We had net income available
            to Ionis common stockholders for the fourth quarter of 2021. As a result, we computed diluted net income per share using the weighted-average number of common shares and dilutive common equivalent shares outstanding during the period</td>
</tr>
</table></td></tr>
</table>
<div style="display: none;">
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_IncrementalCommonSharesAttributableToEmployeeStockPurchasePlan">
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Additional shares included in the calculation of diluted EPS as a result of the potentially dilutive effect of shares issuable related to employee stock purchase plan.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_IncrementalCommonSharesAttributableToEmployeeStockPurchasePlan</td>
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<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
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<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_WeightedAverageNumberOfSharesOwnedInSubsidiary">
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Number of shares owned in the subsidiary during the reporting period determined by relating the portion of time within a reporting period that shares have been owned to the total time in that period.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_WeightedAverageNumberOfSharesOwnedInSubsidiary</td>
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<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Total costs of sales and operating expenses for the period.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 220<br> -SubTopic 10<br> -Section S99<br> -Paragraph 2<br> -Subparagraph (SX 210.5-03)<br> -URI http://asc.fasb.org/extlink&amp;oid=123367319&amp;loc=SL114868664-224227<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_CostsAndExpenses</td>
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<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
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<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
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<td>duration</td>
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<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Contractual interest rate for funds borrowed, under the debt agreement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 470<br> -SubTopic 20<br> -Section 50<br> -Paragraph 1B<br> -Subparagraph (b)<br> -URI http://asc.fasb.org/extlink&amp;oid=123466505&amp;loc=SL123495323-112611<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 210<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.5-02.22(a)(1))<br> -URI http://asc.fasb.org/extlink&amp;oid=120391452&amp;loc=d3e13212-122682<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_DebtInstrumentInterestRateStatedPercentage</td>
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<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of increase (decrease) to net income used for calculating diluted earnings per share (EPS), resulting from the assumed exercise of dilutive convertible securities excluding adjustments related to ESOP convertible preferred stock, stock options, and restrictive stock units.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_DilutiveSecuritiesEffectOnBasicEarningsPerShareOther</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_EarningsPerShareBasic">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The amount of net income (loss) for the period per each share of common stock or unit outstanding during the reporting period.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 815<br> -SubTopic 40<br> -Section 65<br> -Paragraph 1<br> -Subparagraph (e)(4)<br> -URI http://asc.fasb.org/extlink&amp;oid=123482062&amp;loc=SL123482106-238011<br><br>Reference 2: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 250<br> -SubTopic 10<br> -Section 50<br> -Paragraph 3<br> -URI http://asc.fasb.org/extlink&amp;oid=124431687&amp;loc=d3e22583-107794<br><br>Reference 3: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 250<br> -SubTopic 10<br> -Section 50<br> -Paragraph 11<br> -Subparagraph (b)<br> -URI http://asc.fasb.org/extlink&amp;oid=124431687&amp;loc=d3e22694-107794<br><br>Reference 4: 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-Paragraph 7<br> -URI http://asc.fasb.org/extlink&amp;oid=125511455&amp;loc=d3e1337-109256<br><br>Reference 8: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 815<br> -SubTopic 40<br> -Section 65<br> -Paragraph 1<br> -Subparagraph (f)<br> -URI http://asc.fasb.org/extlink&amp;oid=123482062&amp;loc=SL123482106-238011<br><br>Reference 9: http://www.xbrl.org/2003/role/exampleRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 260<br> -SubTopic 10<br> -Section 55<br> -Paragraph 52<br> -URI http://asc.fasb.org/extlink&amp;oid=125512782&amp;loc=d3e4984-109258<br><br>Reference 10: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 944<br> -SubTopic 220<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.7-04(23))<br> -URI http://asc.fasb.org/extlink&amp;oid=120400993&amp;loc=SL114874131-224263<br><br>Reference 11: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 260<br> -SubTopic 10<br> -Section 55<br> -Paragraph 15<br> -URI http://asc.fasb.org/extlink&amp;oid=125512782&amp;loc=d3e3842-109258<br><br>Reference 12: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 250<br> -SubTopic 10<br> -Section 50<br> -Paragraph 7<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=124431687&amp;loc=d3e22644-107794<br><br>Reference 13: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 260<br> -SubTopic 10<br> -Section 50<br> -Paragraph 1<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=124432515&amp;loc=d3e3550-109257<br><br>Reference 14: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 220<br> -SubTopic 10<br> -Section S99<br> -Paragraph 2<br> -Subparagraph (SX 210.5-03(25))<br> -URI http://asc.fasb.org/extlink&amp;oid=123367319&amp;loc=SL114868664-224227<br><br>Reference 15: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 260<br> -SubTopic 10<br> -Section 45<br> -Paragraph 2<br> -URI http://asc.fasb.org/extlink&amp;oid=125511455&amp;loc=d3e1252-109256<br><br>Reference 16: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 260<br> -SubTopic 10<br> -Section 45<br> -Paragraph 60B<br> -Subparagraph (d)<br> -URI http://asc.fasb.org/extlink&amp;oid=125511455&amp;loc=SL5780133-109256<br><br>Reference 17: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 942<br> -SubTopic 220<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.9-04(27))<br> -URI http://asc.fasb.org/extlink&amp;oid=120399700&amp;loc=SL114874048-224260<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_EarningsPerShareBasic</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>dtr-types:perShareItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_EarningsPerShareDiluted">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The amount of net income (loss) for the period available to each share of common stock or common unit outstanding during the reporting period and to each share or unit that would have been outstanding assuming the issuance of common shares or units for all dilutive potential common shares or units outstanding during the reporting period.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/exampleRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 260<br> -SubTopic 10<br> -Section 55<br> -Paragraph 52<br> -URI http://asc.fasb.org/extlink&amp;oid=125512782&amp;loc=d3e4984-109258<br><br>Reference 2: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 250<br> -SubTopic 10<br> -Section 50<br> -Paragraph 7<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=124431687&amp;loc=d3e22644-107794<br><br>Reference 3: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 260<br> -SubTopic 10<br> -Section 55<br> -Paragraph 15<br> -URI http://asc.fasb.org/extlink&amp;oid=125512782&amp;loc=d3e3842-109258<br><br>Reference 4: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 260<br> -SubTopic 10<br> -Section 45<br> -Paragraph 2<br> -URI http://asc.fasb.org/extlink&amp;oid=125511455&amp;loc=d3e1252-109256<br><br>Reference 5: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 250<br> -SubTopic 10<br> -Section 50<br> -Paragraph 11<br> -Subparagraph (b)<br> -URI http://asc.fasb.org/extlink&amp;oid=124431687&amp;loc=d3e22694-107794<br><br>Reference 6: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 250<br> -SubTopic 10<br> -Section 50<br> -Paragraph 4<br> -URI http://asc.fasb.org/extlink&amp;oid=124431687&amp;loc=d3e22595-107794<br><br>Reference 7: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 250<br> -SubTopic 10<br> -Section 50<br> -Paragraph 3<br> -URI http://asc.fasb.org/extlink&amp;oid=124431687&amp;loc=d3e22583-107794<br><br>Reference 8: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 260<br> -SubTopic 10<br> -Section 45<br> -Paragraph 60B<br> -Subparagraph (d)<br> -URI http://asc.fasb.org/extlink&amp;oid=125511455&amp;loc=SL5780133-109256<br><br>Reference 9: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 815<br> -SubTopic 40<br> -Section 65<br> -Paragraph 1<br> -Subparagraph (f)<br> -URI http://asc.fasb.org/extlink&amp;oid=123482062&amp;loc=SL123482106-238011<br><br>Reference 10: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 942<br> -SubTopic 220<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.9-04(27))<br> -URI http://asc.fasb.org/extlink&amp;oid=120399700&amp;loc=SL114874048-224260<br><br>Reference 11: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 260<br> -SubTopic 10<br> -Section 50<br> -Paragraph 1<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=124432515&amp;loc=d3e3550-109257<br><br>Reference 12: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 944<br> -SubTopic 220<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.7-04(23))<br> -URI http://asc.fasb.org/extlink&amp;oid=120400993&amp;loc=SL114874131-224263<br><br>Reference 13: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 250<br> -SubTopic 10<br> -Section 50<br> -Paragraph 11<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=124431687&amp;loc=d3e22694-107794<br><br>Reference 14: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 260<br> -SubTopic 10<br> -Section 45<br> -Paragraph 7<br> -URI http://asc.fasb.org/extlink&amp;oid=125511455&amp;loc=d3e1337-109256<br><br>Reference 15: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 815<br> -SubTopic 40<br> -Section 65<br> -Paragraph 1<br> -Subparagraph (e)(4)<br> -URI http://asc.fasb.org/extlink&amp;oid=123482062&amp;loc=SL123482106-238011<br><br>Reference 16: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 220<br> -SubTopic 10<br> -Section S99<br> -Paragraph 2<br> -Subparagraph (SX 210.5-03(25))<br> -URI http://asc.fasb.org/extlink&amp;oid=123367319&amp;loc=SL114868664-224227<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_EarningsPerShareDiluted</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>dtr-types:perShareItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_IncrementalCommonSharesAttributableToConversionOfDebtSecurities">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Additional shares included in the calculation of diluted EPS as a result of the potentially dilutive effect of convertible debt securities using the if-converted method.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 260<br> -SubTopic 10<br> -Section 45<br> -Paragraph 40<br> -Subparagraph (c)<br> -URI http://asc.fasb.org/extlink&amp;oid=125511455&amp;loc=d3e1930-109256<br><br>Reference 2: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 260<br> -SubTopic 10<br> -Section 45<br> -Paragraph 42<br> -URI http://asc.fasb.org/extlink&amp;oid=125511455&amp;loc=d3e2029-109256<br><br>Reference 3: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 260<br> -SubTopic 10<br> -Section 50<br> -Paragraph 1<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=124432515&amp;loc=d3e3550-109257<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_IncrementalCommonSharesAttributableToConversionOfDebtSecurities</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:sharesItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_IncrementalCommonSharesAttributableToShareBasedPaymentArrangements">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Additional shares included in the calculation of diluted EPS as a result of the potentially dilutive effect of share based payment arrangements using the treasury stock method.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 260<br> -SubTopic 10<br> -Section 45<br> -Paragraph 22<br> -URI http://asc.fasb.org/extlink&amp;oid=125511455&amp;loc=d3e1707-109256<br><br>Reference 2: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 260<br> -SubTopic 10<br> -Section 50<br> -Paragraph 1<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=124432515&amp;loc=d3e3550-109257<br><br>Reference 3: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 260<br> -SubTopic 10<br> -Section 45<br> -Paragraph 28A<br> -URI http://asc.fasb.org/extlink&amp;oid=125511455&amp;loc=d3e1500-109256<br><br>Reference 4: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 260<br> -SubTopic 10<br> -Section 45<br> -Paragraph 23<br> -Subparagraph (c)<br> -URI http://asc.fasb.org/extlink&amp;oid=125511455&amp;loc=d3e1757-109256<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_IncrementalCommonSharesAttributableToShareBasedPaymentArrangements</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:sharesItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_NetIncomeLoss">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The portion of profit or loss for the period, net of income taxes, which is attributable to the parent.</p></div>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_NetIncomeLoss</td>
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<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
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<tr>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount, after deduction of tax, noncontrolling interests, dividends on preferred stock and participating securities; of income (loss) available to common shareholders.</p></div>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_NetIncomeLossAvailableToCommonStockholdersBasic</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
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<tr>
<td><strong> Period Type:</strong></td>
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</div></td></tr>
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<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount, after deduction of tax, noncontrolling interests, dividends on preferred stock and participating securities, and addition from assumption of issuance of common shares for dilutive potential common shares; of income (loss) available to common shareholders.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 260<br> -SubTopic 10<br> -Section 45<br> -Paragraph 40<br> -Subparagraph (b)(2)<br> -URI http://asc.fasb.org/extlink&amp;oid=125511455&amp;loc=d3e1930-109256<br><br>Reference 2: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 260<br> -SubTopic 10<br> -Section 45<br> -Paragraph 40<br> -Subparagraph (b)(3)<br> -URI http://asc.fasb.org/extlink&amp;oid=125511455&amp;loc=d3e1930-109256<br><br>Reference 3: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 260<br> -SubTopic 10<br> -Section 45<br> -Paragraph 60B<br> -Subparagraph (c)<br> -URI http://asc.fasb.org/extlink&amp;oid=125511455&amp;loc=SL5780133-109256<br><br>Reference 4: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 260<br> -SubTopic 10<br> -Section 50<br> -Paragraph 1<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=124432515&amp;loc=d3e3550-109257<br><br>Reference 5: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 260<br> -SubTopic 10<br> -Section 45<br> -Paragraph 40<br> -Subparagraph (b)(1)<br> -URI http://asc.fasb.org/extlink&amp;oid=125511455&amp;loc=d3e1930-109256<br><br>Reference 6: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 260<br> -SubTopic 10<br> -Section 45<br> -Paragraph 16<br> -URI http://asc.fasb.org/extlink&amp;oid=125511455&amp;loc=d3e1505-109256<br><br>Reference 7: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 260<br> -SubTopic 10<br> -Section 45<br> -Paragraph 40<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=125511455&amp;loc=d3e1930-109256<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_NetIncomeLossAvailableToCommonStockholdersDiluted</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
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<td><strong> Data Type:</strong></td>
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<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
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<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:stringItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_OperatingIncomeLoss">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The net result for the period of deducting operating expenses from operating revenues.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/exampleRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 280<br> -SubTopic 10<br> -Section 50<br> -Paragraph 31<br> -URI http://asc.fasb.org/extlink&amp;oid=123359005&amp;loc=d3e8924-108599<br><br>Reference 2: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 280<br> -SubTopic 10<br> -Section 50<br> -Paragraph 30<br> -Subparagraph (b)<br> -URI http://asc.fasb.org/extlink&amp;oid=123359005&amp;loc=d3e8906-108599<br><br>Reference 3: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 280<br> -SubTopic 10<br> -Section 50<br> -Paragraph 32<br> -Subparagraph (c)<br> -URI http://asc.fasb.org/extlink&amp;oid=123359005&amp;loc=d3e8933-108599<br><br>Reference 4: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 280<br> -SubTopic 10<br> -Section 50<br> -Paragraph 32<br> -Subparagraph (f)<br> -URI http://asc.fasb.org/extlink&amp;oid=123359005&amp;loc=d3e8933-108599<br><br>Reference 5: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 280<br> -SubTopic 10<br> -Section 50<br> -Paragraph 22<br> -URI http://asc.fasb.org/extlink&amp;oid=123359005&amp;loc=d3e8736-108599<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_OperatingIncomeLoss</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_ProfitLoss">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The consolidated profit or loss for the period, net of income taxes, including the portion attributable to the noncontrolling interest.</p></div>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ProfitLoss</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_Revenues">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of revenue recognized from goods sold, services rendered, insurance premiums, or other activities that constitute an earning process. Includes, but is not limited to, investment and interest income before deduction of interest expense when recognized as a component of revenue, and sales and trading gain (loss).</p></div>
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&lt;div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;1. Organization and Significant Accounting Policies&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Basis of Presentation&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;In our consolidated financial statements we included the accounts of Ionis Pharmaceuticals, Inc. and the consolidated
    results of our subsidiary, Akcea Therapeutics, Inc. and its wholly owned subsidiaries (&#x201c;we&#x201d;, &#x201c;us&#x201d; or &#x201c;our&#x201d;). We formed Akcea in December 2014. In July 2017, Akcea completed an initial public offering, or IPO, which reduced our ownership of Akcea&#x2019;s
    common stock below 100 percent. In October 2020, we completed a merger transaction with Akcea such that following the completion of the merger,
    Akcea became our wholly owned subsidiary. We will refer to this transaction as the Akcea Merger throughout the remainder of this document. We reflected changes in our ownership percentage in our financial statements as an adjustment to noncontrolling
    interest in the period the changes occurred&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;.&lt;/span&gt;&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Organization and Business Activity&lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;We incorporated in California on January 10, 1989. In conjunction with our IPO, we reorganized as a Delaware corporation
    in April 1991. We were organized principally to develop human therapeutic medicines using antisense technology. In December 2015, we changed our name from Isis Pharmaceuticals, Inc. to Ionis Pharmaceuticals, Inc.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Basic and Diluted Net Income (Loss) per Share&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;"&gt;Basic net income (loss) per share&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;We compute basic net income (loss) per share by dividing the total net income (loss) attributable to our common
    stockholders by our weighted-average number of common shares outstanding during the period. For the year ended December 31, 2021, we did not have to consider Akcea results separately in our calculation because we owned 100 percent of Akcea for the entire period. Our basic net loss per share for the year ended December 31, 2021 was $0.20.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;For the years ended December 31, 2020 and 2019, we calculated total net income (loss) attributable to our common
    stockholders for each year using our net income (loss) for Ionis on a stand-alone basis plus our share of Akcea&#x2019;s net income (loss) for the period. To calculate the portion of Akcea&#x2019;s net income (loss) attributable to our ownership for each year, we
    multiplied Akcea&#x2019;s income (loss) per share by the weighted average shares we owned in Akcea during the period. As a result of this calculation, our total net income (loss) available to Ionis common stockholders for the calculation of net income (loss)
    per share is different than net income (loss) attributable to Ionis Pharmaceuticals, Inc. common stockholders in our consolidated statements of operations for each year.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;We calculated our basic net loss per share for the year ended December 31, 2020 as follows (in thousands, except
    per share amounts):&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;"&gt;


  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; border-bottom: #000000 2px solid; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Year Ended December 31, 2020&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Weighted&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Average Shares&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Owned in Akcea&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Akcea&lt;/span&gt;&#x2019;&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;s&lt;/span&gt;&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Net Loss&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Per Share&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Basic Net Loss&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Per Share&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Calculation&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 64%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Akcea&#x2019;s net loss in the pre-merger period attributable to our ownership&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;77,095&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(1.45&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(111,775&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 64%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Akcea&#x2019;s net loss in the post-merger period attributable to our ownership&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(85,987&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 64%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Akcea&#x2019;s total net loss attributable to our ownership&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(197,762&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 64%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Ionis&#x2019; stand-alone net loss&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(246,702&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 64%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Net loss available to Ionis common stockholders&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(444,464&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 64%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Weighted average shares outstanding&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;139,612&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 64%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Basic net loss per share&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(3.18&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;We calculated our basic net income per share for the year ended December 31, 2019 as follows (in thousands, except per share amounts):&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;"&gt;


  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; border-bottom: #000000 2px solid; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Year Ended December 31, 2019&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Weighted&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Average Shares&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Owned in Akcea&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Akcea&lt;/span&gt;&#x2019;&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;s&lt;/span&gt;&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Net Income&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Per Share&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Basic Net Income&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Per Share&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Calculation&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 64%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Common shares&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;70,100&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;0.49&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;34,073&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 64%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Akcea&#x2019;s net income attributable to our ownership&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;34,073&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 64%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Ionis&#x2019; stand-alone net income&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;246,487&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 64%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Net income available to Ionis common stockholders&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;280,560&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 64%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Weighted average shares outstanding&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;139,998&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 64%; padding-bottom: 4px; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Basic net income per share&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;2.00&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 12pt;"&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;"&gt;Diluted net income (loss) per share&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;For the years ended December 31, 2021 and 2020, we incurred a net loss; therefore, we did not include dilutive common
    equivalent shares in the computation of diluted net loss per share because the effect would have been anti-dilutive. Common stock underlying the following would have had an anti-dilutive effect on net loss per share:&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;"&gt;


  &lt;tr&gt;

    &lt;td style="width: 36pt;"/&gt;

    &lt;td style="width: 18pt; vertical-align: top; align: right; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x25cf;&lt;/td&gt;

    &lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;
          &lt;div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;0.125 percent&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt; convertible senior notes, or &lt;/span&gt;0.125%&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt; Notes;&lt;/span&gt;&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;"&gt;


  &lt;tr&gt;

    &lt;td style="width: 36pt;"/&gt;

    &lt;td style="width: 18pt; vertical-align: top; align: right; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x25cf;&lt;/td&gt;

    &lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;
          &lt;div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt;Note hedges related to the &lt;/span&gt;0.125%&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt; Notes;&lt;/span&gt;&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;"&gt;


  &lt;tr&gt;

    &lt;td style="width: 36pt;"/&gt;

    &lt;td style="width: 18pt; vertical-align: top; align: right; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x25cf;&lt;/td&gt;

    &lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;
          &lt;div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;1 percent&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt; convertible senior notes, or &lt;/span&gt;1%&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt; Notes;&lt;/span&gt;&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;"&gt;


  &lt;tr&gt;

    &lt;td style="width: 36pt;"/&gt;

    &lt;td style="width: 18pt; vertical-align: top; align: right; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x25cf;&lt;/td&gt;

    &lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Dilutive stock options;&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;"&gt;


  &lt;tr&gt;

    &lt;td style="width: 36pt;"/&gt;

    &lt;td style="width: 18pt; vertical-align: top; align: right; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x25cf;&lt;/td&gt;

    &lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Unvested restricted stock units, or RSUs;&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;"&gt;


  &lt;tr&gt;

    &lt;td style="width: 36pt;"/&gt;

    &lt;td style="width: 18pt; vertical-align: top; align: right; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x25cf;&lt;/td&gt;

    &lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Unvested performance restricted stock units, or PRSUs; and&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;"&gt;


  &lt;tr&gt;

    &lt;td style="width: 36pt;"/&gt;

    &lt;td style="width: 18pt; vertical-align: top; align: right; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x25cf;&lt;/td&gt;

    &lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Employee Stock Purchase Plan, or ESPP.&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;For the year ended December 31, 2021, common stock underlying the following would also have had an anti-dilutive effect on
    net loss per share:&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;"&gt;


  &lt;tr&gt;

    &lt;td style="width: 36pt;"/&gt;

    &lt;td style="width: 18pt; vertical-align: top; align: right; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x25cf;&lt;/td&gt;

    &lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;
          &lt;div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;0 percent&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt; convertible senior notes, or &lt;/span&gt;0%&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt; Notes; and&lt;/span&gt;&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;"&gt;


  &lt;tr&gt;

    &lt;td style="width: 36pt;"/&gt;

    &lt;td style="width: 18pt; vertical-align: top; align: right; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x25cf;&lt;/td&gt;

    &lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;
          &lt;div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt;Note hedges related to the &lt;/span&gt;0%&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt; Notes.&lt;/span&gt;&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Additionally as of December 31, 2021, we had warrants related to our 0 percent and 0.125 percent Notes outstanding. We will include the shares issuable
    under these warrants in our calculation of diluted earnings per share when the average market price per share of our common stock for the reporting period exceeds the strike price of the warrants.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt;For the
      year ended December 31, 2019, we reported net income available to Ionis common stockholders. As a result, we computed diluted net income per share using the weighted-average number of common shares and dilutive common equivalent shares outstanding
      during each period.&lt;/span&gt; We calculated our diluted net income per share as follows &lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt;(in thousands except per share amounts):&lt;/span&gt;&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;"&gt;


  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; border-bottom: #000000 2px solid;" valign="bottom"&gt;
          &lt;div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Year Ended December 31, 2019&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Net Income Available&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;to Ionis Common&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Stockholders&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;(Numerator)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Shares&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;(Denominator)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Per-Share&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Amount&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 64%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Net income available to Ionis common stockholders&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;280,560&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;139,998&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;2.00&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 64%;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Effect of dilutive securities:&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 64%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -8.9pt; margin-left: 18pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Shares issuable upon exercise of stock options&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x2014;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;2,090&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 64%;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: 0.1pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Shares issuable upon restricted stock award issuance&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x2014;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;766&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 64%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: 9.1pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Shares issuable related to our ESPP&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x2014;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;18&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 64%;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: 9.1pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt;Shares issuable related to our &lt;/span&gt;0.125&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt; percent convertible notes&lt;/span&gt;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;860&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;217&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 64%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: 9.1pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Shares issuable related to our 1 percent convertible notes&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;9,527&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;10,075&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 64%; padding-bottom: 4px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;290,947&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;153,164&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;1.90&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;div style="text-align: left;"&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Revenue Recognition&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;span style="text-decoration: underline;"&gt;Our Revenue Sources&lt;/span&gt;&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;We generally recognize revenue when we have satisfied all contractual obligations and are reasonably assured of collecting
    the resulting receivable. We are often entitled to bill our customers and receive payment from our customers in advance of recognizing the revenue. In the instances in which we have received payment from our customers in advance of recognizing revenue,
    we include the amounts in deferred revenue on our consolidated balance sheet.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;At contract inception, we analyze our collaboration arrangements to assess whether such arrangements involve joint
    operating activities performed by parties that are both active participants in the activities and exposed to significant risks and rewards dependent on the commercial success of such activities and therefore within the scope of ASC Topic 808,
    Collaborative Arrangements (ASC 808).&#160; For collaboration arrangements within the scope of ASC 808 that contain multiple elements, we first determine which elements of the collaboration reflect a vendor-customer relationship and therefore within the
    scope of ASC 606. When we determine elements of a collaboration do not reflect a vendor-customer relationship, we consistently apply the reasonable and rational policy election we made by analogizing to authoritative accounting literature.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;We evaluate the income statement classification for presentation of amounts due from or owed to other participants
    associated with multiple activities in a collaboration arrangement based on the nature of each separate activity. For example, in our eplontersen collaboration with AstraZeneca, we recognize funding received from AstraZeneca for co-development
    activities as revenue. While, we recognize cost sharing payments to and from AstraZeneca associated with co-commercialization activities and co-medical affairs activities as SG&amp;amp;A expense and research and development expense, respectively.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;"&gt;Commercial Revenue: SPINRAZA royalties and Licensing and other royalty revenue&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;We earn commercial revenue primarily in the form of royalty payments on net sales of SPINRAZA. We will also recognize as
    commercial revenue sales milestone payments and royalties we earn under our other partnerships.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;"&gt;Commercial Revenue: TEGSEDI and WAYLIVRA revenue, net&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;We began commercializing TEGSEDI and WAYLIVRA in Europe in January 2021 and TEGSEDI in North America in April 2021 through distribution
    agreements with Swedish Orphan Biovitrum AB, or Sobi. Under our agreements, we are responsible for supplying finished goods inventory to Sobi and Sobi is responsible for selling each medicine to the end customer. As a result of these agreements, we
    earn a distribution fee on net sales from Sobi for each medicine.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Prior to the second quarter of 2021 in North America, we sold TEGSEDI through exclusive distribution agreements with third-party logistics
    companies, or 3PLs, that took title to TEGSEDI. The 3PLs then distributed TEGSEDI to a specialty pharmacy and a specialty distributor, which we collectively refer to as wholesalers, who then distributed TEGSEDI to health care providers and patients. In
    the United States, or U.S., we had a single 3PL as our sole customer and in Canada we also had a single 3PL as our sole customer. Prior to 2021 in Europe, we sold TEGSEDI and WAYLIVRA to hospitals and pharmacies, which were our customers, using 3PLs as
    distributors.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt;Under our collaboration agreement with PTC
      Therapeutics International Limited, or PTC, PTC is responsible for commercializing TEGSEDI and WAYLIVRA in Latin America and Caribbean countries. In the third quarter of 2021, we earned a &lt;/span&gt;$4 million milestone payment from PTC when WAYLIVRA was approved in Brazil, which we included in TEGSEDI and WAYLIVRA revenue in our consolidated statement of operations. Under our agreement, we
    started receiving royalties from PTC for TEGSEDI sales beginning in December 2021.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: left; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;"&gt;Research and development revenue under collaborative agreements&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;We often enter into collaboration agreements to license and sell our technology on an exclusive or non-exclusive basis.
    Our collaboration agreements typically contain multiple elements, or performance obligations, including technology licenses or options to obtain technology licenses, research and development, or R&amp;amp;D, services, and manufacturing services.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;We provide details about our collaboration agreements in Note 6, &lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;"&gt;Collaborative Arrangements and Licensing Agreements.&lt;/span&gt;&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;&#160;&lt;/span&gt;For each collaboration, we discuss our specific revenue
    recognition conclusions, including our significant performance obligations under each collaboration.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: left; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;span style="text-decoration: underline;"&gt;Steps to Recognize Revenue&lt;/span&gt;&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;We use a five-step process to determine the amount of revenue we should recognize and when we should recognize it. The
    five step process is as follows:&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;"&gt;


  &lt;tr&gt;

    &lt;td style="width: 36pt;"/&gt;

    &lt;td style="width: 18pt; vertical-align: top; align: right; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic; font-weight: bold;"&gt;1.&lt;/td&gt;

    &lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;
          &lt;div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic; font-weight: bold;"&gt;Identify the contract&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Accounting rules require us to first determine if we have a contract with our partner, including confirming that we have met each of the
    following criteria:&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;"&gt;


  &lt;tr&gt;

    &lt;td style="width: 36pt;"/&gt;

    &lt;td style="width: 18pt; vertical-align: top; align: right; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x25cf;&lt;/td&gt;

    &lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;
          &lt;div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;We and our partner approved the contract and we are both committed to perform our obligations;&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;"&gt;


  &lt;tr&gt;

    &lt;td style="width: 36pt;"/&gt;

    &lt;td style="width: 18pt; vertical-align: top; align: right; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x25cf;&lt;/td&gt;

    &lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;
          &lt;div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;We have identified our rights, our partner&#x2019;s rights and the payment terms;&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;"&gt;


  &lt;tr&gt;

    &lt;td style="width: 36pt;"/&gt;

    &lt;td style="width: 18pt; vertical-align: top; align: right; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x25cf;&lt;/td&gt;

    &lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;
          &lt;div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;We have concluded that the contract has commercial substance, meaning that the risk, timing, or amount of our future cash flows is expected to change as a result of the
            contract; and&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;"&gt;


  &lt;tr&gt;

    &lt;td style="width: 36pt;"/&gt;

    &lt;td style="width: 18pt; vertical-align: top; align: right; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x25cf;&lt;/td&gt;

    &lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;
          &lt;div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;We believe collectability of the consideration is probable.&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;"&gt;


  &lt;tr&gt;

    &lt;td style="width: 36pt;"/&gt;

    &lt;td style="width: 18pt; vertical-align: top; align: right;"&gt;&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold; font-style: italic;"&gt;2.&lt;/span&gt;&lt;/td&gt;

    &lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;
          &lt;div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic; font-weight: bold;"&gt;Identify the performance obligations&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;We next identify our performance obligations, which represent the distinct goods and services we are required to provide under the
    contract.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt;Often we enter into a collaboration agreement
      in which we provide our partner with an option to license a medicine in the future. We may also provide our partner with an option to request that we provide additional goods or services in the future, such as active pharmaceutical ingredient, or
      API. We evaluate whether these options are material rights at the inception of the agreement. If we determine an option is a material right, we will consider the option a separate performance obligation. Historically, we have concluded that the
      options we grant to license a medicine in the future or to provide additional goods and services as requested by our partner are not material rights because these items are contingent upon future events that may not occur and are not priced at a
      significant discount. When a partner exercises its option to license a medicine or requests additional goods or services, then we identify a new performance obligation for that item&lt;/span&gt;.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;In some cases, we deliver a license at the start of an agreement. If we determine that our partner has full use of the license and we do
    not have any additional material performance obligations related to the license after delivery, then we consider the license to be a separate performance obligation. For example, in the fourth quarter of 2021, we received a $200 million upfront payment when we entered into an agreement with AstraZeneca to jointly develop and commercialize eplontersen. We recognized the upfront
    payment in full in the fourth quarter of 2021 because we did not have any remaining performance obligations after we delivered the license to AstraZeneca.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;"&gt;


  &lt;tr&gt;

    &lt;td style="width: 36pt;"/&gt;

    &lt;td style="width: 18pt; vertical-align: top; align: right; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic; font-weight: bold;"&gt;3.&lt;/td&gt;

    &lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;
          &lt;div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic; font-weight: bold;"&gt;Determine the transaction price&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;We then determine the transaction price by reviewing the amount of consideration we are eligible to earn under the
        collaboration agreement, including any variable consideration. Under our collaboration agreements, consideration typically includes fixed consideration in the form of an upfront payment and variable consideration in the form of potential milestone
        payments, license fees and royalties. At the start of an agreement, our transaction price usually consists of only the upfront payment. We do not typically include any payments we may receive in the future in our initial transaction price because
        the payments are not probable and are contingent on certain future events. We reassess the total transaction price at each reporting period to determine if we should include additional payments in the transaction price.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
    &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt;Milestone payments are our most common type
      of variable consideration. We recognize milestone payments using the most likely amount method because we will either receive the milestone payment or we will not, which makes the potential milestone payment a binary event. The most likely amount
      method requires us to determine the likelihood of earning the milestone payment. We include a milestone payment in the transaction price once it is probable we will achieve the milestone event. Most often, we do not consider our milestone payments
      probable until we or our partner achieve the milestone event because the majority of our milestone payments are contingent upon events that are not within our control and/ or are usually based on scientific progress which is inherently uncertain. For
      example, in the fourth quarter of 2021, we earned&lt;/span&gt; a $10 million &lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt;milestone payment from AstraZeneca when AstraZeneca advanced a target for a metabolic disease. We did not consider the milestone payment probable until AstraZeneca achieved the milestone event because advancing the target was
      contingent on AstraZeneca initiating a Phase 1 study and was not within our control. We recognized the milestone payment in full in the period the milestone event was achieved because we did not have any remaining performance obligations related to
      the milestone payment&lt;/span&gt;.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;"&gt;


  &lt;tr&gt;

    &lt;td style="width: 36pt;"/&gt;

    &lt;td style="width: 18pt; vertical-align: top; align: right; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic; font-weight: bold;"&gt;4.&lt;/td&gt;

    &lt;td style="width: auto; vertical-align: top; text-align: left;"&gt;
          &lt;div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic; font-weight: bold;"&gt;Allocate the transaction price&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Next, we allocate the transaction price to
        each of our performance obligations. When we have to allocate the transaction price to more than &lt;/span&gt;one&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt; performance obligation, we make estimates of the relative
        stand-alone selling price of each performance obligation because we do not typically sell our goods or services on a stand-alone basis. We then allocate the transaction price to each performance obligation based on the relative stand-alone selling
        price. We do not reallocate the transaction price after the start of an agreement to reflect subsequent changes in stand-alone selling prices.&lt;/span&gt;&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
    &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;We may engage a &lt;/span&gt;third&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt; party, independent valuation specialist to assist us with determining a stand-alone selling price for collaborations in which we deliver a license at the start of an agreement.
      We estimate the stand-alone selling price of these licenses using valuation methodologies, such as the relief from royalty method. Under this method, we estimate the amount of income, net of taxes, for the license. We then discount the projected
      income to present value. The significant inputs we use to determine the projected income of a license could include&lt;/span&gt;:&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;"&gt;


  &lt;tr&gt;

    &lt;td style="width: 36pt;"/&gt;

    &lt;td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x25cf;&lt;/td&gt;

    &lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Estimated future product sales;&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;"&gt;


  &lt;tr&gt;

    &lt;td style="width: 36pt;"/&gt;

    &lt;td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x25cf;&lt;/td&gt;

    &lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Estimated royalties we may receive from future product sales;&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;"&gt;


  &lt;tr&gt;

    &lt;td style="width: 36pt;"/&gt;

    &lt;td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x25cf;&lt;/td&gt;

    &lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Estimated contractual milestone payments we may receive;&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;"&gt;


  &lt;tr&gt;

    &lt;td style="width: 36pt;"/&gt;

    &lt;td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x25cf;&lt;/td&gt;

    &lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Expenses we expect to incur;&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;"&gt;


  &lt;tr&gt;

    &lt;td style="width: 36pt;"/&gt;

    &lt;td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x25cf;&lt;/td&gt;

    &lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Estimated income taxes; and&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;"&gt;


  &lt;tr&gt;

    &lt;td style="width: 36pt;"/&gt;

    &lt;td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x25cf;&lt;/td&gt;

    &lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;A discount rate.&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;We typically estimate the selling price of R&amp;amp;D services by using our internal estimates of the cost to perform the
    specific services. The significant inputs we use to determine the selling price of our R&amp;amp;D services include:&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;"&gt;


  &lt;tr&gt;

    &lt;td style="width: 36pt;"/&gt;

    &lt;td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x25cf;&lt;/td&gt;

    &lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;The number of internal hours we estimate we will spend performing these services;&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;"&gt;


  &lt;tr&gt;

    &lt;td style="width: 36pt;"/&gt;

    &lt;td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x25cf;&lt;/td&gt;

    &lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;The estimated cost of work we will perform;&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;"&gt;


  &lt;tr&gt;

    &lt;td style="width: 36pt;"/&gt;

    &lt;td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x25cf;&lt;/td&gt;

    &lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;The estimated cost of work that we will contract with third parties to perform; and&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;"&gt;


  &lt;tr&gt;

    &lt;td style="width: 36pt;"/&gt;

    &lt;td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x25cf;&lt;/td&gt;

    &lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;The estimated cost of API we will use.&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;For purposes of determining the stand-alone selling price of the R&amp;amp;D services we perform and the API we will deliver,
    accounting guidance requires us to include a markup for a reasonable profit margin.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;"&gt;


  &lt;tr&gt;

    &lt;td style="width: 36pt;"/&gt;

    &lt;td style="width: 18pt; vertical-align: top; align: right; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic; font-weight: bold;"&gt;5.&lt;/td&gt;

    &lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;
          &lt;div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic; font-weight: bold;"&gt;Recognize revenue&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;We recognize revenue in &lt;/span&gt;one&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt; of &lt;/span&gt;two&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt; ways, over time or at a point in time. We recognize revenue over time when we are
        executing on our performance obligation over time and our partner receives benefit over time. For example, we recognize revenue over time when we provide R&amp;amp;D services. We recognize revenue at a point in time when our partner receives full use
        of an item at a specific point in time. For example, we recognize revenue at a point in time when we deliver a license or API to a partner.&lt;/span&gt;&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
    &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;For R&amp;amp;D services that we recognize over
      time, we measure our progress using an input method. The input methods we use are based on the effort we expend or costs we incur toward the satisfaction of our performance obligation. We estimate the amount of effort we expend, including the time we
      estimate it will take us to complete the activities, or costs we incur in a given period, relative to the estimated total effort or costs to satisfy the performance obligation. This results in a percentage that we multiply by the transaction price to
      determine the amount of revenue we recognize each period. This approach requires us to make numerous estimates and use significant judgement. If our estimates or judgements change over the course of the collaboration, they may affect the timing and
      amount of revenue that we recognize in the current and future periods.&lt;/span&gt; Refer to Note 6, &lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;"&gt;Collaborative Arrangements and Licensing Agreements&lt;/span&gt;,
    for further discussion of the cumulative catch up adjustment we made.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: left; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;The following are examples of when we typically recognize revenue based on the types of payments we receive.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: left; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;"&gt;&lt;span style="text-decoration: underline;"&gt;Commercial Revenue: SPINRAZA royalties and Licensing and other royalty revenue&lt;/span&gt;&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;We recognize royalty revenue, including
      royalties from SPINRAZA sales, in the period in which the counterparty sells the related product and recognizes the related revenue, which in certain cases may require us to estimate our royalty revenue&lt;/span&gt;.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: left; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;"&gt;&lt;span style="text-decoration: underline;"&gt;Commercial Revenue: TEGSEDI and WAYLIVRA revenue, net&lt;/span&gt;&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Under our distribution agreements with Sobi we concluded that our performance obligation is to provide services to
      Sobi over the term of the agreement, which includes supplying finished goods inventory to Sobi and because we retained the marketing authorization for TEGSEDI and WAYLIVRA we are responsible for leading the global commercial strategy for each
      medicine. We view this performance obligation as a series of distinct activities that are substantially the same. Therefore, we recognize as revenue the price Sobi pays us for the inventory when we deliver the finished goods inventory to Sobi. We
      also recognize distribution fee revenue based on Sobi&#x2019;s net sales of TEGSEDI and WAYLIVRA in the period in which the sales occurred. Under our agreements with Sobi, Sobi does not generally have a right of return.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt;Prior to our distribution agreements with
      Sobi, we recognized TEGSEDI and WAYLIVRA commercial revenue in the period when our customer obtained control of our products, which occurred at a point in time upon transfer of title to the customer. We classified payments to customers or other
      parties in the distribution channel for services that were distinct and priced at fair value as selling, general and administrative, or SG&amp;amp;A, expenses in our consolidated statements of operations. We classified payments to customers or other
      parties in the distribution channel that did not meet those criteria as a reduction of revenue, as discussed further below. We excluded from revenues taxes collected from customers relating to TEGSEDI and WAYLIVRA commercial revenue and remitted
      these amounts to governmental authorities&lt;/span&gt;.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;"&gt;Reserves for TEGSEDI and WAYLIVRA commercial revenue&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Prior to our distribution agreements with Sobi, we recorded TEGSEDI and WAYLIVRA commercial revenue at our net sales
      price, or transaction price. We included in our transaction price estimated reserves for discounts, returns, chargebacks, rebates and other allowances that we offered within contracts between us and our customers, wholesalers, distributors, health
      care providers and other indirect customers. We estimated our reserves using the amounts we have earned or we could claim on the associated sales. We classified our reserves as a reduction of accounts receivable when we were not required to make a
      payment or as a current liability when we were required to make a payment. In certain cases, our estimates included a range of possible outcomes that were probability weighted for relevant factors such as our historical experience, current
      contractual and statutory requirements, specific known market events and trends, industry data and forecasted customer buying and payment patterns. Overall, our reserves reflected our best estimates under the terms of our respective contracts. When
      calculating our reserves and related TEGSEDI and WAYLIVRA commercial revenue, we only recognized amounts to the extent that we considered it probable that we would not have to reverse a significant amount of the cumulative sales we previously
      recognized in a future period. Under our agreements with Sobi, we transferred all reserves to Sobi.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: left; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;The following were the components of variable consideration related to TEGSEDI and WAYLIVRA product sales prior to our agreements with Sobi:&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="text-align: justify; margin-left: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;"&gt;Chargebacks: &lt;/span&gt;&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt;In the U.S., we estimated obligations resulting from contractual commitments with the government and other entities to sell products to qualified healthcare
      providers at prices lower than the list prices charged to our U.S. customer. Our U.S. customer charged us for the difference between what it paid for the product and the selling price to the qualified healthcare providers. We also estimated the
      amount of chargebacks related to our estimated product remaining in the distribution channel at the end of the reporting period that we expected our customer to sell to healthcare providers in future periods. We recorded these reserves as a reduction
      to contracts receivable on our consolidated balance sheet&lt;/span&gt;.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="text-align: justify; margin-left: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic; color: #000000;"&gt;Government rebates&lt;/span&gt;&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt;: We were subject to discount obligations under government programs, including Medicaid and Medicare programs in the U.S. and we recorded reserves for government
      rebates based on statutory discount rates and estimated utilization. We estimated Medicaid and Medicare rebates based on a range of possible outcomes that were probability weighted for the estimated payer mix. We recorded these reserves as an accrued
      liability on our consolidated balance sheet with a corresponding offset reducing our product sales in the same period we recognized the related sale. For Medicare, we also estimated the number of patients in the prescription drug coverage gap for
      whom we would owe an additional liability under the Medicare Part D program. On a quarterly basis, we updated our estimates and recorded any adjustments in the period that we identified the adjustments&lt;/span&gt;.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="text-align: justify; margin-left: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;"&gt;Managed care rebates: &lt;/span&gt;&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt;We were subject to rebates in connection with agreements with certain contracted commercial payers. We recorded these rebates as a liability on our consolidated
      balance sheet in the same period we recognized the related revenue. We estimated our managed care rebates based on our estimated payer mix and the applicable contractual rebate rate&lt;/span&gt;.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="text-align: justify; margin-left: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;"&gt;Trade discounts: &lt;/span&gt;&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt;We provided customary invoice discounts on product sales to our U.S. customer for prompt payment. We recorded this discount as a reduction of product sales in the
      period in which we recognized the related product revenue&lt;/span&gt;.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="text-align: justify; margin-left: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;"&gt;Distribution services&lt;/span&gt;: &lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt;We received and paid for various distribution services from our U.S. and European customers (prior to our agreement with Sobi) and wholesalers in the U.S. We
      classified the costs for services we received that are either not distinct from the sale of the product or for which we could not reasonably estimate the fair value as a reduction of product sales. To the extent that the services we received are
      distinct from the sale of the product, we classified the costs for such services as SG&amp;amp;A expenses.&lt;/span&gt;&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="text-align: justify; margin-left: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;"&gt;Product returns: &lt;/span&gt;&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt;Our U.S. customer had return rights and the wholesalers had limited return rights primarily related to the product&#x2019;s expiration date. We estimated the amount of
      product sales that our customer may return. We recorded our return estimate as an accrued refund liability on our consolidated balance sheet with a corresponding offset reducing our product sales in the same period we recognized the related sale.
      Based on our distribution model for product sales, contractual inventory limits with our customer and wholesalers and the price of the product, we had minimal returns. Our European customers generally only took title to the product after they
      received an order and therefore they did not maintain excess inventory levels of our products. Accordingly, we had limited return risk in Europe and we did not estimate returns in Europe&lt;/span&gt;.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: left; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;"&gt;&lt;span style="text-decoration: underline;"&gt;Research and development revenue under collaboration agreements:&lt;/span&gt;&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: left; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;"&gt;&lt;span style="text-decoration: underline;"&gt;Upfront payments&lt;/span&gt;&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt;When we enter into a collaboration agreement
      with an upfront payment, we typically record the entire upfront payment as deferred revenue if our only performance obligation is for R&amp;amp;D services we will provide in the future. We amortize the upfront payment into revenue as we perform the
      R&amp;amp;D services. For example, under our collaboration agreement with Roche to&lt;/span&gt;&lt;span style="background-color: #FBFBFB; font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt; develop IONIS-FB-L&lt;/span&gt;&lt;sub style="color: #000000;"&gt;Rx&lt;/sub&gt;&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt; for the treatment of complement-mediated diseases, we received a $&lt;/span&gt;75&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt; million upfront payment in the fourth quarter of 2018. We allocated the upfront payment to our
      single performance obligation, R&amp;amp;D services. We are amortizing the $&lt;/span&gt;75&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt; million upfront payment using an input method over the estimated period of time we are providing R&amp;amp;D services&lt;/span&gt;.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;"&gt;&lt;span style="text-decoration: underline;"&gt;Milestone payments&lt;/span&gt;&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;We are required to include additional consideration in the transaction price when it is probable. We typically
        include milestone payments for R&amp;amp;D services in the transaction price when they are achieved. We include these milestone payments when they are achieved because typically there is considerable uncertainty in the research and development
        processes that trigger these payments. Similarly, we include approval milestone payments in the transaction price once the medicine is approved by the applicable regulatory agency. We will recognize sales-based milestone payments in the period in
        which we achieve the milestone under the sales-based royalty exception allowed under accounting rules.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt;We recognize milestone payments that relate
      to an ongoing performance obligation over our period of performance. For example, in the fourth quarter of 2021, we achieved a&lt;/span&gt; $7.5&#160;&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt;million milestone payment from Biogen when we advanced&lt;/span&gt;&#160;&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt;a &lt;/span&gt;target
    under our 2018 strategic collaboration.&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt; We added this payment to the transaction price and allocated it to our R&amp;amp;D services performance obligation. We are
      recognizing revenue related to this milestone payment over our estimated period of performance&lt;/span&gt;.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Conversely, we recognize in full those milestone payments that we earn based on our partners&#x2019; activities when our partner achieves the
    milestone event and we do not have a performance obligation. For example, in the fourth quarter of 2021, we recognized $15 million in milestone
    payments when Biogen advanced two targets under our 2018 strategic collaboration. &lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt;We concluded that the milestone payments were not related to our R&amp;amp;D services performance obligation. Therefore, we recognized the milestone payments in full in the fourth quarter of 2021.&lt;/span&gt;&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;"&gt;&lt;span style="text-decoration: underline;"&gt;License fees&lt;/span&gt;&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt;We generally recognize as revenue the total
      amount we determine to be the relative stand-alone selling price of a license when we deliver the license to our partner. This is because our partner has full use of the license and we do not have any additional performance obligations related to the
      license after delivery. For example, in the fourth quarter of 2021, we earned a&lt;/span&gt; $60&#160;&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt;million license fee from Biogen when Biogen licensed ION306, an investigational medicine in development to treat SMA.&lt;/span&gt;&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;"&gt;&lt;span style="text-decoration: underline;"&gt;Sublicense fees&lt;/span&gt;&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt;We recognize sublicense fee revenue in the
      period in which a party, who has already licensed our technology, further licenses the technology to another party because we do not have any performance obligations related to the sublicense. &lt;/span&gt;For example, in the fourth quarter of 2020, we
    earned a $41.2 million sublicense fee from Alnylam Pharmaceuticals for its sublicense of our technology to Sanofi Genzyme.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic; font-weight: bold;"&gt;Amendments to Agreements&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;From time to time we amend our collaboration agreements. When this occurs, we are required to assess the following items
    to determine the accounting for the amendment:&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;"&gt;


  &lt;tr&gt;

    &lt;td style="width: 36pt;"/&gt;

    &lt;td style="width: 18pt; vertical-align: top; align: right; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;1)&lt;/td&gt;

    &lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;
          &lt;div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;If the additional goods and/or services are distinct from the other performance obligations in the original agreement; and&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;"&gt;


  &lt;tr&gt;

    &lt;td style="width: 36pt;"/&gt;

    &lt;td style="width: 18pt; vertical-align: top; align: right; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;2)&lt;/td&gt;

    &lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;
          &lt;div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;If the goods and/or services are at a stand-alone selling price.&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;If we conclude the goods and/or services in the amendment are distinct from the performance obligations in the
        original agreement and at a stand-alone selling price, we account for the amendment as a separate agreement. If we conclude the goods and/or services are not distinct and are sold at a stand-alone selling price, we then assess whether the remaining
        goods or services are distinct from those already provided. If the goods and/or services are distinct from what we have already provided, then we allocate the remaining transaction price from the original agreement and the additional transaction
        price from the amendment to the remaining goods and/or services. If the goods and/or services are not distinct from what we have already provided, we update the transaction price for our single performance obligation and recognize any change in our
        estimated revenue as a cumulative adjustment.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
    &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;For example, in May 2015, we entered into an exclusive license agreement with Bayer to develop and commercialize IONIS-FXI&lt;sub&gt;Rx&lt;/sub&gt;
    for the prevention of thrombosis. As part of the agreement, Bayer paid us a $100 million upfront payment. At the onset of the agreement, we were
    responsible for completing a Phase 2 study of IONIS-FXI&lt;sub&gt;Rx&lt;/sub&gt; in people with end-stage renal disease on hemodialysis and for providing an initial supply of API. In February 2017, we amended our agreement with Bayer to advance IONIS-FXI&lt;sub&gt;Rx&lt;/sub&gt;
    and to initiate development of fesomersen, which Bayer licensed. As part of the 2017 amendment, Bayer paid us $75 million. We are also eligible
    to receive milestone payments and tiered royalties on gross margins of IONIS-FXI&lt;sub&gt;Rx&lt;/sub&gt; and fesomersen. Under the 2017 amendment, we concluded we had a new agreement with three performance obligations. These performance obligations were to deliver the license of fesomersen, to provide R&amp;amp;D services and to deliver API. We allocated the $75 million transaction price to these performance obligations. Refer to Note 6, &lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;"&gt;Collaborative Arrangements and Licensing Agreements&lt;/span&gt;, for further discussion of the Bayer collaboration.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic; font-weight: bold;"&gt;Multiple agreements&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;From time to time, we may enter into separate agreements at or near the same time with the same partner. We evaluate such
    agreements to determine whether we should account for them individually as distinct arrangements or whether the separate agreements should be combined and accounted for together. We evaluate the following to determine the accounting for the agreements:&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;"&gt;


  &lt;tr&gt;

    &lt;td style="width: 36pt;"/&gt;

    &lt;td style="width: 18pt; vertical-align: top; align: right; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x25cf;&lt;/td&gt;

    &lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;
          &lt;div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Whether the agreements were negotiated together with a single objective;&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;"&gt;


  &lt;tr&gt;

    &lt;td style="width: 36pt;"/&gt;

    &lt;td style="width: 18pt; vertical-align: top; align: right; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x25cf;&lt;/td&gt;

    &lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;
          &lt;div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Whether the amount of consideration in one contract depends on the price or performance of the other agreement; or&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;"&gt;


  &lt;tr&gt;

    &lt;td style="width: 36pt;"/&gt;

    &lt;td style="width: 18pt; vertical-align: top; align: right; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x25cf;&lt;/td&gt;

    &lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;
          &lt;div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Whether the goods and/or services promised under the agreements are a single performance obligation.&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Our evaluation involves significant judgment to determine whether a group of agreements might be so closely related that accounting
    guidance requires us to account for them as a combined arrangement.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;For example, in the second quarter of 2018, we entered into two separate agreements with Biogen at the same time: &lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt;a new strategic neurology collaboration
      agreement and a stock purchase agreement, or SPA. We evaluated the Biogen agreements to determine whether we should treat the agreements separately or combine them. We considered that the agreements were negotiated concurrently and in contemplation
      of one another. Based on these facts and circumstances, we concluded that we should evaluate the provisions of the agreements on a combined basis.&lt;/span&gt;&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: left; text-indent: -54pt; margin-left: 54pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Contracts Receivable&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt;Our contracts receivable balance represents
      the amounts we have billed our partners or customers and that are due to us unconditionally for goods we have delivered or services we have performed. When we bill our partners or customers with payment terms based on the passage of time, we consider
      the contracts receivable to be unconditional. We typically receive payment within one &lt;/span&gt;&lt;span style="-sec-ix-hidden:Fact_e2c2673a057f412ebd5831ca8712546a"&gt;quarter&lt;/span&gt;&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt; of billing our partner or customer&lt;/span&gt;.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;As of December 31, 2021, approximately 93.8 percent of our contracts receivables were from two significant customers. As of December 31, 2020, approximately 99.5 percent of our contracts receivables were from two
    significant customers.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Unbilled SPINRAZA Royalties&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Our unbilled SPINRAZA royalties represent our right to receive consideration from Biogen in advance of when we are
    eligible to bill Biogen for SPINRAZA royalties. We include these unbilled amounts in other current assets on our consolidated balance sheet.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: left; text-indent: -54pt; margin-left: 54pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Deferred Revenue&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt;We are often entitled to bill our customers
      and receive payment from our customers in advance of our obligation to provide services or transfer goods to our partners. In these instances, we include the amounts in deferred revenue on our consolidated balance sheet.&lt;/span&gt; During the years ended
    December 31, 2021 and 2020, we recognized $98.1 million and $100.4 million of revenue from amounts that were in our beginning deferred revenue balance for each respective period. For further discussion, refer to our revenue recognition policy above.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Cost of Sales&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Our cost of sales includes manufacturing costs, transportation and freight costs and indirect overhead costs associated with the
    manufacturing and distribution of our products. We also may include certain period costs related to manufacturing services and inventory adjustments in cost of sales. We also may include certain period costs related to manufacturing services and
    inventory adjustments in cost of sales.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Research, Development and Patent Expenses&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Our research and development expenses include wages, benefits, facilities, supplies, external
    services, clinical trial and manufacturing costs and other expenses that are directly related to our research and development operations. We expense research and development costs as we incur them. When we make payments for research and development
    services prior to the services being rendered, we record those amounts as prepaid assets on our consolidated balance sheet and we expense them as the services are provided. For the years ended December 31, 2021, 2020 and 2019, research and development expenses were $638.2 million, $531.0 million and $461.5 million, respectively. A
    portion of the costs included in research and development expenses are costs associated with our partner agreements.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;We capitalize costs consisting principally of outside legal costs and filing fees related to obtaining
    patents. We amortize patent costs over the useful life of the patent, beginning with the date the U.S. Patent and Trademark Office, or foreign equivalent, issues the patent. The weighted average remaining amortizable life of our issued patents was 10.2 years at December 31, 2021.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;The cost of our patents capitalized on our consolidated balance sheet at December 31, 2021 and 2020 was $38.4 million and $37.0 million, respectively.
    Accumulated amortization related to patents was $9.4 million and $9.1 million at December 31, 2021 and 2020, respectively.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Based on our existing patents, we estimate amortization expense related to patents in each of
    the next five years to be the following:&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;"&gt;


  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; border-bottom: #000000 2px solid;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Year Ending December 31,&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Amortization&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;(in millions)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 88%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;span style="text-indent: 0pt;"&gt;2022&lt;/span&gt;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;2.2&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 88%;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;span style="text-indent: 0pt;"&gt;2023&lt;/span&gt;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;2.1&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 88%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;span style="text-indent: 0pt;"&gt;2024&lt;/span&gt;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;1.9&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 88%;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;span style="text-indent: 0pt;"&gt;2025&lt;/span&gt;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;1.8&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 88%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;span style="text-indent: 0pt;"&gt;2026&lt;/span&gt;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;1.8&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 12pt;"&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;We review our capitalized patent costs regularly to ensure that they include costs for patents and patent applications
    that have future value. When we identify patents and patent applications that we are not actively pursuing, we write off any associated costs. In 2021,
    2020 and 2019, patent expenses
    were $5.3 million, $4.1 million and $4.2 million, respectively, and included non-cash charges related to the write-down of our patent costs to their estimated net realizable values of $2.7 million, $1.9 million and $2.2 million, respectively.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Accrued Liabilities&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Our accrued liabilities consisted of the following (in thousands):&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;"&gt;


  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;

        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="6" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;December 31,&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;2021&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;2020&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 76%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Clinical expenses&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;65,730&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;39,477&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 76%;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -18pt; margin-left: 18pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;In-licensing expenses&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;8,044&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;8,264&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 76%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -18pt; margin-left: 18pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Commercial expenses&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;2,471&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;11,559&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 76%; padding-bottom: 2px;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -18pt; margin-left: 18pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Other miscellaneous expenses&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;12,315&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;30,861&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 76%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Total accrued liabilities&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;88,560&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;90,161&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 12pt;"&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: left; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;"&gt;Estimated Liability for Clinical Development Costs&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;We have numerous medicines in preclinical studies and/or clinical trials at clinical sites throughout the world. On at least a quarterly
    basis, we estimate our liability for preclinical and clinical development costs we have incurred and services that we have received but for which we have not yet been billed and maintain an accrual to cover these costs. These costs primarily relate to
    third-party clinical management costs, laboratory and analysis costs, toxicology studies and investigator grants. We estimate our liability using assumptions about study and patient activities and the related expected expenses for those activities
    determined based on the contracted fees with our service providers. The assumptions we use represent our best estimates of the activity and expenses at the time of our accrual and involve inherent uncertainties and the application of our judgment. Upon
    settlement, these costs may differ materially from the amounts accrued in our consolidated financial statements. Our historical accrual estimates have not been materially different from our actual amounts.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Noncontrolling Interest in Akcea Therapeutics, Inc.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt;Since Akcea&#x2019;s IPO in July 2017 and prior to
      the Akcea Merger in October 2020, the shares of Akcea&#x2019;s common stock third parties owned represented an interest in Akcea&#x2019;s equity that we did not control. During this period our ownership ranged from &lt;/span&gt;68 percent&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt; to &lt;/span&gt;77 percent&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt;. However, as we maintained overall control of Akcea through our voting interest, we
      reflected the assets, liabilities and results of operations of Akcea in our consolidated financial statements. Since Akcea&#x2019;s IPO in July 2017 and through the closing of the Akcea Merger, we reflected the noncontrolling interest attributable to other
      owners of Akcea&#x2019;s common stock on a separate line on our statement of operations and a separate line within stockholders&#x2019; equity in our consolidated balance sheet. In addition, through the closing of the Akcea Merger, we recorded a noncontrolling
      interest adjustment to account for the stock options Akcea granted, which if exercised, would have diluted our ownership in Akcea. This adjustment was a reclassification within stockholders&#x2019; equity from additional paid-in capital to noncontrolling
      interest in Akcea equal to the amount of stock-based compensation expense Akcea had recognized. Additionally, w&lt;/span&gt;e reflected changes in our ownership percentage in our financial statements as an adjustment to noncontrolling interest in the
    period the change occurred.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Concentration of Credit Risk&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Financial instruments that potentially subject us to concentrations of credit risk consist primarily of cash equivalents,
    short-term investments and receivables. We place our cash equivalents and short-term investments with reputable financial institutions. We primarily invest our excess cash in commercial paper and debt instruments of the U.S. Treasury, financial
    institutions, corporations, and U.S. government agencies with strong credit ratings and an investment grade rating at or above A-1, P-1 or F-1 by Moody&#x2019;s, Standard &amp;amp; Poor&#x2019;s, or S&amp;amp;P, or Fitch, respectively. We have established guidelines
    relative to diversification and maturities that maintain safety and liquidity. We periodically review and modify these guidelines to maximize trends in yields and interest rates without compromising safety and liquidity.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Cash, Cash Equivalents and Investments&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;We consider all liquid investments with maturities of three months or less when we purchase them to be cash equivalents.
    Our short-term investments have initial maturities of greater than three months from date of purchase. We classify our short-term debt investments as &#x201c;available-for-sale&#x201d; and carry them at fair market value based upon prices on the last day of the
    fiscal period for identical or similar items. We record unrealized gains and losses on debt securities as a separate component of comprehensive income (loss) and include net realized gains and losses in gain (loss) on investments in our consolidated
    statement of operations. We use the specific identification method to determine the cost of securities sold.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;We also have equity investments of less than 20 percent ownership in publicly and privately held biotechnology companies
      that we received as part of a technology license or partner agreement. At December 31, 2021, we held equity investments in three publicly held companies, Antisense Therapeutics Limited, or ATL, Bicycle Therapeutics plc, or Bicycle, and ProQR Therapeutics N.V., or ProQR. We
      also held equity investments in seven privately-held companies, Aro Biotherapeutics, Atlantic Pharmaceuticals Limited, Dynacure SAS, Empirico,
      Inc., Flamingo Therapeutics BV, YourBio Health, Inc. (formerly Seventh Sense Biosystems) and Suzhou-Ribo Life Science Co, Ltd.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;We are required to measure and record our equity investments at fair value and to recognize the changes in fair value in our consolidated
    statement of operations. We account for our equity investments in privately held companies at their cost minus impairments, plus or minus changes resulting from observable price changes in orderly transactions for the identical or similar investment of
    the same issuer. For example, d&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt;uring 2020, we revalued our investments in &lt;/span&gt;three&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt; privately held companies, Dynacure, Suzhou-Ribo and Aro Biotherapeutics because the companies
      sold additional equity securities that were similar to the equity we own. As a result of these observable price changes, we recognized a $&lt;/span&gt;6.3&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt; million gain on our investment in Dynacure, a $&lt;/span&gt;3.0&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt; million gain on our investment in Suzhou-Ribo and a $&lt;/span&gt;5.5&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt; million gain on our investment in Aro Biotherapeutics in our consolidated statement of operations during 2020 because the sales were at higher prices compared to
      our recorded value.&lt;/span&gt;&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Inventory Valuation&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;We reflect our inventory on our consolidated balance sheet at the lower of cost or net realizable value under the first-in, first-out
    method, or FIFO. We capitalize the costs of raw materials that we purchase for use in producing our medicines because until we use these raw materials, they have alternative future uses, which we refer to as clinical raw materials. We include in
    inventory raw material costs for medicines that we manufacture for our partners under contractual terms and that we use primarily in our clinical development activities and drug products. We can use each of our raw materials in multiple products and,
    as a result, each raw material has future economic value independent of the development status of any single medicine. For example, if one of our medicines failed, we could use the raw materials for that medicine to manufacture our other medicines. We
    expense these costs as R&amp;amp;D expenses when we begin to manufacture API for a particular medicine if the medicine has not been approved for marketing by a regulatory agency. Our raw materials- commercial inventory includes API for our commercial
    medicines. We capitalize material, labor and overhead costs as part of our raw materials- commercial inventory.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;We review our inventory periodically and reduce the carrying value of items we consider to be slow moving or obsolete to
    their estimated net realizable value based on forecasted demand compared to quantities on hand. We consider several factors in estimating the net realizable value, including shelf life of our inventory, alternative uses for our medicines in development
    and historical write-offs. We recorded an &lt;span style="-sec-ix-hidden:Fact_df7c1770e27a4789b9f7ad5345f29256"&gt;&lt;span style="-sec-ix-hidden:Fact_7ba6995a24424942b581829d4ed245cc"&gt;insignificant&lt;/span&gt;&lt;/span&gt; amount of inventory write-offs during the years ended December 31, 2021 and 2020.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Our inventory consisted of the following (in thousands):&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;"&gt;


  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;

        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="6" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;December 31,&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;2021&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;2020&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Raw materials:&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 76%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 19.4pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Raw materials- clinical&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;14,507&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;9,206&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 76%; padding-bottom: 2px;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -18pt; margin-left: 28.4pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Raw materials- commercial&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;4,139&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;7,502&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 76%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 28.45pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Total raw materials&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;18,646&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;16,708&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 76%;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Work in process&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;5,770&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;2,252&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 76%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Finished goods&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;390&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;3,005&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 76%; padding-bottom: 4px;" valign="bottom"&gt;
          &lt;div style="text-align: justify; margin-left: 28.45pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Total inventory&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;24,806&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;21,965&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;div style="text-align: left;"&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Property, Plant and Equipment&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;We carry our property, plant and equipment at cost and depreciate it on the straight-line method
    over its estimated useful life, which consists of the following (in thousands):&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;"&gt;


  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;

        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Estimated Useful&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="6" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;December 31,&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Lives (in years)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;2021&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;2020&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Computer software, laboratory, manufacturing and other equipment&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;3 to 10&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;72,802&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;68,990&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Building, building improvements and building systems&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;15 to 40&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;144,046&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;137,879&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Land improvements&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" rowspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: rgb(0, 0, 0); font-family: 'Times New Roman',Times,serif; font-size: 10pt; text-align: center;"&gt;20&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;10,077&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;8,391&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Leasehold improvements&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;5 to 15&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;20,144&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;17,263&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Furniture and fixtures&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;5 to 10&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;10,591&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;12,871&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 64%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;257,660&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;245,394&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Less accumulated depreciation&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(102,653&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(87,379&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 64%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;155,007&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;158,015&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Land&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;23,062&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;23,062&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 64%; padding-bottom: 4px;" valign="bottom"&gt;
          &lt;div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#160;Total&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;178,069&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;181,077&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 12pt;"&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;We depreciate our leasehold improvements using the shorter of the estimated useful life or remaining lease term.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Fair Value of Financial Instruments&lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;We have estimated the fair value of our financial instruments. The amounts reported for cash, accounts receivable,
    accounts payable and accrued expenses approximate the fair value because of their short maturities. We report our investment securities at their estimated fair value based on quoted market prices for identical or similar instruments.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Leases&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;We determine if an arrangement contains a lease at inception. We currently only have operating leases. We recognize a
    right-of-use operating lease asset and associated short- and long-term operating lease liability on our consolidated balance sheet for operating leases greater than one year. Our right-of-use assets represent our right to use an underlying asset for
    the lease term and our lease liabilities represent our obligation to make lease payments arising from the lease arrangement. We recognize our right-of-use operating lease assets and lease liabilities based on the present value of the future minimum
    lease payments we will pay over the lease term.&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;&#160;&lt;/span&gt;We determine the lease term at the inception of each lease, and in certain cases our lease term could
    include renewal options if we concluded we were reasonably certain that we will exercise the renewal option. When we exercise a lease option that was not previously included in the initial lease term, we reassess our right-of-use asset and lease
    liabilities for the new lease term.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;As our leases do not provide an interest rate implicit in the lease, we used our incremental borrowing rate, based on the
    information available on the date we adopted Topic 842 (January 2019), as of the lease inception date or at the lease option extension date in determining the present value of future payments. We recognize rent expense for our minimum lease payments on
    a straight-line basis over the expected term of our lease. We recognize period expenses, such as common area maintenance expenses, in the period we incur the expense.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Long-Lived Assets&lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;We evaluate long-lived assets, which include property, plant and equipment and patent costs, for impairment on at least a
    quarterly basis and whenever events or changes in circumstances indicate that we may not be able to recover the carrying amount of such assets. We recorded charges of $2.7 million, $1.9 million and $2.2 million for the years ended December 31, 2021, 2020 and 2019, respectively, related to the
    write-down of patents.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Use of Estimates&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;We prepare our consolidated financial statements in conformity with accounting principles generally accepted in the U.S.
    that require us to make estimates and assumptions that affect the amounts reported in our consolidated financial statements and accompanying notes. Actual results could differ from our estimates.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Stock-Based Compensation Expense&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;We measure stock-based compensation expense for equity-classified awards, principally related to stock options, RSUs,
    PRSUs and stock purchase rights under our ESPP based on the estimated fair value of the award on the date of grant. We recognize the value of the portion of the award that we ultimately expect to vest as stock-based compensation expense over the
    requisite service period in our consolidated statements of operations. We reduce stock-based compensation expense for estimated forfeitures at the time of grant and revise in subsequent periods if actual forfeitures differ from those estimates. We use
    the Black-Scholes model to estimate the fair value of stock options granted and stock purchase rights under our ESPP.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;On the grant date, we use our stock price and assumptions regarding a number of variables to determine the estimated fair
    value of stock-based payment awards. These variables include, but are not limited to, our expected stock price volatility over the term of the awards, and actual and projected employee stock option exercise behaviors. The expected term of stock options
    granted represents the period of time that we expect them to be outstanding. We estimate the expected term of options granted based on historical exercise patterns.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;We recognize compensation expense for stock options granted, RSUs, PRSUs and stock purchase rights under the ESPP using
    the accelerated multiple-option approach. Under the accelerated multiple-option approach (also known as the graded-vesting method), we recognize compensation expense over the requisite service period for each separately vesting tranche of the award as
    though the award were in substance multiple awards, which results in the expense being front-loaded over the vesting period.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt;In December 2020, we amended and restated the
      Akcea 2015 equity plan, including renaming the plan as the Ionis Pharmaceuticals, Inc. 2020 Equity Incentive Plan, or 2020 Plan. As a result, all employees are now under an Ionis stock plan and subject to the same Black-Scholes assumptions&lt;/span&gt;.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;"&gt;RSU&#x2019;s:&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;The fair value of RSUs is based on the market price of our common stock on the date of grant. The RSUs we have granted to
    employees vest annually over a four-year period. The RSUs we granted to our board of directors prior to June 2020 vest annually over a four-year period. RSUs granted to our board of directors after June 2020 fully vest after one year.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;"&gt;PRSU&#x2019;s:&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Beginning in 2020, we added PRSU awards to the compensation for our Chief Executive Officer, Dr. Brett Monia. Under the
    terms of the grants, &lt;span style="-sec-ix-hidden:Fact_65d15117ab79462e81dfb8bbb86a0107"&gt;&lt;span style="-sec-ix-hidden:Fact_e9934b85c6af480197be8d0d8b5ea434"&gt;&lt;span style="-sec-ix-hidden:Fact_5599af32346c4fce91fa6d27caf4b474"&gt;one third&lt;/span&gt;&lt;/span&gt;&lt;/span&gt; of the PRSUs may vest at the end of three separate performance periods spread over the three years following the date of
    grant (i.e., the one-year period commencing on the date of grant and ending on the first anniversary of the date of grant; the two-year period commencing on the date of grant and ending on the second anniversary of the date of grant; and the three-year period commencing on the date of grant and ending on the third anniversary of the date of grant) based on our relative total shareholder return, or TSR, as compared to a
    peer group of companies, and as measured, in each case, at the end of the applicable performance period. Under the terms of the grants no number
    of PRSUs is guaranteed to vest and the actual number of PRSUs that will vest at the end of each performance period may be anywhere from zero to
    150 percent of the target number depending on our relative TSR.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;We determined the fair value of Dr. Monia&#x2019;s PRSUs using a Monte Carlo model because the performance target is based on our
    relative TSR, which represents a market condition. We are recognizing the grant date fair value of these awards as stock-based compensation expense using the accelerated multiple-option approach over the vesting period. The weighted-average grant date
    fair value of PRSUs granted to Dr. Monia for the years ended December 31, 2021 and 2020 were $77.17 and $93.09 per share, respectively.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;See Note 4, &lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;"&gt;Stockholders&#x2019;
      Equity,&lt;/span&gt; for additional information regarding our stock-based compensation plans.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Accumulated Other Comprehensive Loss&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 12pt;"&gt;&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Accumulated
      other comprehensive loss is comprised of unrealized gains and losses on investments, net of taxes and currency translation adjustments. The following table summarizes changes in accumulated other comprehensive loss for the years ended December 31, 2021, 2020 and 2019 (in thousands):&lt;/span&gt;&lt;/div&gt;

&lt;div style="text-align: justify;"&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;"&gt;


  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;

        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="10" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Year Ended December 31,&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;2021&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;2020&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;2019&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Beginning balance accumulated other comprehensive loss&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(21,071&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(25,290&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(32,016&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 64%;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9pt; margin-left: 18pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Unrealized gains (losses) on securities, net of tax (1)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(11,486&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;3,729&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;6,633&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9pt; margin-left: 18pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Currency translation adjustment&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(111&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;617&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;93&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 64%; padding-bottom: 2px;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9pt; margin-left: 18pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Adjustments to other comprehensive loss from purchase of noncontrolling interest of Akcea
            Therapeutics, Inc.&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x2014;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(127&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x2014;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Net other comprehensive loss for the period&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(11,597&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;4,219&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;6,726&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 64%; padding-bottom: 4px;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Ending balance accumulated other comprehensive loss&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(32,668&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(21,071&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(25,290&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;________________&lt;/div&gt;

&lt;div&gt;
    &lt;table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;"&gt;


  &lt;tr&gt;

    &lt;td style="width: 18pt; vertical-align: top; align: right;"&gt;
            &lt;div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(1)&lt;/div&gt;
          &lt;/td&gt;

    &lt;td style="width: auto; vertical-align: top;"&gt;
            &lt;div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;We did not have tax expense included in our other comprehensive loss for the years ended December 31, 2021 and 2020. For the year ended December 31,
              2019, we had a tax benefit of $1.4
              million included in other comprehensive loss.&#160;&lt;/div&gt;
          &lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;
    &lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Convertible Debt&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;"&gt;Adoption of ASU 2020-06&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;In August 2020, the FASB issued ASU 2020-06, which simplifies the accounting for convertible debt instruments, amends the
    guidance on derivative scope exceptions for contracts in an entity&#x2019;s own equity, and modifies the guidance on diluted earnings per share calculations. We adopted ASU 2020-06 on January 1, 2021 under the full retrospective approach, which required us to
    revise our prior period financial statements. This guidance impacted our accounting for outstanding convertible debt. At January 1, 2021, we had two
    outstanding convertible notes, our 0.125% Notes, which mature in December 2024, and our 1% Notes, which matured in November 2021. In April 2021, we completed a $632.5 million
    offering of 0% Notes primarily to repurchase a majority of our 1% Notes. We accounted for our 0% Notes under ASU 2020-06 at issuance. Refer to Note
    3, &lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;"&gt;Long-Term Obligations and Commitments&lt;/span&gt;, for further information.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;The updated guidance eliminates the cash conversion accounting model we previously followed in Accounting Standard
    Codification, or ASC, 470-20, which required us to separate each of our convertible debt instruments at issuance into two units of accounting, a liability component, based on our nonconvertible debt borrowing rate at issuance, and an equity component.
    Under ASU 2020-06, we now account for each of our convertible debt instruments as a single unit of accounting, a liability, because we concluded that the conversion features do not require bifurcation as a derivative under ASC 815-15 and we did not
    issue our convertible debt instruments at a substantial premium. Since we adopted ASU 2020-06 using the full retrospective approach, we were required to apply the guidance to all convertible debt instruments we had outstanding as of January 1, 2019. We
    recomputed the basis of each convertible debt instrument as if we accounted for each as a single unit of accounting at issuance. This update included recalculating the amortization of debt issuance costs using an updated effective interest rate. As a
    result of adopting ASU 2020-06, we recorded a cumulative adjustment to decrease our additional paid in capital and our accumulated deficit at January 1, 2019. We have updated these financial statements to reflect the cumulative adjustment for the
    periods presented. We have labeled our prior period financial statements &#x201c;as revised&#x201d; to indicate the change required under the new accounting guidance. Below is a summary of the change in our balance sheet at December 31, 2020 and statement of
    operations from the years ended December 31, 2020 and 2019 under the ASC 470-20 legacy guidance compared to the new ASU 2020-06 guidance we adopted:&lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;The following table summarizes the adjustments we made to the consolidated balance sheet we
    originally reported at December 31, 2020 to adopt ASU 2020-06 (in thousands):&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;"&gt;


  &lt;tr&gt;

    &lt;td style="vertical-align: top; padding-bottom: 2px;" valign="bottom"&gt;

        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="10" style="vertical-align: top; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;December 31, 2020&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;As Previously&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Reported&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;ASU 2020-06&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Adjustment&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;As Revised&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 64%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;1 percent convertible
            senior notes&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;293,161&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;15,648&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;308,809&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 64%;" valign="bottom"&gt;
          &lt;div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;0.125 percent convertible
            senior notes&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;455,719&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;84,417&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;540,136&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 64%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Additional paid-in-capital&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;2,113,646&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(218,127&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;1,895,519&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 64%;" valign="bottom"&gt;
          &lt;div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Accumulated deficit&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(1,249,368&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;118,062&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(1,131,306&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#160;&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt;Under ASU 2020-06, our revised
      ending balances for our &lt;/span&gt;1%&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt; Notes and &lt;/span&gt;0.125%&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt; Notes as of December 31, 2020 represent the principal
      balance of each convertible debt instrument less debt issuance costs. Additionally, because we have deferred tax assets related to our convertible debt instruments, we also adjusted these amounts as part of our adoption of ASU 2020-06. However,
      because we have a full valuation allowance on our deferred tax assets, there was &lt;/span&gt;no&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt; impact to our consolidated balance sheet related to our deferred tax assets.&lt;/span&gt;&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#160;&lt;span style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; color: #000000;"&gt;&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt;The following
      tables summarize the adjustments we made to the consolidated statement of operations we originally reported for the years ended December 31, 2020 and 2019 to adopt ASU 2020-06 (in thousands):&lt;/span&gt;&lt;/span&gt;&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;"&gt;


  &lt;tr&gt;

    &lt;td style="vertical-align: top; padding-bottom: 2px;" valign="bottom"&gt;

        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="10" style="vertical-align: top; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Year Ended December 31, 2020&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;As Previously&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Reported&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;ASU 2020-06&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Adjustment&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;As Revised&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 64%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Interest expense&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(44,990&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;35,480&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(9,510&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 64%;" valign="bottom"&gt;
          &lt;div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Loss before income tax expense&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(170,032&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;35,480&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(134,552&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 64%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Income tax expense&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(316,734&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(28,457&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(345,191&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 64%;" valign="bottom"&gt;
          &lt;div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Net loss&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(486,766&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;7,023&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(479,743&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 64%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Net loss attributable to Ionis Pharmaceuticals, Inc. common stockholders&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(451,286&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;7,023&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(444,263&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 64%;" valign="bottom"&gt;
          &lt;div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Basic and diluted net loss per share&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(3.23&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;0.05&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(3.18&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;"&gt;


  &lt;tr&gt;

    &lt;td style="vertical-align: top; padding-bottom: 2px;" valign="bottom"&gt;

        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="10" style="vertical-align: top; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Year Ended December 31, 2019&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;As Previously&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Reported&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;ASU 2020-06&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Adjustment&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;As Revised&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 64%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Interest expense&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(48,768&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;36,328&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(12,440&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 64%;" valign="bottom"&gt;
          &lt;div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Loss on early retirement of debt&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(21,865&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(44,331&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(66,196&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 64%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Income before income tax benefit (expense)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;346,769&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(8,003&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;338,766&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 64%;" valign="bottom"&gt;
          &lt;div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Income tax expense&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(43,507&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(8,000&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(51,507&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 64%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Net income&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;303,262&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(16,003&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;287,259&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 64%;" valign="bottom"&gt;
          &lt;div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Net income attributable to Ionis Pharmaceuticals, Inc. common stockholders&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;294,146&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(16,003&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;278,143&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 64%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Basic net income per share&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;2.12&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(0.12&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;2.00&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 64%;" valign="bottom"&gt;
          &lt;div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Diluted net income per share&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;2.08&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(0.18&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;1.90&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Under ASU 2020-06, our revised interest expense is lower because we are no longer recording non-cash
    interest expense related to a debt discount. This decrease was partially offset by the increase in interest expense related to the amortization of debt issuance costs because we no longer allocate a portion of our debt issuance costs to stockholders&#x2019;
    equity at issuance. Instead, the entire debt issuance costs were recorded as a contra-liability on our consolidated balance sheet at issuance and we are amortizing them over the contractual term using an updated effective interest rate. Our updated
    effective interest rates for our 1% Notes and 0.125%
    Notes were 1.4 percent and 0.5 percent,
    respectively.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;The following tables summarize the adjustments we made to our consolidated statements of
    stockholders&#x2019; equity we originally reported at December 31, 2020 and 2019 to adopt ASU 2020-06 (in thousands):&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;"&gt;


  &lt;tr&gt;

    &lt;td style="vertical-align: top; padding-bottom: 2px;" valign="bottom"&gt;

        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="10" style="vertical-align: top; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;December 31, 2020&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;As Previously&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Reported&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;ASU 2020-06&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Adjustment&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;As Revised&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 64%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Additional paid-in-capital&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;2,113,646&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(218,127&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;1,895,519&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 64%;" valign="bottom"&gt;
          &lt;div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Accumulated deficit&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(1,249,368&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;118,062&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(1,131,306&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 64%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Total stockholders&#x2019; equity&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;843,347&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(100,065&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;743,282&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;"&gt;


  &lt;tr&gt;

    &lt;td style="vertical-align: top; padding-bottom: 2px;" valign="bottom"&gt;

        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="10" style="vertical-align: top; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;December 31, 2019&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;As Previously&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Reported&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;ASU 2020-06&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Adjustment&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;As Revised&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 64%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Additional paid-in-capital&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;2,203,778&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(218,128&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;1,985,650&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 64%;" valign="bottom"&gt;
          &lt;div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Accumulated deficit&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(707,534&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;111,039&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(596,495&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 64%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Total stockholders&#x2019; equity&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;1,684,547&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(107,088&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;1,577,459&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Call Spread&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;In conjunction with the issuance of our 0% Notes and 0.125% Notes in April 2021 and December 2019, respectively, we entered
    into call spread transactions, which were comprised of purchasing note hedges and selling warrants. We account for the note hedges and warrants as separate freestanding financial instruments and treat each instrument as a separate unit of accounting.
    We determined that the note hedges and warrants do not meet the definition of a liability using the guidance contained in ASC Topic 480; therefore, we account for the note hedges and warrants using the Derivatives and Hedging &#x2013; Contracts in Entity&#x2019;s
    Own Equity accounting guidance contained in ASC Topic 815. We determined that the note hedges and warrants meet the definition of a derivative, are indexed to our stock and meet the criteria to be classified in shareholders&#x2019; equity. We recorded the
    aggregate amount paid for the note hedges and the aggregate amount received for the warrants as additional paid-in capital in our consolidated balance sheet. We reassess our ability to continue to classify the note hedges and warrants in shareholders&#x2019;
    equity at each reporting period.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Segment Information&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;In 2021, we began operating as a single segment, Ionis operations, because our chief decision maker reviews operating
    results on an aggregate basis and manages our operations as a &lt;span style="-sec-ix-hidden:Fact_33bc30118e9548358994c912eadf2161"&gt;single&lt;/span&gt; operating segment. Previously, we had operated as two operating segments, Ionis Core and Akcea Therapeutics. We completed the Akcea Merger in October 2020 and fully integrated Akcea&#x2019;s operations into ours
    as of January 1, 2021&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;.&lt;/span&gt;&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Fair Value Measurements&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;We use a three-tier fair value hierarchy to prioritize the inputs used in our fair value measurements. These tiers
    include: Level 1, defined as observable inputs such as quoted prices in active markets for identical assets, which includes our money market funds and treasury securities classified as available-for-sale securities and our investment in equity
    securities in publicly held biotechnology companies; Level 2, defined as inputs other than quoted prices in active markets that are either directly or indirectly observable, which includes our fixed income securities and commercial paper classified as
    available-for-sale securities; and Level 3, defined as unobservable inputs in which little or no market data exists, therefore requiring us to develop our own assumptions. We classify most of our securities as Level 2. We obtain the fair value of our
    Level 2 investments from our custodian bank or from a professional pricing service. We validate the fair value of our Level 2 investments by understanding the pricing model used by the custodian banks or professional pricing service provider and
    comparing that fair value to the fair value based on observable market prices.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;The following tables present the major security types we held at December 31, 2021 and 2020&#160;&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt;that we regularly measure and carry at fair value&lt;/span&gt;. As of December 31, 2021, our Bicycle investment was subject to trading restrictions that extend to the third quarter of 2022; as
    a result, we included a lack of marketability discount in valuing this investment, which is a Level 3 input. As of December 31, 2020, we did not
    have any investments that we valued using Level 3 inputs. The following tables segregate each security type by the level within the fair value hierarchy of the valuation techniques we utilized to determine the respective securities&#x2019; fair value (in
    thousands):&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;"&gt;


  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;At&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;December 31, 2021&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Quoted Prices in&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Active Markets&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;(Level 1)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Significant Other&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Observable Inputs&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;(Level 2)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Significant&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Unobservable Inputs&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;(Level 3)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 52%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Cash equivalents (1)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;541,199&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;541,199&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x2014;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x2014;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 52%;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Corporate debt securities (2)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;764,059&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x2014;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;764,059&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x2014;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 52%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Debt securities issued by U.S. government agencies (2)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;120,868&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x2014;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;120,868&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x2014;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 52%;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Debt securities issued by the U.S. Treasury (2)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;182,634&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;182,634&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x2014;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x2014;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 52%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Debt securities issued by states of the U.S. and political subdivisions of the states (3)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;174,464&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x2014;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;174,464&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x2014;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 52%;" valign="bottom"&gt;
          &lt;div&gt;
            &lt;div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Other municipal debt securities (2)&lt;/div&gt;
          &lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;6,099&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x2014;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;6,099&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x2014;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 52%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div&gt;
            &lt;div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Investment in Bicycle Therapeutics plc (4)&lt;/div&gt;
          &lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;14,330&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x2014;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x2014;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;14,330&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 52%; padding-bottom: 2px;" valign="bottom"&gt;
          &lt;div&gt;
            &lt;div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Investment in ProQR Therapeutics N.V. (4)&lt;/div&gt;
          &lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;3,875&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;3,875&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x2014;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x2014;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 52%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -8.9pt; margin-left: 22.55pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Total&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;1,807,528&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;727,708&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;1,065,490&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;14,330&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;"&gt;


  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;

        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;At&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;December 31, 2020&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Quoted Prices in&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Active Markets&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;(Level 1)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Significant Other&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Observable Inputs&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;(Level 2)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Cash equivalents (1)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;221,125&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;221,125&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x2014;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 64%;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Corporate debt securities (5)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;846,315&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x2014;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;846,315&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Debt securities issued by U.S. government agencies (2)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;174,861&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x2014;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;174,861&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 64%;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Debt securities issued by the U.S. Treasury (6)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;358,497&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;358,497&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x2014;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Debt securities issued by states of the U.S. and political subdivisions of the states (2)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;136,309&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x2014;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;136,309&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 64%;" valign="bottom"&gt;
          &lt;div&gt;
            &lt;div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Other municipal debt securities (2)&lt;/div&gt;
          &lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;6,225&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x2014;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;6,225&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div&gt;
            &lt;div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Investment in ProQR Therapeutics N.V. (4)&lt;/div&gt;
          &lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;2,031&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;2,031&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x2014;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 64%; padding-bottom: 4px;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -8.9pt; margin-left: 22.55pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Total&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;1,745,363&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;581,653&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;1,163,710&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;________________&lt;/div&gt;

&lt;table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;"&gt;


  &lt;tr&gt;

    &lt;td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(1)&lt;/td&gt;

    &lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Included in cash and cash
            equivalents on our consolidated balance sheet.&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;"&gt;


  &lt;tr&gt;

    &lt;td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(2)&lt;/td&gt;

    &lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Included in short-term
            investments.&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;"&gt;


  &lt;tr&gt;

    &lt;td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(3)&lt;/td&gt;

    &lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$2.3 million included in cash and cash equivalents on our consolidated balance sheet, with the difference included in short-term investments on our
            consolidated balance sheet.&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;"&gt;


  &lt;tr&gt;

    &lt;td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(4)&lt;/td&gt;

    &lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Included in other current assets
            on our consolidated balance sheet.&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;"&gt;


  &lt;tr&gt;

    &lt;td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(5)&lt;/td&gt;

    &lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$10.0 million included in cash and cash equivalents on our consolidated balance sheet, with the difference included in short-term investments on our
            consolidated balance sheet.&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;"&gt;


  &lt;tr&gt;

    &lt;td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(6)&lt;/td&gt;

    &lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$17.5 million included in cash and cash equivalents on our consolidated balance sheet, with the difference included in short-term investments on our
            consolidated balance sheet.&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;"&gt;Convertible Notes&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Our 0.125% Notes and 0% Notes had a fair value of $495.4 million and $559.2 million at December 31, 2021, respectively. We determine the fair value of our notes based on quoted market prices for these notes, which are Level 2
    measurements because the notes do not trade regularly.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Income Taxes&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;We account for income taxes using the asset and liability method, which requires the recognition of deferred tax assets and liabilities
    for the expected future tax consequences of events that have been recognized in our financial statements or tax returns. In addition, deferred tax assets are recorded for the future benefit of utilizing net operating losses and research and development
    credit carryforwards. We record a valuation allowance when necessary to reduce our net deferred tax assets to the amount expected to be realized.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;We apply the authoritative accounting guidance prescribing a threshold and measurement attribute for the financial recognition and
    measurement of a tax position taken or expected to be taken in a tax return. We recognize liabilities for uncertain tax positions based on a two-step process. The first step is to evaluate the tax position for recognition by determining if the weight
    of available evidence indicates that it is more likely than not that the position will be sustained on audit, including resolution of related appeals or litigation processes, if any. The second step requires us to estimate and measure the tax benefit
    as the largest amount that is more than 50 percent likely to be realized upon ultimate settlement.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;We are required to use significant judgment in evaluating our uncertain tax positions and determining our provision for income taxes.
    Although we believe our reserves are reasonable, no assurance can be given that the final tax outcome of these matters will not be different from that which is reflected in our historical income tax provisions and accruals. We adjust these reserves for
    changing facts and circumstances, such as the closing of a tax audit or the refinement of an estimate. To the extent that the final tax outcome of these matters is different than the amounts recorded, such differences may impact the provision for
    income taxes in the period in which such determination is made.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;We are also required to use significant judgment in determining any valuation allowance recorded against our deferred tax assets. In
    assessing the need for a valuation allowance, we consider all available evidence, including scheduled reversal of deferred tax liabilities, past operating results, the feasibility of tax planning strategies and estimates of future taxable income. We
    base our estimates of future taxable income on assumptions that are consistent with our plans. The assumptions we use represent our best estimates and involve inherent uncertainties and the application of our judgment. Should actual amounts differ from
    our estimates, the amount of our tax expense and liabilities we recognize could be materially impacted. We record a valuation allowance to reduce the balance of our net deferred tax assets to the amount we believe is more-likely-than-not to be
    realized.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;We do not provide for a U.S. income tax liability and foreign withholding taxes on undistributed foreign earnings of our foreign
    subsidiaries.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Impact of Recently Issued Accounting Standards&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;As disclosed in the &#x201c;Convertible Debt&#x201d; policy above within this footnote, we adopted the simplified accounting for
    convertible debt instrument guidance (ASU 2020-06) on January 1, 2021. Refer to the section above for the impact of adoption. We do not expect any other recently issued accounting standards to have a material impact to our financial results.&lt;/div&gt;
</us-gaap:OrganizationConsolidationBasisOfPresentationBusinessDescriptionAndAccountingPoliciesTextBlock>
    <us-gaap:ConsolidationPolicyTextBlock
      contextRef="c20210101to20211231"
      id="Text_8c102e683032408d831953ba9e81ff45">
&lt;div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Basis of Presentation&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;In our consolidated financial statements we included the accounts of Ionis Pharmaceuticals, Inc. and the consolidated
    results of our subsidiary, Akcea Therapeutics, Inc. and its wholly owned subsidiaries (&#x201c;we&#x201d;, &#x201c;us&#x201d; or &#x201c;our&#x201d;). We formed Akcea in December 2014. In July 2017, Akcea completed an initial public offering, or IPO, which reduced our ownership of Akcea&#x2019;s
    common stock below 100 percent. In October 2020, we completed a merger transaction with Akcea such that following the completion of the merger,
    Akcea became our wholly owned subsidiary. We will refer to this transaction as the Akcea Merger throughout the remainder of this document. We reflected changes in our ownership percentage in our financial statements as an adjustment to noncontrolling
    interest in the period the changes occurred&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;.&lt;/span&gt;&lt;/div&gt;
</us-gaap:ConsolidationPolicyTextBlock>
    <us-gaap:MinorityInterestOwnershipPercentageByParent
      contextRef="c20170630_OwnershipAxis_AkceaTherapeuticsIncMember_RangeAxis_MaximumMember"
      decimals="2"
      id="Fact_a88597664460426696b9ccf265c067d6"
      unitRef="U003">1</us-gaap:MinorityInterestOwnershipPercentageByParent>
    <us-gaap:EarningsPerSharePolicyTextBlock
      contextRef="c20210101to20211231"
      id="Text_47e97970a2d74b528c3d5e13d3b65bad">
&lt;div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Basic and Diluted Net Income (Loss) per Share&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;"&gt;Basic net income (loss) per share&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;We compute basic net income (loss) per share by dividing the total net income (loss) attributable to our common
    stockholders by our weighted-average number of common shares outstanding during the period. For the year ended December 31, 2021, we did not have to consider Akcea results separately in our calculation because we owned 100 percent of Akcea for the entire period. Our basic net loss per share for the year ended December 31, 2021 was $0.20.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;For the years ended December 31, 2020 and 2019, we calculated total net income (loss) attributable to our common
    stockholders for each year using our net income (loss) for Ionis on a stand-alone basis plus our share of Akcea&#x2019;s net income (loss) for the period. To calculate the portion of Akcea&#x2019;s net income (loss) attributable to our ownership for each year, we
    multiplied Akcea&#x2019;s income (loss) per share by the weighted average shares we owned in Akcea during the period. As a result of this calculation, our total net income (loss) available to Ionis common stockholders for the calculation of net income (loss)
    per share is different than net income (loss) attributable to Ionis Pharmaceuticals, Inc. common stockholders in our consolidated statements of operations for each year.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;We calculated our basic net loss per share for the year ended December 31, 2020 as follows (in thousands, except
    per share amounts):&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;"&gt;


  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; border-bottom: #000000 2px solid; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Year Ended December 31, 2020&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Weighted&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Average Shares&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Owned in Akcea&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Akcea&lt;/span&gt;&#x2019;&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;s&lt;/span&gt;&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Net Loss&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Per Share&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Basic Net Loss&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Per Share&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Calculation&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 64%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Akcea&#x2019;s net loss in the pre-merger period attributable to our ownership&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;77,095&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(1.45&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(111,775&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 64%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Akcea&#x2019;s net loss in the post-merger period attributable to our ownership&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(85,987&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 64%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Akcea&#x2019;s total net loss attributable to our ownership&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(197,762&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 64%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Ionis&#x2019; stand-alone net loss&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(246,702&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 64%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Net loss available to Ionis common stockholders&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(444,464&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 64%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Weighted average shares outstanding&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;139,612&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 64%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Basic net loss per share&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(3.18&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;We calculated our basic net income per share for the year ended December 31, 2019 as follows (in thousands, except per share amounts):&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;"&gt;


  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; border-bottom: #000000 2px solid; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Year Ended December 31, 2019&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Weighted&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Average Shares&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Owned in Akcea&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Akcea&lt;/span&gt;&#x2019;&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;s&lt;/span&gt;&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Net Income&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Per Share&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Basic Net Income&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Per Share&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Calculation&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 64%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Common shares&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;70,100&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;0.49&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;34,073&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 64%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Akcea&#x2019;s net income attributable to our ownership&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;34,073&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 64%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Ionis&#x2019; stand-alone net income&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;246,487&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 64%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Net income available to Ionis common stockholders&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;280,560&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 64%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Weighted average shares outstanding&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;139,998&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 64%; padding-bottom: 4px; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Basic net income per share&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;2.00&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 12pt;"&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;"&gt;Diluted net income (loss) per share&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;For the years ended December 31, 2021 and 2020, we incurred a net loss; therefore, we did not include dilutive common
    equivalent shares in the computation of diluted net loss per share because the effect would have been anti-dilutive. Common stock underlying the following would have had an anti-dilutive effect on net loss per share:&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;"&gt;


  &lt;tr&gt;

    &lt;td style="width: 36pt;"/&gt;

    &lt;td style="width: 18pt; vertical-align: top; align: right; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x25cf;&lt;/td&gt;

    &lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;
          &lt;div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;0.125 percent&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt; convertible senior notes, or &lt;/span&gt;0.125%&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt; Notes;&lt;/span&gt;&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;"&gt;


  &lt;tr&gt;

    &lt;td style="width: 36pt;"/&gt;

    &lt;td style="width: 18pt; vertical-align: top; align: right; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x25cf;&lt;/td&gt;

    &lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;
          &lt;div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt;Note hedges related to the &lt;/span&gt;0.125%&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt; Notes;&lt;/span&gt;&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;"&gt;


  &lt;tr&gt;

    &lt;td style="width: 36pt;"/&gt;

    &lt;td style="width: 18pt; vertical-align: top; align: right; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x25cf;&lt;/td&gt;

    &lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;
          &lt;div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;1 percent&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt; convertible senior notes, or &lt;/span&gt;1%&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt; Notes;&lt;/span&gt;&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;"&gt;


  &lt;tr&gt;

    &lt;td style="width: 36pt;"/&gt;

    &lt;td style="width: 18pt; vertical-align: top; align: right; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x25cf;&lt;/td&gt;

    &lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Dilutive stock options;&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;"&gt;


  &lt;tr&gt;

    &lt;td style="width: 36pt;"/&gt;

    &lt;td style="width: 18pt; vertical-align: top; align: right; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x25cf;&lt;/td&gt;

    &lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Unvested restricted stock units, or RSUs;&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;"&gt;


  &lt;tr&gt;

    &lt;td style="width: 36pt;"/&gt;

    &lt;td style="width: 18pt; vertical-align: top; align: right; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x25cf;&lt;/td&gt;

    &lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Unvested performance restricted stock units, or PRSUs; and&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;"&gt;


  &lt;tr&gt;

    &lt;td style="width: 36pt;"/&gt;

    &lt;td style="width: 18pt; vertical-align: top; align: right; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x25cf;&lt;/td&gt;

    &lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Employee Stock Purchase Plan, or ESPP.&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;For the year ended December 31, 2021, common stock underlying the following would also have had an anti-dilutive effect on
    net loss per share:&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;"&gt;


  &lt;tr&gt;

    &lt;td style="width: 36pt;"/&gt;

    &lt;td style="width: 18pt; vertical-align: top; align: right; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x25cf;&lt;/td&gt;

    &lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;
          &lt;div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;0 percent&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt; convertible senior notes, or &lt;/span&gt;0%&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt; Notes; and&lt;/span&gt;&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;"&gt;


  &lt;tr&gt;

    &lt;td style="width: 36pt;"/&gt;

    &lt;td style="width: 18pt; vertical-align: top; align: right; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x25cf;&lt;/td&gt;

    &lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;
          &lt;div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt;Note hedges related to the &lt;/span&gt;0%&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt; Notes.&lt;/span&gt;&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Additionally as of December 31, 2021, we had warrants related to our 0 percent and 0.125 percent Notes outstanding. We will include the shares issuable
    under these warrants in our calculation of diluted earnings per share when the average market price per share of our common stock for the reporting period exceeds the strike price of the warrants.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt;For the
      year ended December 31, 2019, we reported net income available to Ionis common stockholders. As a result, we computed diluted net income per share using the weighted-average number of common shares and dilutive common equivalent shares outstanding
      during each period.&lt;/span&gt; We calculated our diluted net income per share as follows &lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt;(in thousands except per share amounts):&lt;/span&gt;&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;"&gt;


  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; border-bottom: #000000 2px solid;" valign="bottom"&gt;
          &lt;div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Year Ended December 31, 2019&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Net Income Available&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;to Ionis Common&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Stockholders&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;(Numerator)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Shares&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;(Denominator)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Per-Share&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Amount&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 64%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Net income available to Ionis common stockholders&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;280,560&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;139,998&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;2.00&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 64%;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Effect of dilutive securities:&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 64%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -8.9pt; margin-left: 18pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Shares issuable upon exercise of stock options&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x2014;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;2,090&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 64%;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: 0.1pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Shares issuable upon restricted stock award issuance&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x2014;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;766&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 64%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: 9.1pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Shares issuable related to our ESPP&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x2014;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;18&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 64%;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: 9.1pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt;Shares issuable related to our &lt;/span&gt;0.125&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt; percent convertible notes&lt;/span&gt;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;860&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;217&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 64%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: 9.1pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Shares issuable related to our 1 percent convertible notes&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;9,527&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;10,075&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 64%; padding-bottom: 4px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;290,947&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;153,164&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;1.90&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;
</us-gaap:EarningsPerSharePolicyTextBlock>
    <us-gaap:MinorityInterestOwnershipPercentageByParent
      contextRef="c20211231_OwnershipAxis_AkceaTherapeuticsIncMember"
      decimals="2"
      id="Fact_f65a71d42ef046458f851b185dab48a4"
      unitRef="U003">1</us-gaap:MinorityInterestOwnershipPercentageByParent>
    <us-gaap:EarningsPerShareBasic
      contextRef="c20210101to20211231"
      decimals="2"
      id="Fact_a97fd98180da49a2889ec6c1d1bbecdb"
      unitRef="U004">-0.20</us-gaap:EarningsPerShareBasic>
    <us-gaap:ScheduleOfEarningsPerShareBasicByCommonClassTextBlock
      contextRef="c20210101to20211231"
      id="Text_6255ce3fc5024406b256c4e5a5be9dd3">
&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;We calculated our basic net loss per share for the year ended December 31, 2020 as follows (in thousands, except
    per share amounts):&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;"&gt;


  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; border-bottom: #000000 2px solid; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Year Ended December 31, 2020&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Weighted&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Average Shares&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Owned in Akcea&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Akcea&lt;/span&gt;&#x2019;&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;s&lt;/span&gt;&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Net Loss&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Per Share&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Basic Net Loss&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Per Share&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Calculation&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 64%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Akcea&#x2019;s net loss in the pre-merger period attributable to our ownership&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;77,095&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(1.45&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(111,775&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 64%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Akcea&#x2019;s net loss in the post-merger period attributable to our ownership&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(85,987&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 64%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Akcea&#x2019;s total net loss attributable to our ownership&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(197,762&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 64%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Ionis&#x2019; stand-alone net loss&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(246,702&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 64%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Net loss available to Ionis common stockholders&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(444,464&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 64%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Weighted average shares outstanding&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;139,612&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 64%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Basic net loss per share&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(3.18&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;We calculated our basic net income per share for the year ended December 31, 2019 as follows (in thousands, except per share amounts):&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;"&gt;


  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; border-bottom: #000000 2px solid; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Year Ended December 31, 2019&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Weighted&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Average Shares&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Owned in Akcea&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Akcea&lt;/span&gt;&#x2019;&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;s&lt;/span&gt;&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Net Income&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Per Share&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Basic Net Income&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Per Share&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Calculation&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 64%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Common shares&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;70,100&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;0.49&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;34,073&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 64%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Akcea&#x2019;s net income attributable to our ownership&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;34,073&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 64%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Ionis&#x2019; stand-alone net income&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;246,487&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 64%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Net income available to Ionis common stockholders&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;280,560&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 64%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Weighted average shares outstanding&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;139,998&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 64%; padding-bottom: 4px; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Basic net income per share&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;2.00&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;
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    <us-gaap:DebtInstrumentInterestRateStatedPercentage
      contextRef="c20211231_DebtInstrumentAxis_ConvertibleSeniorNotes0125PercentMember"
      decimals="5"
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    <us-gaap:ScheduleOfEarningsPerShareBasicAndDilutedTableTextBlock
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&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt;For the
      year ended December 31, 2019, we reported net income available to Ionis common stockholders. As a result, we computed diluted net income per share using the weighted-average number of common shares and dilutive common equivalent shares outstanding
      during each period.&lt;/span&gt; We calculated our diluted net income per share as follows &lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt;(in thousands except per share amounts):&lt;/span&gt;&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;"&gt;


  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; border-bottom: #000000 2px solid;" valign="bottom"&gt;
          &lt;div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Year Ended December 31, 2019&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Net Income Available&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;to Ionis Common&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Stockholders&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;(Numerator)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Shares&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;(Denominator)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Per-Share&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Amount&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 64%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Net income available to Ionis common stockholders&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;280,560&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;139,998&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;2.00&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 64%;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Effect of dilutive securities:&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 64%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -8.9pt; margin-left: 18pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Shares issuable upon exercise of stock options&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x2014;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;2,090&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 64%;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: 0.1pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Shares issuable upon restricted stock award issuance&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x2014;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;766&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 64%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: 9.1pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Shares issuable related to our ESPP&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x2014;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;18&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 64%;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: 9.1pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt;Shares issuable related to our &lt;/span&gt;0.125&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt; percent convertible notes&lt;/span&gt;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;860&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;217&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 64%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: 9.1pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Shares issuable related to our 1 percent convertible notes&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;9,527&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;10,075&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 64%; padding-bottom: 4px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;290,947&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;153,164&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;1.90&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;
</us-gaap:ScheduleOfEarningsPerShareBasicAndDilutedTableTextBlock>
    <us-gaap:NetIncomeLossAvailableToCommonStockholdersBasic
      contextRef="c20190101to20191231"
      decimals="-3"
      id="Fact_25cedd63d24b4e3cadd5de6e6561e3d0"
      unitRef="U001">280560000</us-gaap:NetIncomeLossAvailableToCommonStockholdersBasic>
    <us-gaap:WeightedAverageNumberOfSharesOutstandingBasic
      contextRef="c20190101to20191231"
      decimals="-3"
      id="Fact_f83e7ce8079c4f8792d25cf0a3180881"
      unitRef="U002">139998000</us-gaap:WeightedAverageNumberOfSharesOutstandingBasic>
    <us-gaap:EarningsPerShareBasic
      contextRef="c20190101to20191231"
      decimals="2"
      id="Fact_9c3daccea9ff4f1fa72d6f6aadac88d6"
      unitRef="U004">2.00</us-gaap:EarningsPerShareBasic>
    <us-gaap:IncrementalCommonSharesAttributableToShareBasedPaymentArrangements
      contextRef="c20190101to20191231_AwardTypeAxis_EmployeeStockOptionMember"
      decimals="-3"
      id="Fact_11a6a9977b2f48598eaa6900a453bd6f"
      unitRef="U002">2090000</us-gaap:IncrementalCommonSharesAttributableToShareBasedPaymentArrangements>
    <us-gaap:IncrementalCommonSharesAttributableToShareBasedPaymentArrangements
      contextRef="c20190101to20191231_AwardTypeAxis_RestrictedStockMember"
      decimals="-3"
      id="Fact_4954ae5f6ddd492ebfa194fa4e433af5"
      unitRef="U002">766000</us-gaap:IncrementalCommonSharesAttributableToShareBasedPaymentArrangements>
    <ions:IncrementalCommonSharesAttributableToEmployeeStockPurchasePlan
      contextRef="c20190101to20191231"
      decimals="-3"
      id="Fact_55d56f94b31648de9bea741ae54c4e79"
      unitRef="U002">18000</ions:IncrementalCommonSharesAttributableToEmployeeStockPurchasePlan>
    <us-gaap:DilutiveSecuritiesEffectOnBasicEarningsPerShareOther
      contextRef="c20190101to20191231_DebtInstrumentAxis_ConvertibleSeniorNotes0125PercentMember"
      decimals="-3"
      id="Fact_e4ef33f4bfd343ac900fed3faf5436d6"
      unitRef="U001">860000</us-gaap:DilutiveSecuritiesEffectOnBasicEarningsPerShareOther>
    <us-gaap:IncrementalCommonSharesAttributableToConversionOfDebtSecurities
      contextRef="c20190101to20191231_DebtInstrumentAxis_ConvertibleSeniorNotes0125PercentMember"
      decimals="-3"
      id="Fact_d794fdb7dd074852a61d0b91dd8373f4"
      unitRef="U002">217000</us-gaap:IncrementalCommonSharesAttributableToConversionOfDebtSecurities>
    <us-gaap:DilutiveSecuritiesEffectOnBasicEarningsPerShareOther
      contextRef="c20190101to20191231_DebtInstrumentAxis_ConvertibleSeniorNotes1PercentMember"
      decimals="-3"
      id="Fact_c886afc42ae34446b61b4e2216f8d7d7"
      unitRef="U001">9527000</us-gaap:DilutiveSecuritiesEffectOnBasicEarningsPerShareOther>
    <us-gaap:IncrementalCommonSharesAttributableToConversionOfDebtSecurities
      contextRef="c20190101to20191231_DebtInstrumentAxis_ConvertibleSeniorNotes1PercentMember"
      decimals="-3"
      id="Fact_5b1cb8e2ccc24dfd8aadee86ec362583"
      unitRef="U002">10075000</us-gaap:IncrementalCommonSharesAttributableToConversionOfDebtSecurities>
    <us-gaap:NetIncomeLossAvailableToCommonStockholdersDiluted
      contextRef="c20190101to20191231"
      decimals="-3"
      id="Fact_f82cfb848ace4686aec051c3fdf525f3"
      unitRef="U001">290947000</us-gaap:NetIncomeLossAvailableToCommonStockholdersDiluted>
    <us-gaap:WeightedAverageNumberOfDilutedSharesOutstanding
      contextRef="c20190101to20191231"
      decimals="-3"
      id="Fact_0cbcb94bda694ca8908bc4f3fbbfafb6"
      unitRef="U002">153164000</us-gaap:WeightedAverageNumberOfDilutedSharesOutstanding>
    <us-gaap:EarningsPerShareDiluted
      contextRef="c20190101to20191231"
      decimals="2"
      id="Fact_2f931201b7f34aa3b2c56410ad892c3d"
      unitRef="U004">1.90</us-gaap:EarningsPerShareDiluted>
    <us-gaap:RevenueFromContractWithCustomerPolicyTextBlock
      contextRef="c20210101to20211231"
      id="Text_fe4f7603d54b47ad88a34d684805e9ce">
&lt;div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Revenue Recognition&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;span style="text-decoration: underline;"&gt;Our Revenue Sources&lt;/span&gt;&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;We generally recognize revenue when we have satisfied all contractual obligations and are reasonably assured of collecting
    the resulting receivable. We are often entitled to bill our customers and receive payment from our customers in advance of recognizing the revenue. In the instances in which we have received payment from our customers in advance of recognizing revenue,
    we include the amounts in deferred revenue on our consolidated balance sheet.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;At contract inception, we analyze our collaboration arrangements to assess whether such arrangements involve joint
    operating activities performed by parties that are both active participants in the activities and exposed to significant risks and rewards dependent on the commercial success of such activities and therefore within the scope of ASC Topic 808,
    Collaborative Arrangements (ASC 808).&#160; For collaboration arrangements within the scope of ASC 808 that contain multiple elements, we first determine which elements of the collaboration reflect a vendor-customer relationship and therefore within the
    scope of ASC 606. When we determine elements of a collaboration do not reflect a vendor-customer relationship, we consistently apply the reasonable and rational policy election we made by analogizing to authoritative accounting literature.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;We evaluate the income statement classification for presentation of amounts due from or owed to other participants
    associated with multiple activities in a collaboration arrangement based on the nature of each separate activity. For example, in our eplontersen collaboration with AstraZeneca, we recognize funding received from AstraZeneca for co-development
    activities as revenue. While, we recognize cost sharing payments to and from AstraZeneca associated with co-commercialization activities and co-medical affairs activities as SG&amp;amp;A expense and research and development expense, respectively.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;"&gt;Commercial Revenue: SPINRAZA royalties and Licensing and other royalty revenue&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;We earn commercial revenue primarily in the form of royalty payments on net sales of SPINRAZA. We will also recognize as
    commercial revenue sales milestone payments and royalties we earn under our other partnerships.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;"&gt;Commercial Revenue: TEGSEDI and WAYLIVRA revenue, net&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;We began commercializing TEGSEDI and WAYLIVRA in Europe in January 2021 and TEGSEDI in North America in April 2021 through distribution
    agreements with Swedish Orphan Biovitrum AB, or Sobi. Under our agreements, we are responsible for supplying finished goods inventory to Sobi and Sobi is responsible for selling each medicine to the end customer. As a result of these agreements, we
    earn a distribution fee on net sales from Sobi for each medicine.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Prior to the second quarter of 2021 in North America, we sold TEGSEDI through exclusive distribution agreements with third-party logistics
    companies, or 3PLs, that took title to TEGSEDI. The 3PLs then distributed TEGSEDI to a specialty pharmacy and a specialty distributor, which we collectively refer to as wholesalers, who then distributed TEGSEDI to health care providers and patients. In
    the United States, or U.S., we had a single 3PL as our sole customer and in Canada we also had a single 3PL as our sole customer. Prior to 2021 in Europe, we sold TEGSEDI and WAYLIVRA to hospitals and pharmacies, which were our customers, using 3PLs as
    distributors.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt;Under our collaboration agreement with PTC
      Therapeutics International Limited, or PTC, PTC is responsible for commercializing TEGSEDI and WAYLIVRA in Latin America and Caribbean countries. In the third quarter of 2021, we earned a &lt;/span&gt;$4 million milestone payment from PTC when WAYLIVRA was approved in Brazil, which we included in TEGSEDI and WAYLIVRA revenue in our consolidated statement of operations. Under our agreement, we
    started receiving royalties from PTC for TEGSEDI sales beginning in December 2021.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: left; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;"&gt;Research and development revenue under collaborative agreements&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;We often enter into collaboration agreements to license and sell our technology on an exclusive or non-exclusive basis.
    Our collaboration agreements typically contain multiple elements, or performance obligations, including technology licenses or options to obtain technology licenses, research and development, or R&amp;amp;D, services, and manufacturing services.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;We provide details about our collaboration agreements in Note 6, &lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;"&gt;Collaborative Arrangements and Licensing Agreements.&lt;/span&gt;&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;&#160;&lt;/span&gt;For each collaboration, we discuss our specific revenue
    recognition conclusions, including our significant performance obligations under each collaboration.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: left; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;span style="text-decoration: underline;"&gt;Steps to Recognize Revenue&lt;/span&gt;&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;We use a five-step process to determine the amount of revenue we should recognize and when we should recognize it. The
    five step process is as follows:&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;"&gt;


  &lt;tr&gt;

    &lt;td style="width: 36pt;"/&gt;

    &lt;td style="width: 18pt; vertical-align: top; align: right; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic; font-weight: bold;"&gt;1.&lt;/td&gt;

    &lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;
          &lt;div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic; font-weight: bold;"&gt;Identify the contract&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Accounting rules require us to first determine if we have a contract with our partner, including confirming that we have met each of the
    following criteria:&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;"&gt;


  &lt;tr&gt;

    &lt;td style="width: 36pt;"/&gt;

    &lt;td style="width: 18pt; vertical-align: top; align: right; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x25cf;&lt;/td&gt;

    &lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;
          &lt;div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;We and our partner approved the contract and we are both committed to perform our obligations;&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;"&gt;


  &lt;tr&gt;

    &lt;td style="width: 36pt;"/&gt;

    &lt;td style="width: 18pt; vertical-align: top; align: right; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x25cf;&lt;/td&gt;

    &lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;
          &lt;div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;We have identified our rights, our partner&#x2019;s rights and the payment terms;&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;"&gt;


  &lt;tr&gt;

    &lt;td style="width: 36pt;"/&gt;

    &lt;td style="width: 18pt; vertical-align: top; align: right; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x25cf;&lt;/td&gt;

    &lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;
          &lt;div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;We have concluded that the contract has commercial substance, meaning that the risk, timing, or amount of our future cash flows is expected to change as a result of the
            contract; and&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;"&gt;


  &lt;tr&gt;

    &lt;td style="width: 36pt;"/&gt;

    &lt;td style="width: 18pt; vertical-align: top; align: right; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x25cf;&lt;/td&gt;

    &lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;
          &lt;div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;We believe collectability of the consideration is probable.&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;"&gt;


  &lt;tr&gt;

    &lt;td style="width: 36pt;"/&gt;

    &lt;td style="width: 18pt; vertical-align: top; align: right;"&gt;&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold; font-style: italic;"&gt;2.&lt;/span&gt;&lt;/td&gt;

    &lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;
          &lt;div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic; font-weight: bold;"&gt;Identify the performance obligations&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;We next identify our performance obligations, which represent the distinct goods and services we are required to provide under the
    contract.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt;Often we enter into a collaboration agreement
      in which we provide our partner with an option to license a medicine in the future. We may also provide our partner with an option to request that we provide additional goods or services in the future, such as active pharmaceutical ingredient, or
      API. We evaluate whether these options are material rights at the inception of the agreement. If we determine an option is a material right, we will consider the option a separate performance obligation. Historically, we have concluded that the
      options we grant to license a medicine in the future or to provide additional goods and services as requested by our partner are not material rights because these items are contingent upon future events that may not occur and are not priced at a
      significant discount. When a partner exercises its option to license a medicine or requests additional goods or services, then we identify a new performance obligation for that item&lt;/span&gt;.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;In some cases, we deliver a license at the start of an agreement. If we determine that our partner has full use of the license and we do
    not have any additional material performance obligations related to the license after delivery, then we consider the license to be a separate performance obligation. For example, in the fourth quarter of 2021, we received a $200 million upfront payment when we entered into an agreement with AstraZeneca to jointly develop and commercialize eplontersen. We recognized the upfront
    payment in full in the fourth quarter of 2021 because we did not have any remaining performance obligations after we delivered the license to AstraZeneca.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;"&gt;


  &lt;tr&gt;

    &lt;td style="width: 36pt;"/&gt;

    &lt;td style="width: 18pt; vertical-align: top; align: right; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic; font-weight: bold;"&gt;3.&lt;/td&gt;

    &lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;
          &lt;div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic; font-weight: bold;"&gt;Determine the transaction price&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;We then determine the transaction price by reviewing the amount of consideration we are eligible to earn under the
        collaboration agreement, including any variable consideration. Under our collaboration agreements, consideration typically includes fixed consideration in the form of an upfront payment and variable consideration in the form of potential milestone
        payments, license fees and royalties. At the start of an agreement, our transaction price usually consists of only the upfront payment. We do not typically include any payments we may receive in the future in our initial transaction price because
        the payments are not probable and are contingent on certain future events. We reassess the total transaction price at each reporting period to determine if we should include additional payments in the transaction price.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
    &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt;Milestone payments are our most common type
      of variable consideration. We recognize milestone payments using the most likely amount method because we will either receive the milestone payment or we will not, which makes the potential milestone payment a binary event. The most likely amount
      method requires us to determine the likelihood of earning the milestone payment. We include a milestone payment in the transaction price once it is probable we will achieve the milestone event. Most often, we do not consider our milestone payments
      probable until we or our partner achieve the milestone event because the majority of our milestone payments are contingent upon events that are not within our control and/ or are usually based on scientific progress which is inherently uncertain. For
      example, in the fourth quarter of 2021, we earned&lt;/span&gt; a $10 million &lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt;milestone payment from AstraZeneca when AstraZeneca advanced a target for a metabolic disease. We did not consider the milestone payment probable until AstraZeneca achieved the milestone event because advancing the target was
      contingent on AstraZeneca initiating a Phase 1 study and was not within our control. We recognized the milestone payment in full in the period the milestone event was achieved because we did not have any remaining performance obligations related to
      the milestone payment&lt;/span&gt;.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;"&gt;


  &lt;tr&gt;

    &lt;td style="width: 36pt;"/&gt;

    &lt;td style="width: 18pt; vertical-align: top; align: right; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic; font-weight: bold;"&gt;4.&lt;/td&gt;

    &lt;td style="width: auto; vertical-align: top; text-align: left;"&gt;
          &lt;div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic; font-weight: bold;"&gt;Allocate the transaction price&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Next, we allocate the transaction price to
        each of our performance obligations. When we have to allocate the transaction price to more than &lt;/span&gt;one&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt; performance obligation, we make estimates of the relative
        stand-alone selling price of each performance obligation because we do not typically sell our goods or services on a stand-alone basis. We then allocate the transaction price to each performance obligation based on the relative stand-alone selling
        price. We do not reallocate the transaction price after the start of an agreement to reflect subsequent changes in stand-alone selling prices.&lt;/span&gt;&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
    &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;We may engage a &lt;/span&gt;third&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt; party, independent valuation specialist to assist us with determining a stand-alone selling price for collaborations in which we deliver a license at the start of an agreement.
      We estimate the stand-alone selling price of these licenses using valuation methodologies, such as the relief from royalty method. Under this method, we estimate the amount of income, net of taxes, for the license. We then discount the projected
      income to present value. The significant inputs we use to determine the projected income of a license could include&lt;/span&gt;:&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;"&gt;


  &lt;tr&gt;

    &lt;td style="width: 36pt;"/&gt;

    &lt;td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x25cf;&lt;/td&gt;

    &lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Estimated future product sales;&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;"&gt;


  &lt;tr&gt;

    &lt;td style="width: 36pt;"/&gt;

    &lt;td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x25cf;&lt;/td&gt;

    &lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Estimated royalties we may receive from future product sales;&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;"&gt;


  &lt;tr&gt;

    &lt;td style="width: 36pt;"/&gt;

    &lt;td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x25cf;&lt;/td&gt;

    &lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Estimated contractual milestone payments we may receive;&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;"&gt;


  &lt;tr&gt;

    &lt;td style="width: 36pt;"/&gt;

    &lt;td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x25cf;&lt;/td&gt;

    &lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Expenses we expect to incur;&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;"&gt;


  &lt;tr&gt;

    &lt;td style="width: 36pt;"/&gt;

    &lt;td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x25cf;&lt;/td&gt;

    &lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Estimated income taxes; and&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;"&gt;


  &lt;tr&gt;

    &lt;td style="width: 36pt;"/&gt;

    &lt;td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x25cf;&lt;/td&gt;

    &lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;A discount rate.&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;We typically estimate the selling price of R&amp;amp;D services by using our internal estimates of the cost to perform the
    specific services. The significant inputs we use to determine the selling price of our R&amp;amp;D services include:&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;"&gt;


  &lt;tr&gt;

    &lt;td style="width: 36pt;"/&gt;

    &lt;td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x25cf;&lt;/td&gt;

    &lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;The number of internal hours we estimate we will spend performing these services;&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;"&gt;


  &lt;tr&gt;

    &lt;td style="width: 36pt;"/&gt;

    &lt;td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x25cf;&lt;/td&gt;

    &lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;The estimated cost of work we will perform;&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;"&gt;


  &lt;tr&gt;

    &lt;td style="width: 36pt;"/&gt;

    &lt;td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x25cf;&lt;/td&gt;

    &lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;The estimated cost of work that we will contract with third parties to perform; and&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;"&gt;


  &lt;tr&gt;

    &lt;td style="width: 36pt;"/&gt;

    &lt;td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x25cf;&lt;/td&gt;

    &lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;The estimated cost of API we will use.&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;For purposes of determining the stand-alone selling price of the R&amp;amp;D services we perform and the API we will deliver,
    accounting guidance requires us to include a markup for a reasonable profit margin.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;"&gt;


  &lt;tr&gt;

    &lt;td style="width: 36pt;"/&gt;

    &lt;td style="width: 18pt; vertical-align: top; align: right; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic; font-weight: bold;"&gt;5.&lt;/td&gt;

    &lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;
          &lt;div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic; font-weight: bold;"&gt;Recognize revenue&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;We recognize revenue in &lt;/span&gt;one&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt; of &lt;/span&gt;two&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt; ways, over time or at a point in time. We recognize revenue over time when we are
        executing on our performance obligation over time and our partner receives benefit over time. For example, we recognize revenue over time when we provide R&amp;amp;D services. We recognize revenue at a point in time when our partner receives full use
        of an item at a specific point in time. For example, we recognize revenue at a point in time when we deliver a license or API to a partner.&lt;/span&gt;&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
    &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;For R&amp;amp;D services that we recognize over
      time, we measure our progress using an input method. The input methods we use are based on the effort we expend or costs we incur toward the satisfaction of our performance obligation. We estimate the amount of effort we expend, including the time we
      estimate it will take us to complete the activities, or costs we incur in a given period, relative to the estimated total effort or costs to satisfy the performance obligation. This results in a percentage that we multiply by the transaction price to
      determine the amount of revenue we recognize each period. This approach requires us to make numerous estimates and use significant judgement. If our estimates or judgements change over the course of the collaboration, they may affect the timing and
      amount of revenue that we recognize in the current and future periods.&lt;/span&gt; Refer to Note 6, &lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;"&gt;Collaborative Arrangements and Licensing Agreements&lt;/span&gt;,
    for further discussion of the cumulative catch up adjustment we made.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: left; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;The following are examples of when we typically recognize revenue based on the types of payments we receive.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: left; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;"&gt;&lt;span style="text-decoration: underline;"&gt;Commercial Revenue: SPINRAZA royalties and Licensing and other royalty revenue&lt;/span&gt;&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;We recognize royalty revenue, including
      royalties from SPINRAZA sales, in the period in which the counterparty sells the related product and recognizes the related revenue, which in certain cases may require us to estimate our royalty revenue&lt;/span&gt;.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: left; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;"&gt;&lt;span style="text-decoration: underline;"&gt;Commercial Revenue: TEGSEDI and WAYLIVRA revenue, net&lt;/span&gt;&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Under our distribution agreements with Sobi we concluded that our performance obligation is to provide services to
      Sobi over the term of the agreement, which includes supplying finished goods inventory to Sobi and because we retained the marketing authorization for TEGSEDI and WAYLIVRA we are responsible for leading the global commercial strategy for each
      medicine. We view this performance obligation as a series of distinct activities that are substantially the same. Therefore, we recognize as revenue the price Sobi pays us for the inventory when we deliver the finished goods inventory to Sobi. We
      also recognize distribution fee revenue based on Sobi&#x2019;s net sales of TEGSEDI and WAYLIVRA in the period in which the sales occurred. Under our agreements with Sobi, Sobi does not generally have a right of return.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt;Prior to our distribution agreements with
      Sobi, we recognized TEGSEDI and WAYLIVRA commercial revenue in the period when our customer obtained control of our products, which occurred at a point in time upon transfer of title to the customer. We classified payments to customers or other
      parties in the distribution channel for services that were distinct and priced at fair value as selling, general and administrative, or SG&amp;amp;A, expenses in our consolidated statements of operations. We classified payments to customers or other
      parties in the distribution channel that did not meet those criteria as a reduction of revenue, as discussed further below. We excluded from revenues taxes collected from customers relating to TEGSEDI and WAYLIVRA commercial revenue and remitted
      these amounts to governmental authorities&lt;/span&gt;.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;"&gt;Reserves for TEGSEDI and WAYLIVRA commercial revenue&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Prior to our distribution agreements with Sobi, we recorded TEGSEDI and WAYLIVRA commercial revenue at our net sales
      price, or transaction price. We included in our transaction price estimated reserves for discounts, returns, chargebacks, rebates and other allowances that we offered within contracts between us and our customers, wholesalers, distributors, health
      care providers and other indirect customers. We estimated our reserves using the amounts we have earned or we could claim on the associated sales. We classified our reserves as a reduction of accounts receivable when we were not required to make a
      payment or as a current liability when we were required to make a payment. In certain cases, our estimates included a range of possible outcomes that were probability weighted for relevant factors such as our historical experience, current
      contractual and statutory requirements, specific known market events and trends, industry data and forecasted customer buying and payment patterns. Overall, our reserves reflected our best estimates under the terms of our respective contracts. When
      calculating our reserves and related TEGSEDI and WAYLIVRA commercial revenue, we only recognized amounts to the extent that we considered it probable that we would not have to reverse a significant amount of the cumulative sales we previously
      recognized in a future period. Under our agreements with Sobi, we transferred all reserves to Sobi.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: left; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;The following were the components of variable consideration related to TEGSEDI and WAYLIVRA product sales prior to our agreements with Sobi:&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="text-align: justify; margin-left: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;"&gt;Chargebacks: &lt;/span&gt;&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt;In the U.S., we estimated obligations resulting from contractual commitments with the government and other entities to sell products to qualified healthcare
      providers at prices lower than the list prices charged to our U.S. customer. Our U.S. customer charged us for the difference between what it paid for the product and the selling price to the qualified healthcare providers. We also estimated the
      amount of chargebacks related to our estimated product remaining in the distribution channel at the end of the reporting period that we expected our customer to sell to healthcare providers in future periods. We recorded these reserves as a reduction
      to contracts receivable on our consolidated balance sheet&lt;/span&gt;.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="text-align: justify; margin-left: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic; color: #000000;"&gt;Government rebates&lt;/span&gt;&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt;: We were subject to discount obligations under government programs, including Medicaid and Medicare programs in the U.S. and we recorded reserves for government
      rebates based on statutory discount rates and estimated utilization. We estimated Medicaid and Medicare rebates based on a range of possible outcomes that were probability weighted for the estimated payer mix. We recorded these reserves as an accrued
      liability on our consolidated balance sheet with a corresponding offset reducing our product sales in the same period we recognized the related sale. For Medicare, we also estimated the number of patients in the prescription drug coverage gap for
      whom we would owe an additional liability under the Medicare Part D program. On a quarterly basis, we updated our estimates and recorded any adjustments in the period that we identified the adjustments&lt;/span&gt;.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="text-align: justify; margin-left: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;"&gt;Managed care rebates: &lt;/span&gt;&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt;We were subject to rebates in connection with agreements with certain contracted commercial payers. We recorded these rebates as a liability on our consolidated
      balance sheet in the same period we recognized the related revenue. We estimated our managed care rebates based on our estimated payer mix and the applicable contractual rebate rate&lt;/span&gt;.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="text-align: justify; margin-left: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;"&gt;Trade discounts: &lt;/span&gt;&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt;We provided customary invoice discounts on product sales to our U.S. customer for prompt payment. We recorded this discount as a reduction of product sales in the
      period in which we recognized the related product revenue&lt;/span&gt;.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="text-align: justify; margin-left: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;"&gt;Distribution services&lt;/span&gt;: &lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt;We received and paid for various distribution services from our U.S. and European customers (prior to our agreement with Sobi) and wholesalers in the U.S. We
      classified the costs for services we received that are either not distinct from the sale of the product or for which we could not reasonably estimate the fair value as a reduction of product sales. To the extent that the services we received are
      distinct from the sale of the product, we classified the costs for such services as SG&amp;amp;A expenses.&lt;/span&gt;&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="text-align: justify; margin-left: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;"&gt;Product returns: &lt;/span&gt;&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt;Our U.S. customer had return rights and the wholesalers had limited return rights primarily related to the product&#x2019;s expiration date. We estimated the amount of
      product sales that our customer may return. We recorded our return estimate as an accrued refund liability on our consolidated balance sheet with a corresponding offset reducing our product sales in the same period we recognized the related sale.
      Based on our distribution model for product sales, contractual inventory limits with our customer and wholesalers and the price of the product, we had minimal returns. Our European customers generally only took title to the product after they
      received an order and therefore they did not maintain excess inventory levels of our products. Accordingly, we had limited return risk in Europe and we did not estimate returns in Europe&lt;/span&gt;.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: left; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;"&gt;&lt;span style="text-decoration: underline;"&gt;Research and development revenue under collaboration agreements:&lt;/span&gt;&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: left; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;"&gt;&lt;span style="text-decoration: underline;"&gt;Upfront payments&lt;/span&gt;&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt;When we enter into a collaboration agreement
      with an upfront payment, we typically record the entire upfront payment as deferred revenue if our only performance obligation is for R&amp;amp;D services we will provide in the future. We amortize the upfront payment into revenue as we perform the
      R&amp;amp;D services. For example, under our collaboration agreement with Roche to&lt;/span&gt;&lt;span style="background-color: #FBFBFB; font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt; develop IONIS-FB-L&lt;/span&gt;&lt;sub style="color: #000000;"&gt;Rx&lt;/sub&gt;&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt; for the treatment of complement-mediated diseases, we received a $&lt;/span&gt;75&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt; million upfront payment in the fourth quarter of 2018. We allocated the upfront payment to our
      single performance obligation, R&amp;amp;D services. We are amortizing the $&lt;/span&gt;75&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt; million upfront payment using an input method over the estimated period of time we are providing R&amp;amp;D services&lt;/span&gt;.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;"&gt;&lt;span style="text-decoration: underline;"&gt;Milestone payments&lt;/span&gt;&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;We are required to include additional consideration in the transaction price when it is probable. We typically
        include milestone payments for R&amp;amp;D services in the transaction price when they are achieved. We include these milestone payments when they are achieved because typically there is considerable uncertainty in the research and development
        processes that trigger these payments. Similarly, we include approval milestone payments in the transaction price once the medicine is approved by the applicable regulatory agency. We will recognize sales-based milestone payments in the period in
        which we achieve the milestone under the sales-based royalty exception allowed under accounting rules.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt;We recognize milestone payments that relate
      to an ongoing performance obligation over our period of performance. For example, in the fourth quarter of 2021, we achieved a&lt;/span&gt; $7.5&#160;&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt;million milestone payment from Biogen when we advanced&lt;/span&gt;&#160;&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt;a &lt;/span&gt;target
    under our 2018 strategic collaboration.&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt; We added this payment to the transaction price and allocated it to our R&amp;amp;D services performance obligation. We are
      recognizing revenue related to this milestone payment over our estimated period of performance&lt;/span&gt;.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Conversely, we recognize in full those milestone payments that we earn based on our partners&#x2019; activities when our partner achieves the
    milestone event and we do not have a performance obligation. For example, in the fourth quarter of 2021, we recognized $15 million in milestone
    payments when Biogen advanced two targets under our 2018 strategic collaboration. &lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt;We concluded that the milestone payments were not related to our R&amp;amp;D services performance obligation. Therefore, we recognized the milestone payments in full in the fourth quarter of 2021.&lt;/span&gt;&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;"&gt;&lt;span style="text-decoration: underline;"&gt;License fees&lt;/span&gt;&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt;We generally recognize as revenue the total
      amount we determine to be the relative stand-alone selling price of a license when we deliver the license to our partner. This is because our partner has full use of the license and we do not have any additional performance obligations related to the
      license after delivery. For example, in the fourth quarter of 2021, we earned a&lt;/span&gt; $60&#160;&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt;million license fee from Biogen when Biogen licensed ION306, an investigational medicine in development to treat SMA.&lt;/span&gt;&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;"&gt;&lt;span style="text-decoration: underline;"&gt;Sublicense fees&lt;/span&gt;&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt;We recognize sublicense fee revenue in the
      period in which a party, who has already licensed our technology, further licenses the technology to another party because we do not have any performance obligations related to the sublicense. &lt;/span&gt;For example, in the fourth quarter of 2020, we
    earned a $41.2 million sublicense fee from Alnylam Pharmaceuticals for its sublicense of our technology to Sanofi Genzyme.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic; font-weight: bold;"&gt;Amendments to Agreements&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;From time to time we amend our collaboration agreements. When this occurs, we are required to assess the following items
    to determine the accounting for the amendment:&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;"&gt;


  &lt;tr&gt;

    &lt;td style="width: 36pt;"/&gt;

    &lt;td style="width: 18pt; vertical-align: top; align: right; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;1)&lt;/td&gt;

    &lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;
          &lt;div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;If the additional goods and/or services are distinct from the other performance obligations in the original agreement; and&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;"&gt;


  &lt;tr&gt;

    &lt;td style="width: 36pt;"/&gt;

    &lt;td style="width: 18pt; vertical-align: top; align: right; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;2)&lt;/td&gt;

    &lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;
          &lt;div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;If the goods and/or services are at a stand-alone selling price.&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;If we conclude the goods and/or services in the amendment are distinct from the performance obligations in the
        original agreement and at a stand-alone selling price, we account for the amendment as a separate agreement. If we conclude the goods and/or services are not distinct and are sold at a stand-alone selling price, we then assess whether the remaining
        goods or services are distinct from those already provided. If the goods and/or services are distinct from what we have already provided, then we allocate the remaining transaction price from the original agreement and the additional transaction
        price from the amendment to the remaining goods and/or services. If the goods and/or services are not distinct from what we have already provided, we update the transaction price for our single performance obligation and recognize any change in our
        estimated revenue as a cumulative adjustment.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
    &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;For example, in May 2015, we entered into an exclusive license agreement with Bayer to develop and commercialize IONIS-FXI&lt;sub&gt;Rx&lt;/sub&gt;
    for the prevention of thrombosis. As part of the agreement, Bayer paid us a $100 million upfront payment. At the onset of the agreement, we were
    responsible for completing a Phase 2 study of IONIS-FXI&lt;sub&gt;Rx&lt;/sub&gt; in people with end-stage renal disease on hemodialysis and for providing an initial supply of API. In February 2017, we amended our agreement with Bayer to advance IONIS-FXI&lt;sub&gt;Rx&lt;/sub&gt;
    and to initiate development of fesomersen, which Bayer licensed. As part of the 2017 amendment, Bayer paid us $75 million. We are also eligible
    to receive milestone payments and tiered royalties on gross margins of IONIS-FXI&lt;sub&gt;Rx&lt;/sub&gt; and fesomersen. Under the 2017 amendment, we concluded we had a new agreement with three performance obligations. These performance obligations were to deliver the license of fesomersen, to provide R&amp;amp;D services and to deliver API. We allocated the $75 million transaction price to these performance obligations. Refer to Note 6, &lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;"&gt;Collaborative Arrangements and Licensing Agreements&lt;/span&gt;, for further discussion of the Bayer collaboration.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic; font-weight: bold;"&gt;Multiple agreements&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;From time to time, we may enter into separate agreements at or near the same time with the same partner. We evaluate such
    agreements to determine whether we should account for them individually as distinct arrangements or whether the separate agreements should be combined and accounted for together. We evaluate the following to determine the accounting for the agreements:&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;"&gt;


  &lt;tr&gt;

    &lt;td style="width: 36pt;"/&gt;

    &lt;td style="width: 18pt; vertical-align: top; align: right; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x25cf;&lt;/td&gt;

    &lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;
          &lt;div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Whether the agreements were negotiated together with a single objective;&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;"&gt;


  &lt;tr&gt;

    &lt;td style="width: 36pt;"/&gt;

    &lt;td style="width: 18pt; vertical-align: top; align: right; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x25cf;&lt;/td&gt;

    &lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;
          &lt;div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Whether the amount of consideration in one contract depends on the price or performance of the other agreement; or&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;"&gt;


  &lt;tr&gt;

    &lt;td style="width: 36pt;"/&gt;

    &lt;td style="width: 18pt; vertical-align: top; align: right; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x25cf;&lt;/td&gt;

    &lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;
          &lt;div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Whether the goods and/or services promised under the agreements are a single performance obligation.&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Our evaluation involves significant judgment to determine whether a group of agreements might be so closely related that accounting
    guidance requires us to account for them as a combined arrangement.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;For example, in the second quarter of 2018, we entered into two separate agreements with Biogen at the same time: &lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt;a new strategic neurology collaboration
      agreement and a stock purchase agreement, or SPA. We evaluated the Biogen agreements to determine whether we should treat the agreements separately or combine them. We considered that the agreements were negotiated concurrently and in contemplation
      of one another. Based on these facts and circumstances, we concluded that we should evaluate the provisions of the agreements on a combined basis.&lt;/span&gt;&lt;/div&gt;
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&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: left; text-indent: -54pt; margin-left: 54pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Contracts Receivable&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt;Our contracts receivable balance represents
      the amounts we have billed our partners or customers and that are due to us unconditionally for goods we have delivered or services we have performed. When we bill our partners or customers with payment terms based on the passage of time, we consider
      the contracts receivable to be unconditional. We typically receive payment within one &lt;/span&gt;&lt;span style="-sec-ix-hidden:Fact_e2c2673a057f412ebd5831ca8712546a"&gt;quarter&lt;/span&gt;&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt; of billing our partner or customer&lt;/span&gt;.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;As of December 31, 2021, approximately 93.8 percent of our contracts receivables were from two significant customers. As of December 31, 2020, approximately 99.5 percent of our contracts receivables were from two
    significant customers.&lt;/div&gt;
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      unitRef="U008">2</ions:NumberOfSignificantCustomers>
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      contextRef="c20210101to20211231"
      id="Text_11c759b68b4b4c4b94628fcf39b9e913">
&lt;div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Unbilled SPINRAZA Royalties&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Our unbilled SPINRAZA royalties represent our right to receive consideration from Biogen in advance of when we are
    eligible to bill Biogen for SPINRAZA royalties. We include these unbilled amounts in other current assets on our consolidated balance sheet.&lt;/div&gt;
</us-gaap:TradeAndOtherAccountsReceivableUnbilledReceivablesPolicy>
    <us-gaap:RevenueRecognitionPolicyTextBlock
      contextRef="c20210101to20211231"
      id="Text_4fad649cf4524327bf2658a3254aca30">
&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: left; text-indent: -54pt; margin-left: 54pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Deferred Revenue&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt;We are often entitled to bill our customers
      and receive payment from our customers in advance of our obligation to provide services or transfer goods to our partners. In these instances, we include the amounts in deferred revenue on our consolidated balance sheet.&lt;/span&gt; During the years ended
    December 31, 2021 and 2020, we recognized $98.1 million and $100.4 million of revenue from amounts that were in our beginning deferred revenue balance for each respective period. For further discussion, refer to our revenue recognition policy above.&lt;/div&gt;
</us-gaap:RevenueRecognitionPolicyTextBlock>
    <us-gaap:ContractWithCustomerLiabilityRevenueRecognized
      contextRef="c20210101to20211231"
      decimals="-5"
      id="Fact_7a9ec3bea8ad464ca6e12c6aa16435cd"
      unitRef="U001">98100000</us-gaap:ContractWithCustomerLiabilityRevenueRecognized>
    <us-gaap:ContractWithCustomerLiabilityRevenueRecognized
      contextRef="c20200101to20201231"
      decimals="-5"
      id="Fact_ced6b030f6d146bb91eabbce81e6f413"
      unitRef="U001">100400000</us-gaap:ContractWithCustomerLiabilityRevenueRecognized>
    <us-gaap:CostOfSalesPolicyTextBlock
      contextRef="c20210101to20211231"
      id="Text_7bb4849d286842ec8c69f3be8efe749c">
&lt;div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Cost of Sales&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Our cost of sales includes manufacturing costs, transportation and freight costs and indirect overhead costs associated with the
    manufacturing and distribution of our products. We also may include certain period costs related to manufacturing services and inventory adjustments in cost of sales. We also may include certain period costs related to manufacturing services and
    inventory adjustments in cost of sales.&lt;/div&gt;
</us-gaap:CostOfSalesPolicyTextBlock>
    <us-gaap:ResearchAndDevelopmentExpensePolicy
      contextRef="c20210101to20211231"
      id="Text_3a1d8d5acce046e6b43dae80c783423c">
&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Our research and development expenses include wages, benefits, facilities, supplies, external
    services, clinical trial and manufacturing costs and other expenses that are directly related to our research and development operations. We expense research and development costs as we incur them. When we make payments for research and development
    services prior to the services being rendered, we record those amounts as prepaid assets on our consolidated balance sheet and we expense them as the services are provided. For the years ended December 31, 2021, 2020 and 2019, research and development expenses were $638.2 million, $531.0 million and $461.5 million, respectively. A
    portion of the costs included in research and development expenses are costs associated with our partner agreements.&lt;/div&gt;
</us-gaap:ResearchAndDevelopmentExpensePolicy>
    <us-gaap:ResearchAndDevelopmentExpense
      contextRef="c20210101to20211231"
      decimals="-5"
      id="Fact_d0c1565159a044b595630e050bb43a4e"
      unitRef="U001">638200000</us-gaap:ResearchAndDevelopmentExpense>
    <us-gaap:ResearchAndDevelopmentExpense
      contextRef="c20200101to20201231"
      decimals="-5"
      id="Fact_0114d1a3cfd445bbb2a6b5bc9fba079f"
      unitRef="U001">531000000.0</us-gaap:ResearchAndDevelopmentExpense>
    <us-gaap:ResearchAndDevelopmentExpense
      contextRef="c20190101to20191231"
      decimals="-5"
      id="Fact_203e9d3fa0b14eca9d0edbb437f4f325"
      unitRef="U001">461500000</us-gaap:ResearchAndDevelopmentExpense>
    <us-gaap:IntangibleAssetsFiniteLivedPolicy
      contextRef="c20210101to20211231"
      id="Text_4ba9c595a228410fb80294db6e9e8808">
&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;We capitalize costs consisting principally of outside legal costs and filing fees related to obtaining
    patents. We amortize patent costs over the useful life of the patent, beginning with the date the U.S. Patent and Trademark Office, or foreign equivalent, issues the patent. The weighted average remaining amortizable life of our issued patents was 10.2 years at December 31, 2021.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;The cost of our patents capitalized on our consolidated balance sheet at December 31, 2021 and 2020 was $38.4 million and $37.0 million, respectively.
    Accumulated amortization related to patents was $9.4 million and $9.1 million at December 31, 2021 and 2020, respectively.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Based on our existing patents, we estimate amortization expense related to patents in each of
    the next five years to be the following:&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;"&gt;


  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; border-bottom: #000000 2px solid;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Year Ending December 31,&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Amortization&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;(in millions)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 88%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;span style="text-indent: 0pt;"&gt;2022&lt;/span&gt;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;2.2&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 88%;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;span style="text-indent: 0pt;"&gt;2023&lt;/span&gt;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;2.1&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 88%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;span style="text-indent: 0pt;"&gt;2024&lt;/span&gt;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;1.9&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 88%;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;span style="text-indent: 0pt;"&gt;2025&lt;/span&gt;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;1.8&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 88%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;span style="text-indent: 0pt;"&gt;2026&lt;/span&gt;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;1.8&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 12pt;"&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;We review our capitalized patent costs regularly to ensure that they include costs for patents and patent applications
    that have future value. When we identify patents and patent applications that we are not actively pursuing, we write off any associated costs. In 2021,
    2020 and 2019, patent expenses
    were $5.3 million, $4.1 million and $4.2 million, respectively, and included non-cash charges related to the write-down of our patent costs to their estimated net realizable values of $2.7 million, $1.9 million and $2.2 million, respectively.&lt;/div&gt;
</us-gaap:IntangibleAssetsFiniteLivedPolicy>
    <us-gaap:FiniteLivedIntangibleAssetUsefulLife
      contextRef="c20210101to20211231_FiniteLivedIntangibleAssetsByMajorClassAxis_PatentsMember"
      id="Fact_0743de364414479fa413c5d659ce3213">P10Y2M12D</us-gaap:FiniteLivedIntangibleAssetUsefulLife>
    <us-gaap:FiniteLivedIntangibleAssetsGross
      contextRef="c20211231_FiniteLivedIntangibleAssetsByMajorClassAxis_PatentsMember"
      decimals="-5"
      id="Fact_df1e6fe595054242bd56601d34e950e2"
      unitRef="U001">38400000</us-gaap:FiniteLivedIntangibleAssetsGross>
    <us-gaap:FiniteLivedIntangibleAssetsGross
      contextRef="c20201231_FiniteLivedIntangibleAssetsByMajorClassAxis_PatentsMember"
      decimals="-5"
      id="Fact_421e79a98335467eb99a9cba6857377d"
      unitRef="U001">37000000.0</us-gaap:FiniteLivedIntangibleAssetsGross>
    <us-gaap:FiniteLivedIntangibleAssetsAccumulatedAmortization
      contextRef="c20211231_FiniteLivedIntangibleAssetsByMajorClassAxis_PatentsMember"
      decimals="-5"
      id="Fact_414dd9c96ebb45a28f493a17da9dec2e"
      unitRef="U001">9400000</us-gaap:FiniteLivedIntangibleAssetsAccumulatedAmortization>
    <us-gaap:FiniteLivedIntangibleAssetsAccumulatedAmortization
      contextRef="c20201231_FiniteLivedIntangibleAssetsByMajorClassAxis_PatentsMember"
      decimals="-5"
      id="Fact_91380e7cfc944a1e8053aef43d6d897f"
      unitRef="U001">9100000</us-gaap:FiniteLivedIntangibleAssetsAccumulatedAmortization>
    <us-gaap:ScheduleofFiniteLivedIntangibleAssetsFutureAmortizationExpenseTableTextBlock
      contextRef="c20210101to20211231"
      id="Text_94528c9584664d73b67412f9d345feef">
&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Based on our existing patents, we estimate amortization expense related to patents in each of
    the next five years to be the following:&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;"&gt;


  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; border-bottom: #000000 2px solid;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Year Ending December 31,&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Amortization&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;(in millions)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 88%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;span style="text-indent: 0pt;"&gt;2022&lt;/span&gt;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;2.2&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 88%;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;span style="text-indent: 0pt;"&gt;2023&lt;/span&gt;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;2.1&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 88%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;span style="text-indent: 0pt;"&gt;2024&lt;/span&gt;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;1.9&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 88%;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;span style="text-indent: 0pt;"&gt;2025&lt;/span&gt;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;1.8&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 88%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;span style="text-indent: 0pt;"&gt;2026&lt;/span&gt;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;1.8&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;
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      unitRef="U001">1800000</us-gaap:FiniteLivedIntangibleAssetsAmortizationExpenseYearFour>
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      contextRef="c20211231_FiniteLivedIntangibleAssetsByMajorClassAxis_PatentsMember"
      decimals="-5"
      id="Fact_f350bd894a8d412c8d2a916536e277ef"
      unitRef="U001">1800000</us-gaap:FiniteLivedIntangibleAssetsAmortizationExpenseYearFive>
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      contextRef="c20210101to20211231_FiniteLivedIntangibleAssetsByMajorClassAxis_PatentsMember"
      decimals="-5"
      id="Fact_49b21994e36f479d8fb8491e6b0e2bec"
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      decimals="-5"
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      decimals="-5"
      id="Fact_3201b72effcf4c0c8e0d51523e32d64f"
      unitRef="U001">4200000</us-gaap:ResearchAndDevelopmentExpense>
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      contextRef="c20210101to20211231_FiniteLivedIntangibleAssetsByMajorClassAxis_PatentsMember"
      decimals="-5"
      id="Fact_acdbb50a6f92446b87e379e817f900c3"
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      contextRef="c20200101to20201231_FiniteLivedIntangibleAssetsByMajorClassAxis_PatentsMember"
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      id="Fact_3029299725d54805be6165d35d2050b9"
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      contextRef="c20190101to20191231_FiniteLivedIntangibleAssetsByMajorClassAxis_PatentsMember"
      decimals="-5"
      id="Fact_1057b62f0867480b862004e4e8b9e9ed"
      unitRef="U001">2200000</us-gaap:ImpairmentOfIntangibleAssetsFinitelived>
    <us-gaap:ScheduleOfAccruedLiabilitiesTableTextBlock
      contextRef="c20210101to20211231"
      id="Text_dee06e4770204682af8c0b46599d481a">
&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Our accrued liabilities consisted of the following (in thousands):&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;"&gt;


  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;

        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="6" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;December 31,&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;2021&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;2020&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 76%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Clinical expenses&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;65,730&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;39,477&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 76%;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -18pt; margin-left: 18pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;In-licensing expenses&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;8,044&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;8,264&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 76%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -18pt; margin-left: 18pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Commercial expenses&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;2,471&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;11,559&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 76%; padding-bottom: 2px;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -18pt; margin-left: 18pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Other miscellaneous expenses&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;12,315&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;30,861&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 76%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Total accrued liabilities&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;88,560&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;90,161&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;
</us-gaap:ScheduleOfAccruedLiabilitiesTableTextBlock>
    <ions:AccruedClinicalExpenses
      contextRef="c20211231"
      decimals="-3"
      id="Fact_dd19e9b42ea648b5a66ad1c40729f204"
      unitRef="U001">65730000</ions:AccruedClinicalExpenses>
    <ions:AccruedClinicalExpenses
      contextRef="c20201231"
      decimals="-3"
      id="Fact_fac7f03b039f4f02a05228c036fc1f3c"
      unitRef="U001">39477000</ions:AccruedClinicalExpenses>
    <ions:AccruedInLicensingFeesCurrent
      contextRef="c20211231"
      decimals="-3"
      id="Fact_4a54e14632b04a9cb08ecbd7c4f7b264"
      unitRef="U001">8044000</ions:AccruedInLicensingFeesCurrent>
    <ions:AccruedInLicensingFeesCurrent
      contextRef="c20201231"
      decimals="-3"
      id="Fact_a1182bff6aa841d1b17861b49376378a"
      unitRef="U001">8264000</ions:AccruedInLicensingFeesCurrent>
    <ions:AccruedCommercialExpensesCurrent
      contextRef="c20211231"
      decimals="-3"
      id="Fact_991e082179bb4e87b5afb60cdf56fada"
      unitRef="U001">2471000</ions:AccruedCommercialExpensesCurrent>
    <ions:AccruedCommercialExpensesCurrent
      contextRef="c20201231"
      decimals="-3"
      id="Fact_dce6ebe7c0d64208a814a92b3849fcba"
      unitRef="U001">11559000</ions:AccruedCommercialExpensesCurrent>
    <us-gaap:OtherAccruedLiabilitiesCurrent
      contextRef="c20211231"
      decimals="-3"
      id="Fact_36801832e43e415bbc066744d39ceba6"
      unitRef="U001">12315000</us-gaap:OtherAccruedLiabilitiesCurrent>
    <us-gaap:OtherAccruedLiabilitiesCurrent
      contextRef="c20201231"
      decimals="-3"
      id="Fact_558a2514ca9d46d38ef6431a99ec3875"
      unitRef="U001">30861000</us-gaap:OtherAccruedLiabilitiesCurrent>
    <us-gaap:AccruedLiabilitiesCurrent
      contextRef="c20211231"
      decimals="-3"
      id="Fact_d3d4336195b54976b7bcea8d3b30b7ac"
      unitRef="U001">88560000</us-gaap:AccruedLiabilitiesCurrent>
    <us-gaap:AccruedLiabilitiesCurrent
      contextRef="c20201231"
      decimals="-3"
      id="Fact_e91e73e81dd74acab89c06a66144eab3"
      unitRef="U001">90161000</us-gaap:AccruedLiabilitiesCurrent>
    <ions:LiabilityForClinicalDevelopmentCostsPolicyPolicyTextBlock
      contextRef="c20210101to20211231"
      id="Text_567209235aa947d8b744c77c399b99ec">
&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: left; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;"&gt;Estimated Liability for Clinical Development Costs&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;We have numerous medicines in preclinical studies and/or clinical trials at clinical sites throughout the world. On at least a quarterly
    basis, we estimate our liability for preclinical and clinical development costs we have incurred and services that we have received but for which we have not yet been billed and maintain an accrual to cover these costs. These costs primarily relate to
    third-party clinical management costs, laboratory and analysis costs, toxicology studies and investigator grants. We estimate our liability using assumptions about study and patient activities and the related expected expenses for those activities
    determined based on the contracted fees with our service providers. The assumptions we use represent our best estimates of the activity and expenses at the time of our accrual and involve inherent uncertainties and the application of our judgment. Upon
    settlement, these costs may differ materially from the amounts accrued in our consolidated financial statements. Our historical accrual estimates have not been materially different from our actual amounts.&lt;/div&gt;
</ions:LiabilityForClinicalDevelopmentCostsPolicyPolicyTextBlock>
    <us-gaap:ConsolidationSubsidiariesOrOtherInvestmentsConsolidatedEntitiesPolicy
      contextRef="c20210101to20211231"
      id="Text_4a814361d42740b68c1dd2442d40671b">
&lt;div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Noncontrolling Interest in Akcea Therapeutics, Inc.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt;Since Akcea&#x2019;s IPO in July 2017 and prior to
      the Akcea Merger in October 2020, the shares of Akcea&#x2019;s common stock third parties owned represented an interest in Akcea&#x2019;s equity that we did not control. During this period our ownership ranged from &lt;/span&gt;68 percent&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt; to &lt;/span&gt;77 percent&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt;. However, as we maintained overall control of Akcea through our voting interest, we
      reflected the assets, liabilities and results of operations of Akcea in our consolidated financial statements. Since Akcea&#x2019;s IPO in July 2017 and through the closing of the Akcea Merger, we reflected the noncontrolling interest attributable to other
      owners of Akcea&#x2019;s common stock on a separate line on our statement of operations and a separate line within stockholders&#x2019; equity in our consolidated balance sheet. In addition, through the closing of the Akcea Merger, we recorded a noncontrolling
      interest adjustment to account for the stock options Akcea granted, which if exercised, would have diluted our ownership in Akcea. This adjustment was a reclassification within stockholders&#x2019; equity from additional paid-in capital to noncontrolling
      interest in Akcea equal to the amount of stock-based compensation expense Akcea had recognized. Additionally, w&lt;/span&gt;e reflected changes in our ownership percentage in our financial statements as an adjustment to noncontrolling interest in the
    period the change occurred.&lt;/div&gt;
</us-gaap:ConsolidationSubsidiariesOrOtherInvestmentsConsolidatedEntitiesPolicy>
    <us-gaap:MinorityInterestOwnershipPercentageByParent
      contextRef="c20201031_OwnershipAxis_AkceaTherapeuticsIncMember_RangeAxis_MinimumMember"
      decimals="2"
      id="Fact_1097de361427408da42d756b10b489be"
      unitRef="U003">0.68</us-gaap:MinorityInterestOwnershipPercentageByParent>
    <us-gaap:MinorityInterestOwnershipPercentageByParent
      contextRef="c20201031_OwnershipAxis_AkceaTherapeuticsIncMember_RangeAxis_MaximumMember"
      decimals="2"
      id="Fact_5665dba820d74eba9e6f5307d4168e81"
      unitRef="U003">0.77</us-gaap:MinorityInterestOwnershipPercentageByParent>
    <us-gaap:ConcentrationRiskCreditRisk
      contextRef="c20210101to20211231"
      id="Text_2657526565084c29a44990225a255af0">
&lt;div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Concentration of Credit Risk&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Financial instruments that potentially subject us to concentrations of credit risk consist primarily of cash equivalents,
    short-term investments and receivables. We place our cash equivalents and short-term investments with reputable financial institutions. We primarily invest our excess cash in commercial paper and debt instruments of the U.S. Treasury, financial
    institutions, corporations, and U.S. government agencies with strong credit ratings and an investment grade rating at or above A-1, P-1 or F-1 by Moody&#x2019;s, Standard &amp;amp; Poor&#x2019;s, or S&amp;amp;P, or Fitch, respectively. We have established guidelines
    relative to diversification and maturities that maintain safety and liquidity. We periodically review and modify these guidelines to maximize trends in yields and interest rates without compromising safety and liquidity.&lt;/div&gt;
</us-gaap:ConcentrationRiskCreditRisk>
    <us-gaap:InvestmentPolicyTextBlock
      contextRef="c20210101to20211231"
      id="Text_6331a27b92f04118a22313343e337534">
&lt;div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Cash, Cash Equivalents and Investments&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;We consider all liquid investments with maturities of three months or less when we purchase them to be cash equivalents.
    Our short-term investments have initial maturities of greater than three months from date of purchase. We classify our short-term debt investments as &#x201c;available-for-sale&#x201d; and carry them at fair market value based upon prices on the last day of the
    fiscal period for identical or similar items. We record unrealized gains and losses on debt securities as a separate component of comprehensive income (loss) and include net realized gains and losses in gain (loss) on investments in our consolidated
    statement of operations. We use the specific identification method to determine the cost of securities sold.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;We also have equity investments of less than 20 percent ownership in publicly and privately held biotechnology companies
      that we received as part of a technology license or partner agreement. At December 31, 2021, we held equity investments in three publicly held companies, Antisense Therapeutics Limited, or ATL, Bicycle Therapeutics plc, or Bicycle, and ProQR Therapeutics N.V., or ProQR. We
      also held equity investments in seven privately-held companies, Aro Biotherapeutics, Atlantic Pharmaceuticals Limited, Dynacure SAS, Empirico,
      Inc., Flamingo Therapeutics BV, YourBio Health, Inc. (formerly Seventh Sense Biosystems) and Suzhou-Ribo Life Science Co, Ltd.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;We are required to measure and record our equity investments at fair value and to recognize the changes in fair value in our consolidated
    statement of operations. We account for our equity investments in privately held companies at their cost minus impairments, plus or minus changes resulting from observable price changes in orderly transactions for the identical or similar investment of
    the same issuer. For example, d&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt;uring 2020, we revalued our investments in &lt;/span&gt;three&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt; privately held companies, Dynacure, Suzhou-Ribo and Aro Biotherapeutics because the companies
      sold additional equity securities that were similar to the equity we own. As a result of these observable price changes, we recognized a $&lt;/span&gt;6.3&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt; million gain on our investment in Dynacure, a $&lt;/span&gt;3.0&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt; million gain on our investment in Suzhou-Ribo and a $&lt;/span&gt;5.5&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt; million gain on our investment in Aro Biotherapeutics in our consolidated statement of operations during 2020 because the sales were at higher prices compared to
      our recorded value.&lt;/span&gt;&lt;/div&gt;
</us-gaap:InvestmentPolicyTextBlock>
    <ions:NumberOfPubliclyHeldCompaniesInWhichEntityHasEquityInvestment
      contextRef="c20211231"
      decimals="INF"
      id="Fact_b448547c88c7434cbc329f97a4b3ea28"
      unitRef="U009">3</ions:NumberOfPubliclyHeldCompaniesInWhichEntityHasEquityInvestment>
    <ions:NumberOfPrivatelyHeldCompaniesInWhichEntityHasEquityInvestment
      contextRef="c20211231"
      decimals="INF"
      id="Fact_5091e6339b9e4e85943dd42b9d332383"
      unitRef="U009">7</ions:NumberOfPrivatelyHeldCompaniesInWhichEntityHasEquityInvestment>
    <ions:NumberOfInvestmentsInPrivatelyHeldCompaniesThatWereRevalued
      contextRef="c20200101to20201231"
      decimals="INF"
      id="Fact_f7fa3e5a04194e26a2205eb8715ec05c"
      unitRef="U010">3</ions:NumberOfInvestmentsInPrivatelyHeldCompaniesThatWereRevalued>
    <us-gaap:GainLossOnInvestments
      contextRef="c20200101to20201231_FinancialInstrumentAxis_DynacureSasMember"
      decimals="-5"
      id="Fact_cdc5aa89677e4989aa728a9bb2e0edf9"
      unitRef="U001">6300000</us-gaap:GainLossOnInvestments>
    <us-gaap:GainLossOnInvestments
      contextRef="c20200101to20201231_FinancialInstrumentAxis_SuzhouRiboLifeScienceCoLtdMember"
      decimals="-5"
      id="Fact_47b16f5d19a84a8c9a09fbbe96174527"
      unitRef="U001">3000000.0</us-gaap:GainLossOnInvestments>
    <us-gaap:GainLossOnInvestments
      contextRef="c20200101to20201231_FinancialInstrumentAxis_AroBiotherapeuticsMember"
      decimals="-5"
      id="Fact_cf49d586d5334999834bf4a673cb3dfa"
      unitRef="U001">5500000</us-gaap:GainLossOnInvestments>
    <us-gaap:InventoryPolicyTextBlock
      contextRef="c20210101to20211231"
      id="Text_962b0a89596444369c91918399edde59">
&lt;div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Inventory Valuation&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;We reflect our inventory on our consolidated balance sheet at the lower of cost or net realizable value under the first-in, first-out
    method, or FIFO. We capitalize the costs of raw materials that we purchase for use in producing our medicines because until we use these raw materials, they have alternative future uses, which we refer to as clinical raw materials. We include in
    inventory raw material costs for medicines that we manufacture for our partners under contractual terms and that we use primarily in our clinical development activities and drug products. We can use each of our raw materials in multiple products and,
    as a result, each raw material has future economic value independent of the development status of any single medicine. For example, if one of our medicines failed, we could use the raw materials for that medicine to manufacture our other medicines. We
    expense these costs as R&amp;amp;D expenses when we begin to manufacture API for a particular medicine if the medicine has not been approved for marketing by a regulatory agency. Our raw materials- commercial inventory includes API for our commercial
    medicines. We capitalize material, labor and overhead costs as part of our raw materials- commercial inventory.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;We review our inventory periodically and reduce the carrying value of items we consider to be slow moving or obsolete to
    their estimated net realizable value based on forecasted demand compared to quantities on hand. We consider several factors in estimating the net realizable value, including shelf life of our inventory, alternative uses for our medicines in development
    and historical write-offs. We recorded an &lt;span style="-sec-ix-hidden:Fact_df7c1770e27a4789b9f7ad5345f29256"&gt;&lt;span style="-sec-ix-hidden:Fact_7ba6995a24424942b581829d4ed245cc"&gt;insignificant&lt;/span&gt;&lt;/span&gt; amount of inventory write-offs during the years ended December 31, 2021 and 2020.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Our inventory consisted of the following (in thousands):&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;"&gt;


  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;

        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="6" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;December 31,&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;2021&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;2020&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Raw materials:&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 76%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 19.4pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Raw materials- clinical&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;14,507&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;9,206&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 76%; padding-bottom: 2px;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -18pt; margin-left: 28.4pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Raw materials- commercial&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;4,139&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;7,502&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 76%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 28.45pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Total raw materials&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;18,646&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;16,708&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 76%;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Work in process&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;5,770&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;2,252&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 76%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Finished goods&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;390&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;3,005&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 76%; padding-bottom: 4px;" valign="bottom"&gt;
          &lt;div style="text-align: justify; margin-left: 28.45pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Total inventory&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;24,806&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;21,965&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;
</us-gaap:InventoryPolicyTextBlock>
    <us-gaap:ScheduleOfInventoryCurrentTableTextBlock
      contextRef="c20210101to20211231"
      id="Text_42918dc083b14298bf3e140fca4a1e1b">
&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Our inventory consisted of the following (in thousands):&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;"&gt;


  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;

        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="6" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;December 31,&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;2021&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;2020&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Raw materials:&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 76%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 19.4pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Raw materials- clinical&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;14,507&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;9,206&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 76%; padding-bottom: 2px;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -18pt; margin-left: 28.4pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Raw materials- commercial&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;4,139&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;7,502&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 76%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 28.45pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Total raw materials&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;18,646&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;16,708&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 76%;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Work in process&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;5,770&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;2,252&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 76%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Finished goods&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;390&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;3,005&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 76%; padding-bottom: 4px;" valign="bottom"&gt;
          &lt;div style="text-align: justify; margin-left: 28.45pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Total inventory&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;24,806&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;21,965&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;
</us-gaap:ScheduleOfInventoryCurrentTableTextBlock>
    <us-gaap:InventoryRawMaterials
      contextRef="c20211231_PublicUtilitiesInventoryAxis_ClinicalRawMaterialsMember"
      decimals="-3"
      id="Fact_607597dd540146e09e590486dfbfd332"
      unitRef="U001">14507000</us-gaap:InventoryRawMaterials>
    <us-gaap:InventoryRawMaterials
      contextRef="c20201231_PublicUtilitiesInventoryAxis_ClinicalRawMaterialsMember"
      decimals="-3"
      id="Fact_7cb2d5b100c4460fa603ceb958dfa363"
      unitRef="U001">9206000</us-gaap:InventoryRawMaterials>
    <us-gaap:InventoryRawMaterials
      contextRef="c20211231_PublicUtilitiesInventoryAxis_CommercialRawMaterialsMember"
      decimals="-3"
      id="Fact_7ce8ae9ab80f4c6b893833f04a2e1b3a"
      unitRef="U001">4139000</us-gaap:InventoryRawMaterials>
    <us-gaap:InventoryRawMaterials
      contextRef="c20201231_PublicUtilitiesInventoryAxis_CommercialRawMaterialsMember"
      decimals="-3"
      id="Fact_de29fe59994e4eedaaf0e505fe2fa8ce"
      unitRef="U001">7502000</us-gaap:InventoryRawMaterials>
    <us-gaap:InventoryRawMaterials
      contextRef="c20211231"
      decimals="-3"
      id="Fact_128d62d036e2429290b412a68bb359e3"
      unitRef="U001">18646000</us-gaap:InventoryRawMaterials>
    <us-gaap:InventoryRawMaterials
      contextRef="c20201231"
      decimals="-3"
      id="Fact_2a47aa942a2943ed97036570c8b25890"
      unitRef="U001">16708000</us-gaap:InventoryRawMaterials>
    <us-gaap:InventoryWorkInProcess
      contextRef="c20211231"
      decimals="-3"
      id="Fact_85d7f4970a574d26939ed8575266e7f1"
      unitRef="U001">5770000</us-gaap:InventoryWorkInProcess>
    <us-gaap:InventoryWorkInProcess
      contextRef="c20201231"
      decimals="-3"
      id="Fact_84044948dea84b95bf0906aa87b24ba3"
      unitRef="U001">2252000</us-gaap:InventoryWorkInProcess>
    <us-gaap:InventoryFinishedGoods
      contextRef="c20211231"
      decimals="-3"
      id="Fact_e5ad76dbdb1441b68871a7035a59c0b3"
      unitRef="U001">390000</us-gaap:InventoryFinishedGoods>
    <us-gaap:InventoryFinishedGoods
      contextRef="c20201231"
      decimals="-3"
      id="Fact_518f7488f3314fafb99fe4a5c96254f0"
      unitRef="U001">3005000</us-gaap:InventoryFinishedGoods>
    <us-gaap:InventoryNet
      contextRef="c20211231"
      decimals="-3"
      id="Fact_ed1f9a6ae98d4c7cba25f90cb15577f3"
      unitRef="U001">24806000</us-gaap:InventoryNet>
    <us-gaap:InventoryNet
      contextRef="c20201231"
      decimals="-3"
      id="Fact_d2b4370b0072452b9c9faa8459b51794"
      unitRef="U001">21965000</us-gaap:InventoryNet>
    <us-gaap:PropertyPlantAndEquipmentPolicyTextBlock
      contextRef="c20210101to20211231"
      id="Text_cdabff15346b44629390c82abd47c849">
&lt;div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Property, Plant and Equipment&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;We carry our property, plant and equipment at cost and depreciate it on the straight-line method
    over its estimated useful life, which consists of the following (in thousands):&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;"&gt;


  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;

        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Estimated Useful&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="6" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;December 31,&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Lives (in years)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;2021&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;2020&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Computer software, laboratory, manufacturing and other equipment&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;3 to 10&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;72,802&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;68,990&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Building, building improvements and building systems&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;15 to 40&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;144,046&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;137,879&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Land improvements&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" rowspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: rgb(0, 0, 0); font-family: 'Times New Roman',Times,serif; font-size: 10pt; text-align: center;"&gt;20&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;10,077&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;8,391&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Leasehold improvements&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;5 to 15&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;20,144&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;17,263&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Furniture and fixtures&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;5 to 10&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;10,591&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;12,871&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 64%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;257,660&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;245,394&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Less accumulated depreciation&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(102,653&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(87,379&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 64%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;155,007&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;158,015&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Land&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;23,062&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;23,062&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 64%; padding-bottom: 4px;" valign="bottom"&gt;
          &lt;div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#160;Total&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;178,069&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;181,077&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 12pt;"&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;We depreciate our leasehold improvements using the shorter of the estimated useful life or remaining lease term.&lt;/div&gt;
</us-gaap:PropertyPlantAndEquipmentPolicyTextBlock>
    <us-gaap:PropertyPlantAndEquipmentTextBlock
      contextRef="c20210101to20211231"
      id="Text_fa1490903d3d4bf4a66e00ec0646e2ed">
&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;We carry our property, plant and equipment at cost and depreciate it on the straight-line method
    over its estimated useful life, which consists of the following (in thousands):&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;"&gt;


  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;

        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Estimated Useful&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="6" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;December 31,&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Lives (in years)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;2021&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;2020&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Computer software, laboratory, manufacturing and other equipment&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;3 to 10&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;72,802&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;68,990&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Building, building improvements and building systems&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;15 to 40&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;144,046&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;137,879&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Land improvements&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" rowspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: rgb(0, 0, 0); font-family: 'Times New Roman',Times,serif; font-size: 10pt; text-align: center;"&gt;20&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;10,077&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;8,391&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Leasehold improvements&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;5 to 15&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;20,144&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;17,263&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Furniture and fixtures&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;5 to 10&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;10,591&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;12,871&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 64%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;257,660&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;245,394&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Less accumulated depreciation&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(102,653&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(87,379&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 64%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;155,007&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;158,015&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Land&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;23,062&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;23,062&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 64%; padding-bottom: 4px;" valign="bottom"&gt;
          &lt;div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#160;Total&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;178,069&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;181,077&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;
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    <us-gaap:FairValueOfFinancialInstrumentsPolicy
      contextRef="c20210101to20211231"
      id="Text_1c1a3fa5b06c4f8eb0d08a8a2d8e1c26">
&lt;div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Fair Value of Financial Instruments&lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;We have estimated the fair value of our financial instruments. The amounts reported for cash, accounts receivable,
    accounts payable and accrued expenses approximate the fair value because of their short maturities. We report our investment securities at their estimated fair value based on quoted market prices for identical or similar instruments.&lt;/div&gt;
</us-gaap:FairValueOfFinancialInstrumentsPolicy>
    <us-gaap:LesseeLeasesPolicyTextBlock
      contextRef="c20210101to20211231"
      id="Text_5a1cbe260fe343ccafe9ff400e9af2db">
&lt;div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Leases&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;We determine if an arrangement contains a lease at inception. We currently only have operating leases. We recognize a
    right-of-use operating lease asset and associated short- and long-term operating lease liability on our consolidated balance sheet for operating leases greater than one year. Our right-of-use assets represent our right to use an underlying asset for
    the lease term and our lease liabilities represent our obligation to make lease payments arising from the lease arrangement. We recognize our right-of-use operating lease assets and lease liabilities based on the present value of the future minimum
    lease payments we will pay over the lease term.&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;&#160;&lt;/span&gt;We determine the lease term at the inception of each lease, and in certain cases our lease term could
    include renewal options if we concluded we were reasonably certain that we will exercise the renewal option. When we exercise a lease option that was not previously included in the initial lease term, we reassess our right-of-use asset and lease
    liabilities for the new lease term.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;As our leases do not provide an interest rate implicit in the lease, we used our incremental borrowing rate, based on the
    information available on the date we adopted Topic 842 (January 2019), as of the lease inception date or at the lease option extension date in determining the present value of future payments. We recognize rent expense for our minimum lease payments on
    a straight-line basis over the expected term of our lease. We recognize period expenses, such as common area maintenance expenses, in the period we incur the expense.&lt;/div&gt;
</us-gaap:LesseeLeasesPolicyTextBlock>
    <us-gaap:ImpairmentOrDisposalOfLongLivedAssetsIncludingIntangibleAssetsPolicyPolicyTextBlock
      contextRef="c20210101to20211231"
      id="Text_72f861d09ee741518162baaf74392e58">
&lt;div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Long-Lived Assets&lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;We evaluate long-lived assets, which include property, plant and equipment and patent costs, for impairment on at least a
    quarterly basis and whenever events or changes in circumstances indicate that we may not be able to recover the carrying amount of such assets. We recorded charges of $2.7 million, $1.9 million and $2.2 million for the years ended December 31, 2021, 2020 and 2019, respectively, related to the
    write-down of patents.&lt;/div&gt;
</us-gaap:ImpairmentOrDisposalOfLongLivedAssetsIncludingIntangibleAssetsPolicyPolicyTextBlock>
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    <us-gaap:UseOfEstimates
      contextRef="c20210101to20211231"
      id="Text_0a3950b68c174b56bc1921a8ef188db5">
&lt;div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Use of Estimates&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;We prepare our consolidated financial statements in conformity with accounting principles generally accepted in the U.S.
    that require us to make estimates and assumptions that affect the amounts reported in our consolidated financial statements and accompanying notes. Actual results could differ from our estimates.&lt;/div&gt;
</us-gaap:UseOfEstimates>
    <us-gaap:ShareBasedCompensationOptionAndIncentivePlansPolicy
      contextRef="c20210101to20211231"
      id="Text_ad082f24466d4b628f8d68f86e583d6f">
&lt;div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Stock-Based Compensation Expense&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;We measure stock-based compensation expense for equity-classified awards, principally related to stock options, RSUs,
    PRSUs and stock purchase rights under our ESPP based on the estimated fair value of the award on the date of grant. We recognize the value of the portion of the award that we ultimately expect to vest as stock-based compensation expense over the
    requisite service period in our consolidated statements of operations. We reduce stock-based compensation expense for estimated forfeitures at the time of grant and revise in subsequent periods if actual forfeitures differ from those estimates. We use
    the Black-Scholes model to estimate the fair value of stock options granted and stock purchase rights under our ESPP.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;On the grant date, we use our stock price and assumptions regarding a number of variables to determine the estimated fair
    value of stock-based payment awards. These variables include, but are not limited to, our expected stock price volatility over the term of the awards, and actual and projected employee stock option exercise behaviors. The expected term of stock options
    granted represents the period of time that we expect them to be outstanding. We estimate the expected term of options granted based on historical exercise patterns.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;We recognize compensation expense for stock options granted, RSUs, PRSUs and stock purchase rights under the ESPP using
    the accelerated multiple-option approach. Under the accelerated multiple-option approach (also known as the graded-vesting method), we recognize compensation expense over the requisite service period for each separately vesting tranche of the award as
    though the award were in substance multiple awards, which results in the expense being front-loaded over the vesting period.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt;In December 2020, we amended and restated the
      Akcea 2015 equity plan, including renaming the plan as the Ionis Pharmaceuticals, Inc. 2020 Equity Incentive Plan, or 2020 Plan. As a result, all employees are now under an Ionis stock plan and subject to the same Black-Scholes assumptions&lt;/span&gt;.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;"&gt;RSU&#x2019;s:&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;The fair value of RSUs is based on the market price of our common stock on the date of grant. The RSUs we have granted to
    employees vest annually over a four-year period. The RSUs we granted to our board of directors prior to June 2020 vest annually over a four-year period. RSUs granted to our board of directors after June 2020 fully vest after one year.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;"&gt;PRSU&#x2019;s:&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Beginning in 2020, we added PRSU awards to the compensation for our Chief Executive Officer, Dr. Brett Monia. Under the
    terms of the grants, &lt;span style="-sec-ix-hidden:Fact_65d15117ab79462e81dfb8bbb86a0107"&gt;&lt;span style="-sec-ix-hidden:Fact_e9934b85c6af480197be8d0d8b5ea434"&gt;&lt;span style="-sec-ix-hidden:Fact_5599af32346c4fce91fa6d27caf4b474"&gt;one third&lt;/span&gt;&lt;/span&gt;&lt;/span&gt; of the PRSUs may vest at the end of three separate performance periods spread over the three years following the date of
    grant (i.e., the one-year period commencing on the date of grant and ending on the first anniversary of the date of grant; the two-year period commencing on the date of grant and ending on the second anniversary of the date of grant; and the three-year period commencing on the date of grant and ending on the third anniversary of the date of grant) based on our relative total shareholder return, or TSR, as compared to a
    peer group of companies, and as measured, in each case, at the end of the applicable performance period. Under the terms of the grants no number
    of PRSUs is guaranteed to vest and the actual number of PRSUs that will vest at the end of each performance period may be anywhere from zero to
    150 percent of the target number depending on our relative TSR.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;We determined the fair value of Dr. Monia&#x2019;s PRSUs using a Monte Carlo model because the performance target is based on our
    relative TSR, which represents a market condition. We are recognizing the grant date fair value of these awards as stock-based compensation expense using the accelerated multiple-option approach over the vesting period. The weighted-average grant date
    fair value of PRSUs granted to Dr. Monia for the years ended December 31, 2021 and 2020 were $77.17 and $93.09 per share, respectively.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;See Note 4, &lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;"&gt;Stockholders&#x2019;
      Equity,&lt;/span&gt; for additional information regarding our stock-based compensation plans.&lt;/div&gt;
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      decimals="2"
      id="Fact_eb052e2b452448a18d648f4458bf70f7"
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    <us-gaap:StockholdersEquityPolicyTextBlock
      contextRef="c20210101to20211231"
      id="Text_fe65e811f9834fa6a0e8110b7acd77f1">
&lt;div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Accumulated Other Comprehensive Loss&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 12pt;"&gt;&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Accumulated
      other comprehensive loss is comprised of unrealized gains and losses on investments, net of taxes and currency translation adjustments. The following table summarizes changes in accumulated other comprehensive loss for the years ended December 31, 2021, 2020 and 2019 (in thousands):&lt;/span&gt;&lt;/div&gt;

&lt;div style="text-align: justify;"&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;"&gt;


  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;

        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="10" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Year Ended December 31,&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;2021&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;2020&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;2019&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Beginning balance accumulated other comprehensive loss&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(21,071&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(25,290&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(32,016&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 64%;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9pt; margin-left: 18pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Unrealized gains (losses) on securities, net of tax (1)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(11,486&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;3,729&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;6,633&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9pt; margin-left: 18pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Currency translation adjustment&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(111&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;617&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;93&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 64%; padding-bottom: 2px;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9pt; margin-left: 18pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Adjustments to other comprehensive loss from purchase of noncontrolling interest of Akcea
            Therapeutics, Inc.&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x2014;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(127&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x2014;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Net other comprehensive loss for the period&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(11,597&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;4,219&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;6,726&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 64%; padding-bottom: 4px;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Ending balance accumulated other comprehensive loss&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(32,668&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(21,071&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(25,290&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;________________&lt;/div&gt;

&lt;div&gt;
    &lt;table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;"&gt;


  &lt;tr&gt;

    &lt;td style="width: 18pt; vertical-align: top; align: right;"&gt;
            &lt;div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(1)&lt;/div&gt;
          &lt;/td&gt;

    &lt;td style="width: auto; vertical-align: top;"&gt;
            &lt;div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;We did not have tax expense included in our other comprehensive loss for the years ended December 31, 2021 and 2020. For the year ended December 31,
              2019, we had a tax benefit of $1.4
              million included in other comprehensive loss.&#160;&lt;/div&gt;
          &lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;
    &lt;/div&gt;
</us-gaap:StockholdersEquityPolicyTextBlock>
    <us-gaap:ScheduleOfAccumulatedOtherComprehensiveIncomeLossTableTextBlock
      contextRef="c20210101to20211231"
      id="Text_ec1d7d26eac54b93a442dd102450e116">
&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 12pt;"&gt;&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Accumulated
      other comprehensive loss is comprised of unrealized gains and losses on investments, net of taxes and currency translation adjustments. The following table summarizes changes in accumulated other comprehensive loss for the years ended December 31, 2021, 2020 and 2019 (in thousands):&lt;/span&gt;&lt;/div&gt;

&lt;div style="text-align: justify;"&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;"&gt;


  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;

        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="10" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Year Ended December 31,&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;2021&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;2020&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;2019&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Beginning balance accumulated other comprehensive loss&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(21,071&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(25,290&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(32,016&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 64%;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9pt; margin-left: 18pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Unrealized gains (losses) on securities, net of tax (1)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(11,486&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;3,729&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;6,633&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9pt; margin-left: 18pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Currency translation adjustment&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(111&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;617&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;93&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 64%; padding-bottom: 2px;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9pt; margin-left: 18pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Adjustments to other comprehensive loss from purchase of noncontrolling interest of Akcea
            Therapeutics, Inc.&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x2014;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(127&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x2014;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Net other comprehensive loss for the period&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(11,597&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;4,219&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;6,726&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 64%; padding-bottom: 4px;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Ending balance accumulated other comprehensive loss&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(32,668&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(21,071&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(25,290&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;________________&lt;/div&gt;

&lt;div&gt;
    &lt;table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;"&gt;


  &lt;tr&gt;

    &lt;td style="width: 18pt; vertical-align: top; align: right;"&gt;
            &lt;div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(1)&lt;/div&gt;
          &lt;/td&gt;

    &lt;td style="width: auto; vertical-align: top;"&gt;
            &lt;div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;We did not have tax expense included in our other comprehensive loss for the years ended December 31, 2021 and 2020. For the year ended December 31,
              2019, we had a tax benefit of $1.4
              million included in other comprehensive loss.&#160;&lt;/div&gt;
          &lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;
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&lt;div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Convertible Debt&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;"&gt;Adoption of ASU 2020-06&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;In August 2020, the FASB issued ASU 2020-06, which simplifies the accounting for convertible debt instruments, amends the
    guidance on derivative scope exceptions for contracts in an entity&#x2019;s own equity, and modifies the guidance on diluted earnings per share calculations. We adopted ASU 2020-06 on January 1, 2021 under the full retrospective approach, which required us to
    revise our prior period financial statements. This guidance impacted our accounting for outstanding convertible debt. At January 1, 2021, we had two
    outstanding convertible notes, our 0.125% Notes, which mature in December 2024, and our 1% Notes, which matured in November 2021. In April 2021, we completed a $632.5 million
    offering of 0% Notes primarily to repurchase a majority of our 1% Notes. We accounted for our 0% Notes under ASU 2020-06 at issuance. Refer to Note
    3, &lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;"&gt;Long-Term Obligations and Commitments&lt;/span&gt;, for further information.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;The updated guidance eliminates the cash conversion accounting model we previously followed in Accounting Standard
    Codification, or ASC, 470-20, which required us to separate each of our convertible debt instruments at issuance into two units of accounting, a liability component, based on our nonconvertible debt borrowing rate at issuance, and an equity component.
    Under ASU 2020-06, we now account for each of our convertible debt instruments as a single unit of accounting, a liability, because we concluded that the conversion features do not require bifurcation as a derivative under ASC 815-15 and we did not
    issue our convertible debt instruments at a substantial premium. Since we adopted ASU 2020-06 using the full retrospective approach, we were required to apply the guidance to all convertible debt instruments we had outstanding as of January 1, 2019. We
    recomputed the basis of each convertible debt instrument as if we accounted for each as a single unit of accounting at issuance. This update included recalculating the amortization of debt issuance costs using an updated effective interest rate. As a
    result of adopting ASU 2020-06, we recorded a cumulative adjustment to decrease our additional paid in capital and our accumulated deficit at January 1, 2019. We have updated these financial statements to reflect the cumulative adjustment for the
    periods presented. We have labeled our prior period financial statements &#x201c;as revised&#x201d; to indicate the change required under the new accounting guidance. Below is a summary of the change in our balance sheet at December 31, 2020 and statement of
    operations from the years ended December 31, 2020 and 2019 under the ASC 470-20 legacy guidance compared to the new ASU 2020-06 guidance we adopted:&lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;The following table summarizes the adjustments we made to the consolidated balance sheet we
    originally reported at December 31, 2020 to adopt ASU 2020-06 (in thousands):&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;"&gt;


  &lt;tr&gt;

    &lt;td style="vertical-align: top; padding-bottom: 2px;" valign="bottom"&gt;

        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="10" style="vertical-align: top; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;December 31, 2020&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;As Previously&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Reported&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;ASU 2020-06&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Adjustment&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;As Revised&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 64%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;1 percent convertible
            senior notes&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;293,161&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;15,648&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;308,809&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 64%;" valign="bottom"&gt;
          &lt;div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;0.125 percent convertible
            senior notes&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;455,719&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;84,417&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;540,136&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 64%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Additional paid-in-capital&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;2,113,646&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(218,127&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;1,895,519&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 64%;" valign="bottom"&gt;
          &lt;div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Accumulated deficit&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(1,249,368&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;118,062&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(1,131,306&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#160;&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt;Under ASU 2020-06, our revised
      ending balances for our &lt;/span&gt;1%&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt; Notes and &lt;/span&gt;0.125%&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt; Notes as of December 31, 2020 represent the principal
      balance of each convertible debt instrument less debt issuance costs. Additionally, because we have deferred tax assets related to our convertible debt instruments, we also adjusted these amounts as part of our adoption of ASU 2020-06. However,
      because we have a full valuation allowance on our deferred tax assets, there was &lt;/span&gt;no&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt; impact to our consolidated balance sheet related to our deferred tax assets.&lt;/span&gt;&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#160;&lt;span style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; color: #000000;"&gt;&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt;The following
      tables summarize the adjustments we made to the consolidated statement of operations we originally reported for the years ended December 31, 2020 and 2019 to adopt ASU 2020-06 (in thousands):&lt;/span&gt;&lt;/span&gt;&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;"&gt;


  &lt;tr&gt;

    &lt;td style="vertical-align: top; padding-bottom: 2px;" valign="bottom"&gt;

        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="10" style="vertical-align: top; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Year Ended December 31, 2020&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;As Previously&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Reported&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;ASU 2020-06&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Adjustment&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;As Revised&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 64%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Interest expense&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(44,990&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;35,480&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(9,510&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 64%;" valign="bottom"&gt;
          &lt;div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Loss before income tax expense&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(170,032&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;35,480&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(134,552&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 64%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Income tax expense&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(316,734&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(28,457&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(345,191&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 64%;" valign="bottom"&gt;
          &lt;div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Net loss&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(486,766&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;7,023&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(479,743&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 64%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Net loss attributable to Ionis Pharmaceuticals, Inc. common stockholders&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(451,286&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;7,023&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(444,263&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 64%;" valign="bottom"&gt;
          &lt;div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Basic and diluted net loss per share&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(3.23&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;0.05&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(3.18&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;"&gt;


  &lt;tr&gt;

    &lt;td style="vertical-align: top; padding-bottom: 2px;" valign="bottom"&gt;

        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="10" style="vertical-align: top; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Year Ended December 31, 2019&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;As Previously&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Reported&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;ASU 2020-06&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Adjustment&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;As Revised&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 64%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Interest expense&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(48,768&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;36,328&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(12,440&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 64%;" valign="bottom"&gt;
          &lt;div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Loss on early retirement of debt&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(21,865&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(44,331&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(66,196&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 64%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Income before income tax benefit (expense)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;346,769&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(8,003&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;338,766&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 64%;" valign="bottom"&gt;
          &lt;div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Income tax expense&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(43,507&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(8,000&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(51,507&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 64%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Net income&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;303,262&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(16,003&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;287,259&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 64%;" valign="bottom"&gt;
          &lt;div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Net income attributable to Ionis Pharmaceuticals, Inc. common stockholders&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;294,146&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(16,003&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;278,143&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 64%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Basic net income per share&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;2.12&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(0.12&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;2.00&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 64%;" valign="bottom"&gt;
          &lt;div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Diluted net income per share&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;2.08&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(0.18&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;1.90&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Under ASU 2020-06, our revised interest expense is lower because we are no longer recording non-cash
    interest expense related to a debt discount. This decrease was partially offset by the increase in interest expense related to the amortization of debt issuance costs because we no longer allocate a portion of our debt issuance costs to stockholders&#x2019;
    equity at issuance. Instead, the entire debt issuance costs were recorded as a contra-liability on our consolidated balance sheet at issuance and we are amortizing them over the contractual term using an updated effective interest rate. Our updated
    effective interest rates for our 1% Notes and 0.125%
    Notes were 1.4 percent and 0.5 percent,
    respectively.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;The following tables summarize the adjustments we made to our consolidated statements of
    stockholders&#x2019; equity we originally reported at December 31, 2020 and 2019 to adopt ASU 2020-06 (in thousands):&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;"&gt;


  &lt;tr&gt;

    &lt;td style="vertical-align: top; padding-bottom: 2px;" valign="bottom"&gt;

        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="10" style="vertical-align: top; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;December 31, 2020&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;As Previously&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Reported&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;ASU 2020-06&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Adjustment&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;As Revised&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 64%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Additional paid-in-capital&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;2,113,646&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(218,127&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;1,895,519&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 64%;" valign="bottom"&gt;
          &lt;div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Accumulated deficit&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(1,249,368&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;118,062&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(1,131,306&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 64%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Total stockholders&#x2019; equity&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;843,347&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(100,065&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;743,282&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;"&gt;


  &lt;tr&gt;

    &lt;td style="vertical-align: top; padding-bottom: 2px;" valign="bottom"&gt;

        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="10" style="vertical-align: top; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;December 31, 2019&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;As Previously&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Reported&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;ASU 2020-06&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Adjustment&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;As Revised&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 64%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Additional paid-in-capital&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;2,203,778&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(218,128&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;1,985,650&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 64%;" valign="bottom"&gt;
          &lt;div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Accumulated deficit&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(707,534&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;111,039&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(596,495&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 64%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Total stockholders&#x2019; equity&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;1,684,547&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(107,088&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;1,577,459&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;
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&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;The following table summarizes the adjustments we made to the consolidated balance sheet we
    originally reported at December 31, 2020 to adopt ASU 2020-06 (in thousands):&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;"&gt;


  &lt;tr&gt;

    &lt;td style="vertical-align: top; padding-bottom: 2px;" valign="bottom"&gt;

        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="10" style="vertical-align: top; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;December 31, 2020&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;As Previously&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Reported&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;ASU 2020-06&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Adjustment&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;As Revised&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 64%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;1 percent convertible
            senior notes&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;293,161&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;15,648&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;308,809&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 64%;" valign="bottom"&gt;
          &lt;div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;0.125 percent convertible
            senior notes&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;455,719&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;84,417&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;540,136&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 64%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Additional paid-in-capital&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;2,113,646&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(218,127&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;1,895,519&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 64%;" valign="bottom"&gt;
          &lt;div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Accumulated deficit&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(1,249,368&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;118,062&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(1,131,306&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;
&lt;span style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; color: #000000;"&gt;&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt;The following
      tables summarize the adjustments we made to the consolidated statement of operations we originally reported for the years ended December 31, 2020 and 2019 to adopt ASU 2020-06 (in thousands):&lt;/span&gt;&lt;/span&gt;
&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;"&gt;


  &lt;tr&gt;

    &lt;td style="vertical-align: top; padding-bottom: 2px;" valign="bottom"&gt;

        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="10" style="vertical-align: top; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Year Ended December 31, 2020&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;As Previously&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Reported&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;ASU 2020-06&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Adjustment&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;As Revised&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 64%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Interest expense&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(44,990&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;35,480&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(9,510&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 64%;" valign="bottom"&gt;
          &lt;div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Loss before income tax expense&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(170,032&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;35,480&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(134,552&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 64%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Income tax expense&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(316,734&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(28,457&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(345,191&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 64%;" valign="bottom"&gt;
          &lt;div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Net loss&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(486,766&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;7,023&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(479,743&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 64%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Net loss attributable to Ionis Pharmaceuticals, Inc. common stockholders&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(451,286&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;7,023&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(444,263&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 64%;" valign="bottom"&gt;
          &lt;div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Basic and diluted net loss per share&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(3.23&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;0.05&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(3.18&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;"&gt;


  &lt;tr&gt;

    &lt;td style="vertical-align: top; padding-bottom: 2px;" valign="bottom"&gt;

        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="10" style="vertical-align: top; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Year Ended December 31, 2019&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;As Previously&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Reported&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;ASU 2020-06&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Adjustment&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;As Revised&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 64%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Interest expense&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(48,768&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;36,328&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(12,440&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 64%;" valign="bottom"&gt;
          &lt;div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Loss on early retirement of debt&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(21,865&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(44,331&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(66,196&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 64%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Income before income tax benefit (expense)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;346,769&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(8,003&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;338,766&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 64%;" valign="bottom"&gt;
          &lt;div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Income tax expense&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(43,507&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(8,000&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(51,507&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 64%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Net income&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;303,262&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(16,003&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;287,259&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 64%;" valign="bottom"&gt;
          &lt;div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Net income attributable to Ionis Pharmaceuticals, Inc. common stockholders&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;294,146&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(16,003&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;278,143&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 64%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Basic net income per share&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;2.12&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(0.12&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;2.00&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 64%;" valign="bottom"&gt;
          &lt;div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Diluted net income per share&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;2.08&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(0.18&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;1.90&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;The following tables summarize the adjustments we made to our consolidated statements of
    stockholders&#x2019; equity we originally reported at December 31, 2020 and 2019 to adopt ASU 2020-06 (in thousands):&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;"&gt;


  &lt;tr&gt;

    &lt;td style="vertical-align: top; padding-bottom: 2px;" valign="bottom"&gt;

        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="10" style="vertical-align: top; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;December 31, 2020&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;As Previously&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Reported&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;ASU 2020-06&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Adjustment&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;As Revised&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 64%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Additional paid-in-capital&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;2,113,646&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(218,127&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;1,895,519&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 64%;" valign="bottom"&gt;
          &lt;div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Accumulated deficit&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(1,249,368&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;118,062&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(1,131,306&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 64%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Total stockholders&#x2019; equity&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;843,347&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(100,065&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;743,282&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;"&gt;


  &lt;tr&gt;

    &lt;td style="vertical-align: top; padding-bottom: 2px;" valign="bottom"&gt;

        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="10" style="vertical-align: top; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;December 31, 2019&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;As Previously&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Reported&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;ASU 2020-06&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Adjustment&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;As Revised&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 64%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Additional paid-in-capital&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;2,203,778&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(218,128&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;1,985,650&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 64%;" valign="bottom"&gt;
          &lt;div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Accumulated deficit&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(707,534&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;111,039&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(596,495&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 64%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Total stockholders&#x2019; equity&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;1,684,547&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

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    <us-gaap:DerivativesPolicyTextBlock
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&lt;div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Call Spread&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;In conjunction with the issuance of our 0% Notes and 0.125% Notes in April 2021 and December 2019, respectively, we entered
    into call spread transactions, which were comprised of purchasing note hedges and selling warrants. We account for the note hedges and warrants as separate freestanding financial instruments and treat each instrument as a separate unit of accounting.
    We determined that the note hedges and warrants do not meet the definition of a liability using the guidance contained in ASC Topic 480; therefore, we account for the note hedges and warrants using the Derivatives and Hedging &#x2013; Contracts in Entity&#x2019;s
    Own Equity accounting guidance contained in ASC Topic 815. We determined that the note hedges and warrants meet the definition of a derivative, are indexed to our stock and meet the criteria to be classified in shareholders&#x2019; equity. We recorded the
    aggregate amount paid for the note hedges and the aggregate amount received for the warrants as additional paid-in capital in our consolidated balance sheet. We reassess our ability to continue to classify the note hedges and warrants in shareholders&#x2019;
    equity at each reporting period.&lt;/div&gt;
</us-gaap:DerivativesPolicyTextBlock>
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&lt;div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Segment Information&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;In 2021, we began operating as a single segment, Ionis operations, because our chief decision maker reviews operating
    results on an aggregate basis and manages our operations as a &lt;span style="-sec-ix-hidden:Fact_33bc30118e9548358994c912eadf2161"&gt;single&lt;/span&gt; operating segment. Previously, we had operated as two operating segments, Ionis Core and Akcea Therapeutics. We completed the Akcea Merger in October 2020 and fully integrated Akcea&#x2019;s operations into ours
    as of January 1, 2021&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;.&lt;/span&gt;&lt;/div&gt;
</us-gaap:SegmentReportingPolicyPolicyTextBlock>
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      contextRef="c20210101to20211231"
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&lt;div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Fair Value Measurements&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;We use a three-tier fair value hierarchy to prioritize the inputs used in our fair value measurements. These tiers
    include: Level 1, defined as observable inputs such as quoted prices in active markets for identical assets, which includes our money market funds and treasury securities classified as available-for-sale securities and our investment in equity
    securities in publicly held biotechnology companies; Level 2, defined as inputs other than quoted prices in active markets that are either directly or indirectly observable, which includes our fixed income securities and commercial paper classified as
    available-for-sale securities; and Level 3, defined as unobservable inputs in which little or no market data exists, therefore requiring us to develop our own assumptions. We classify most of our securities as Level 2. We obtain the fair value of our
    Level 2 investments from our custodian bank or from a professional pricing service. We validate the fair value of our Level 2 investments by understanding the pricing model used by the custodian banks or professional pricing service provider and
    comparing that fair value to the fair value based on observable market prices.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;The following tables present the major security types we held at December 31, 2021 and 2020&#160;&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt;that we regularly measure and carry at fair value&lt;/span&gt;. As of December 31, 2021, our Bicycle investment was subject to trading restrictions that extend to the third quarter of 2022; as
    a result, we included a lack of marketability discount in valuing this investment, which is a Level 3 input. As of December 31, 2020, we did not
    have any investments that we valued using Level 3 inputs. The following tables segregate each security type by the level within the fair value hierarchy of the valuation techniques we utilized to determine the respective securities&#x2019; fair value (in
    thousands):&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;"&gt;


  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;At&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;December 31, 2021&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Quoted Prices in&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Active Markets&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;(Level 1)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Significant Other&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Observable Inputs&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;(Level 2)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Significant&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Unobservable Inputs&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;(Level 3)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 52%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Cash equivalents (1)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;541,199&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;541,199&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x2014;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x2014;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 52%;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Corporate debt securities (2)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;764,059&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x2014;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;764,059&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x2014;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 52%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Debt securities issued by U.S. government agencies (2)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;120,868&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x2014;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;120,868&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x2014;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 52%;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Debt securities issued by the U.S. Treasury (2)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;182,634&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;182,634&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x2014;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x2014;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 52%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Debt securities issued by states of the U.S. and political subdivisions of the states (3)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;174,464&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x2014;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;174,464&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x2014;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 52%;" valign="bottom"&gt;
          &lt;div&gt;
            &lt;div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Other municipal debt securities (2)&lt;/div&gt;
          &lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;6,099&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x2014;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;6,099&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x2014;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 52%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div&gt;
            &lt;div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Investment in Bicycle Therapeutics plc (4)&lt;/div&gt;
          &lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;14,330&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x2014;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x2014;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;14,330&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 52%; padding-bottom: 2px;" valign="bottom"&gt;
          &lt;div&gt;
            &lt;div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Investment in ProQR Therapeutics N.V. (4)&lt;/div&gt;
          &lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;3,875&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;3,875&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x2014;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x2014;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 52%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -8.9pt; margin-left: 22.55pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Total&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;1,807,528&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;727,708&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;1,065,490&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;14,330&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;"&gt;


  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;

        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;At&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;December 31, 2020&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Quoted Prices in&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Active Markets&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;(Level 1)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Significant Other&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Observable Inputs&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;(Level 2)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Cash equivalents (1)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;221,125&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;221,125&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x2014;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 64%;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Corporate debt securities (5)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;846,315&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x2014;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;846,315&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Debt securities issued by U.S. government agencies (2)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;174,861&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x2014;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;174,861&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 64%;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Debt securities issued by the U.S. Treasury (6)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;358,497&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;358,497&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x2014;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Debt securities issued by states of the U.S. and political subdivisions of the states (2)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;136,309&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x2014;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;136,309&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 64%;" valign="bottom"&gt;
          &lt;div&gt;
            &lt;div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Other municipal debt securities (2)&lt;/div&gt;
          &lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;6,225&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x2014;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;6,225&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div&gt;
            &lt;div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Investment in ProQR Therapeutics N.V. (4)&lt;/div&gt;
          &lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;2,031&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;2,031&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x2014;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 64%; padding-bottom: 4px;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -8.9pt; margin-left: 22.55pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Total&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;1,745,363&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;581,653&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;1,163,710&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;________________&lt;/div&gt;

&lt;table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;"&gt;


  &lt;tr&gt;

    &lt;td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(1)&lt;/td&gt;

    &lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Included in cash and cash
            equivalents on our consolidated balance sheet.&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;"&gt;


  &lt;tr&gt;

    &lt;td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(2)&lt;/td&gt;

    &lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Included in short-term
            investments.&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;"&gt;


  &lt;tr&gt;

    &lt;td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(3)&lt;/td&gt;

    &lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$2.3 million included in cash and cash equivalents on our consolidated balance sheet, with the difference included in short-term investments on our
            consolidated balance sheet.&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;"&gt;


  &lt;tr&gt;

    &lt;td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(4)&lt;/td&gt;

    &lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Included in other current assets
            on our consolidated balance sheet.&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;"&gt;


  &lt;tr&gt;

    &lt;td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(5)&lt;/td&gt;

    &lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$10.0 million included in cash and cash equivalents on our consolidated balance sheet, with the difference included in short-term investments on our
            consolidated balance sheet.&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;"&gt;


  &lt;tr&gt;

    &lt;td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(6)&lt;/td&gt;

    &lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$17.5 million included in cash and cash equivalents on our consolidated balance sheet, with the difference included in short-term investments on our
            consolidated balance sheet.&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;"&gt;Convertible Notes&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Our 0.125% Notes and 0% Notes had a fair value of $495.4 million and $559.2 million at December 31, 2021, respectively. We determine the fair value of our notes based on quoted market prices for these notes, which are Level 2
    measurements because the notes do not trade regularly.&lt;/div&gt;
</us-gaap:FairValueMeasurementPolicyPolicyTextBlock>
    <us-gaap:FairValueAssetsMeasuredOnRecurringBasisTextBlock
      contextRef="c20210101to20211231"
      id="Text_d6b095fbb9c24159b20f66ec3f602d33">
&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;The following tables present the major security types we held at December 31, 2021 and 2020&#160;&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt;that we regularly measure and carry at fair value&lt;/span&gt;. As of December 31, 2021, our Bicycle investment was subject to trading restrictions that extend to the third quarter of 2022; as
    a result, we included a lack of marketability discount in valuing this investment, which is a Level 3 input. As of December 31, 2020, we did not
    have any investments that we valued using Level 3 inputs. The following tables segregate each security type by the level within the fair value hierarchy of the valuation techniques we utilized to determine the respective securities&#x2019; fair value (in
    thousands):&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;"&gt;


  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;At&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;December 31, 2021&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Quoted Prices in&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Active Markets&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;(Level 1)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Significant Other&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Observable Inputs&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;(Level 2)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Significant&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Unobservable Inputs&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;(Level 3)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 52%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Cash equivalents (1)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;541,199&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;541,199&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x2014;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x2014;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 52%;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Corporate debt securities (2)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;764,059&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x2014;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;764,059&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x2014;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 52%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Debt securities issued by U.S. government agencies (2)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;120,868&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x2014;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;120,868&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x2014;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 52%;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Debt securities issued by the U.S. Treasury (2)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;182,634&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;182,634&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x2014;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x2014;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 52%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Debt securities issued by states of the U.S. and political subdivisions of the states (3)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;174,464&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x2014;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;174,464&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x2014;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 52%;" valign="bottom"&gt;
          &lt;div&gt;
            &lt;div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Other municipal debt securities (2)&lt;/div&gt;
          &lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;6,099&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x2014;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;6,099&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x2014;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 52%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div&gt;
            &lt;div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Investment in Bicycle Therapeutics plc (4)&lt;/div&gt;
          &lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;14,330&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x2014;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x2014;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;14,330&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 52%; padding-bottom: 2px;" valign="bottom"&gt;
          &lt;div&gt;
            &lt;div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Investment in ProQR Therapeutics N.V. (4)&lt;/div&gt;
          &lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;3,875&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;3,875&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x2014;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x2014;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 52%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -8.9pt; margin-left: 22.55pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Total&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;1,807,528&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;727,708&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;1,065,490&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;14,330&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;"&gt;


  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;

        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;At&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;December 31, 2020&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Quoted Prices in&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Active Markets&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;(Level 1)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Significant Other&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Observable Inputs&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;(Level 2)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Cash equivalents (1)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;221,125&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;221,125&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x2014;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 64%;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Corporate debt securities (5)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;846,315&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x2014;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;846,315&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Debt securities issued by U.S. government agencies (2)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;174,861&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x2014;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;174,861&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 64%;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Debt securities issued by the U.S. Treasury (6)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;358,497&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;358,497&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x2014;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Debt securities issued by states of the U.S. and political subdivisions of the states (2)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;136,309&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x2014;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;136,309&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 64%;" valign="bottom"&gt;
          &lt;div&gt;
            &lt;div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Other municipal debt securities (2)&lt;/div&gt;
          &lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;6,225&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x2014;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;6,225&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div&gt;
            &lt;div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Investment in ProQR Therapeutics N.V. (4)&lt;/div&gt;
          &lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;2,031&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;2,031&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x2014;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 64%; padding-bottom: 4px;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -8.9pt; margin-left: 22.55pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Total&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;1,745,363&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;581,653&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;1,163,710&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;________________&lt;/div&gt;

&lt;table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;"&gt;


  &lt;tr&gt;

    &lt;td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(1)&lt;/td&gt;

    &lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Included in cash and cash
            equivalents on our consolidated balance sheet.&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;"&gt;


  &lt;tr&gt;

    &lt;td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(2)&lt;/td&gt;

    &lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Included in short-term
            investments.&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;"&gt;


  &lt;tr&gt;

    &lt;td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(3)&lt;/td&gt;

    &lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$2.3 million included in cash and cash equivalents on our consolidated balance sheet, with the difference included in short-term investments on our
            consolidated balance sheet.&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;"&gt;


  &lt;tr&gt;

    &lt;td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(4)&lt;/td&gt;

    &lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Included in other current assets
            on our consolidated balance sheet.&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;"&gt;


  &lt;tr&gt;

    &lt;td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(5)&lt;/td&gt;

    &lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$10.0 million included in cash and cash equivalents on our consolidated balance sheet, with the difference included in short-term investments on our
            consolidated balance sheet.&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;"&gt;


  &lt;tr&gt;

    &lt;td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(6)&lt;/td&gt;

    &lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$17.5 million included in cash and cash equivalents on our consolidated balance sheet, with the difference included in short-term investments on our
            consolidated balance sheet.&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;
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    <us-gaap:IncomeTaxPolicyTextBlock
      contextRef="c20210101to20211231"
      id="Text_ea1db2e5fbf346468e0ca231e0179de4">
&lt;div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Income Taxes&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;We account for income taxes using the asset and liability method, which requires the recognition of deferred tax assets and liabilities
    for the expected future tax consequences of events that have been recognized in our financial statements or tax returns. In addition, deferred tax assets are recorded for the future benefit of utilizing net operating losses and research and development
    credit carryforwards. We record a valuation allowance when necessary to reduce our net deferred tax assets to the amount expected to be realized.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;We apply the authoritative accounting guidance prescribing a threshold and measurement attribute for the financial recognition and
    measurement of a tax position taken or expected to be taken in a tax return. We recognize liabilities for uncertain tax positions based on a two-step process. The first step is to evaluate the tax position for recognition by determining if the weight
    of available evidence indicates that it is more likely than not that the position will be sustained on audit, including resolution of related appeals or litigation processes, if any. The second step requires us to estimate and measure the tax benefit
    as the largest amount that is more than 50 percent likely to be realized upon ultimate settlement.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;We are required to use significant judgment in evaluating our uncertain tax positions and determining our provision for income taxes.
    Although we believe our reserves are reasonable, no assurance can be given that the final tax outcome of these matters will not be different from that which is reflected in our historical income tax provisions and accruals. We adjust these reserves for
    changing facts and circumstances, such as the closing of a tax audit or the refinement of an estimate. To the extent that the final tax outcome of these matters is different than the amounts recorded, such differences may impact the provision for
    income taxes in the period in which such determination is made.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;We are also required to use significant judgment in determining any valuation allowance recorded against our deferred tax assets. In
    assessing the need for a valuation allowance, we consider all available evidence, including scheduled reversal of deferred tax liabilities, past operating results, the feasibility of tax planning strategies and estimates of future taxable income. We
    base our estimates of future taxable income on assumptions that are consistent with our plans. The assumptions we use represent our best estimates and involve inherent uncertainties and the application of our judgment. Should actual amounts differ from
    our estimates, the amount of our tax expense and liabilities we recognize could be materially impacted. We record a valuation allowance to reduce the balance of our net deferred tax assets to the amount we believe is more-likely-than-not to be
    realized.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;We do not provide for a U.S. income tax liability and foreign withholding taxes on undistributed foreign earnings of our foreign
    subsidiaries.&lt;/div&gt;
</us-gaap:IncomeTaxPolicyTextBlock>
    <us-gaap:NewAccountingPronouncementsPolicyPolicyTextBlock
      contextRef="c20210101to20211231"
      id="Text_d5b8727afd8049b8b94bc44800d513c0">
&lt;div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Impact of Recently Issued Accounting Standards&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;As disclosed in the &#x201c;Convertible Debt&#x201d; policy above within this footnote, we adopted the simplified accounting for
    convertible debt instrument guidance (ASU 2020-06) on January 1, 2021. Refer to the section above for the impact of adoption. We do not expect any other recently issued accounting standards to have a material impact to our financial results.&lt;/div&gt;
</us-gaap:NewAccountingPronouncementsPolicyPolicyTextBlock>
    <us-gaap:InvestmentTextBlock
      contextRef="c20210101to20211231"
      id="Text_9571e0c61df44815a452af9dc71349ef">
&lt;div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;2. Investments&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;The following table summarizes the contract maturity of the available-for-sale securities we held as of
    December 31, 2021:&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;"&gt;


  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 88%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;span style="text-indent: 0pt;"&gt;One year&lt;/span&gt; or less&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;51&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;%&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 88%; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;After &lt;span style="text-indent: 0pt;"&gt;one year&lt;/span&gt; but within &lt;span style="text-indent: 0pt;"&gt;two years&lt;/span&gt;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;34&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;%&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 88%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;After &lt;span style="text-indent: 0pt;"&gt;two years&lt;/span&gt; but within &lt;span style="text-indent: 0pt;"&gt;&lt;span style="-sec-ix-hidden:Fact_5b50da2d62974df399b2ebfcfccf0c30"&gt;three and a half years&lt;/span&gt;&lt;/span&gt;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;15&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;%&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 88%; padding-bottom: 4px; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Total&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;100&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;%&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 12pt;"&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;As illustrated above, at December 31, 2021, 85 percent of our available-for-sale securities had a maturity of less than two years.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;All of our available-for-sale securities are available to us for use in our current operations. As a result, we categorize
    all of these securities as current assets even though the stated maturity of some individual securities may be one year or more beyond the balance sheet date.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;At December 31, 2021,
    we had an ownership interest of less than 20 percent &lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;in seven
      private companies and three public companies with which we conduct business. The privately-held companies are &lt;/span&gt;Aro Biotherapeutics,
    Atlantic Pharmaceuticals Limited, Dynacure SAS, Empirico, Inc., Flamingo Therapeutics BV, YourBio Health, Inc. and Suzhou-Ribo Life Science Co, Ltd. The publicly traded companies are Antisense Therapeutics Ltd., Bicycle and ProQR.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;The following is a summary of our investments (in thousands):&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;"&gt;


  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;

        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Amortized&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="6" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Gross Unrealized&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Estimated&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;December 31, 2021&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt; Cost&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Gains&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Losses&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Fair Value&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Available-for-sale securities:&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 52%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Corporate debt securities (1)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;383,870&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;728&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(226&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;384,372&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 52%; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Debt securities issued by U.S. government agencies&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;48,493&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;19&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(18&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;48,494&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 52%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Debt securities issued by the U.S. Treasury (1)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;45,424&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x2014;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(64&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;45,360&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 52%; padding-bottom: 2px; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Debt securities issued by states of the U.S. and political subdivisions of the states&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;134,770&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;45&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(37&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;134,778&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 52%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Total securities with a maturity of one year or less&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;612,557&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;792&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(345&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;613,004&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 52%; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Corporate debt securities&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;382,000&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;331&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(2,644&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;379,687&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 52%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Debt securities issued by U.S. government agencies&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;72,935&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x2014;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(561&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;72,374&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 52%; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Debt securities issued by the U.S. Treasury&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;137,635&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;139&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(500&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;137,274&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 52%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Debt securities issued by states of the U.S. and political subdivisions of the states&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;39,909&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;1&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(224&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;39,686&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 52%; padding-bottom: 2px; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Other municipal debt securities&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;6,136&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x2014;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(37&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;6,099&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 52%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Total securities with a maturity of more than one year&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;638,615&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;471&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(3,966&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;635,120&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 52%; padding-bottom: 2px; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Total available-for-sale securities&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;1,251,172&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;1,263&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(4,311&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;1,248,124&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 52%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Equity securities:&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 52%; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Total equity securities included in other current assets (2)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;11,897&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;7,145&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(837&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;18,205&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 52%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Total equity securities included in deposits and other assets (3)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;15,615&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;16,707&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x2014;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;32,322&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 52%; padding-bottom: 2px; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Total equity securities&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;27,512&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;23,852&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(837&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;50,527&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 52%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Total available-for-sale and equity securities&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;1,278,684&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;25,115&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(5,148&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;1,298,651&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;"&gt;


  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;

        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Amortized&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="6" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Gross Unrealized&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Estimated&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;December 31, 2020&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt; Cost&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Gains&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Losses&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Fair Value&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Available-for-sale securities:&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 52%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Corporate debt securities (1)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;514,182&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;2,194&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(41&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;516,335&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 52%; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Debt securities issued by U.S. government agencies&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;94,234&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;354&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(2&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;94,586&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 52%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Debt securities issued by the U.S. Treasury (1)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;307,576&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;233&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(9&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;307,800&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 52%; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Debt securities issued by states of the U.S. and political subdivisions of the states&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;104,271&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;196&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(12&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;104,455&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 52%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Other municipal debt securities&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;5,191&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x2014;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(7&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;5,184&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 52%; padding-bottom: 2px; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Total securities with a maturity of one year or less&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;1,025,454&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;2,977&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(71&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;1,028,360&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 52%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Corporate debt securities&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;325,079&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;4,941&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(40&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;329,980&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 52%; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Debt securities issued by U.S. government agencies&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;80,099&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;185&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(9&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;80,275&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 52%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Debt securities issued by the U.S. Treasury&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;50,318&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;383&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(4&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;50,697&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 52%; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Debt securities issued by states of the U.S. and political subdivisions of the states&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;31,779&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;91&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(16&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;31,854&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 52%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Other municipal debt securities&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;1,041&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x2014;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x2014;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;1,041&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 52%; padding-bottom: 2px; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Total securities with a maturity of more than one year&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;488,316&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;5,600&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(69&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;493,847&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 52%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Total available-for-sale securities&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;1,513,770&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;8,577&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(140&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;1,522,207&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 52%; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Equity securities:&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 52%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Total equity securities included in other current assets (2)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;4,712&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x2014;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(2,681&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;2,031&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 52%; padding-bottom: 2px; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Total equity securities included in deposits and other assets (3)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;15,062&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;15,938&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x2014;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;31,000&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 52%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Total equity securities&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;19,774&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;15,938&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(2,681&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;33,031&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 52%; padding-bottom: 4px; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Total available-for-sale and equity securities&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;1,533,544&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;24,515&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(2,821&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;1,555,238&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;________________&lt;/div&gt;

&lt;table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;"&gt;


  &lt;tr&gt;

    &lt;td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(1)&lt;/td&gt;

    &lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Includes investments classified
            as cash equivalents on our consolidated balance sheet.&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;"&gt;


  &lt;tr&gt;

    &lt;td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(2)&lt;/td&gt;

    &lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;
          &lt;div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Our equity securities included in other current
            assets consisted of our investments in publicly traded companies. We recognize publicly traded equity securities at fair value.&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;"&gt;


  &lt;tr&gt;

    &lt;td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(3)&lt;/td&gt;

    &lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;
          &lt;div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt;Our equity securities included in deposits and other assets consisted of our investments in privately held companies. We recognize our private company equity securities at&lt;/span&gt; cost minus
            impairments, plus or minus changes resulting from observable price changes in orderly transactions for the identical or similar investment of the same issuer&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt; on our consolidated balance sheet.&lt;/span&gt;&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt;The following is a summary of our investments we
      considered to be temporarily impaired at&#160;&lt;/span&gt;December 31, 2021&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt;&#160;(in thousands). All of these investments have less than 12 months of temporary impairment. We believe that the decline in value of these securities is temporary and is primarily related to the change in market interest rates since
      purchase. We believe it is more likely than not that we will be able to hold our debt securities to maturity. Therefore, we anticipate full recovery of our debt securities&#x2019; amortized cost basis at maturity.&lt;/span&gt;&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;"&gt;


  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;

        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Number of&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Investments&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Estimated&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Fair Value&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Unrealized&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Losses&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Corporate debt securities&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;272&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;552,966&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(2,870&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 64%;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Debt securities issued by U.S. government agencies&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;15&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;114,338&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(579&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Debt securities issued by the U.S. Treasury&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;13&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;134,987&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(564&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 64%;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -11.2pt; margin-left: 11.2pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Debt securities issued by states of the U.S. and political subdivisions of the states&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;425&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;126,401&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(261&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Other municipal debt securities&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;2&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;6,099&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(37&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 64%; padding-bottom: 4px;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Total temporarily impaired securities&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;727&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;934,791&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(4,311&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;
</us-gaap:InvestmentTextBlock>
    <us-gaap:InvestmentsClassifiedByContractualMaturityDateTableTextBlock
      contextRef="c20210101to20211231"
      id="Text_df6d78f5b0db4f2293f255a3abc4674a">
&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;The following table summarizes the contract maturity of the available-for-sale securities we held as of
    December 31, 2021:&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;"&gt;


  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 88%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;span style="text-indent: 0pt;"&gt;One year&lt;/span&gt; or less&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;51&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;%&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 88%; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;After &lt;span style="text-indent: 0pt;"&gt;one year&lt;/span&gt; but within &lt;span style="text-indent: 0pt;"&gt;two years&lt;/span&gt;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;34&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;%&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 88%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;After &lt;span style="text-indent: 0pt;"&gt;two years&lt;/span&gt; but within &lt;span style="text-indent: 0pt;"&gt;&lt;span style="-sec-ix-hidden:Fact_5b50da2d62974df399b2ebfcfccf0c30"&gt;three and a half years&lt;/span&gt;&lt;/span&gt;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;15&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;%&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 88%; padding-bottom: 4px; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Total&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;100&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;%&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;
</us-gaap:InvestmentsClassifiedByContractualMaturityDateTableTextBlock>
    <ions:MaximumContractMaturityPeriodRange1
      contextRef="c20210101to20211231"
      id="Fact_a0389bbbc04d444aa9945a16f2f77b47">P1Y</ions:MaximumContractMaturityPeriodRange1>
    <ions:AvailableForSaleSecuritiesDebtMaturitiesWithinOneYearPercentage
      contextRef="c20211231"
      decimals="2"
      id="Fact_e1a84f7ba1234915827448c633c10e96"
      unitRef="U003">0.51</ions:AvailableForSaleSecuritiesDebtMaturitiesWithinOneYearPercentage>
    <ions:MaximumContractMaturityPeriodRange1
      contextRef="c20210101to20211231"
      id="Fact_a9a809b245674eb5912c14df728dc0f0">P1Y</ions:MaximumContractMaturityPeriodRange1>
    <ions:MaximumContractMaturityPeriodRange2
      contextRef="c20210101to20211231"
      id="Fact_d1dd3aa1c3444cc8babea1f02c42cb74">P2Y</ions:MaximumContractMaturityPeriodRange2>
    <ions:AvailableForSaleSecuritiesDebtMaturitiesAfterOneThroughTwoYearsPercentage
      contextRef="c20211231"
      decimals="2"
      id="Fact_54f16a3082454b16a1368f8660393627"
      unitRef="U003">0.34</ions:AvailableForSaleSecuritiesDebtMaturitiesAfterOneThroughTwoYearsPercentage>
    <ions:MaximumContractMaturityPeriodRange2
      contextRef="c20210101to20211231"
      id="Fact_649df9025a904bcfad6dc6ab6bd4c304">P2Y</ions:MaximumContractMaturityPeriodRange2>
    <ions:AvailableForSaleSecuritiesDebtMaturitiesAfterTwoThroughThreeAndOneHalfYearsPercentage
      contextRef="c20211231"
      decimals="2"
      id="Fact_d60e9c8e586b428c886b9d9653ac0f6e"
      unitRef="U003">0.15</ions:AvailableForSaleSecuritiesDebtMaturitiesAfterTwoThroughThreeAndOneHalfYearsPercentage>
    <ions:AvailableForSaleSecuritiesDebtMaturitiesTotalPercentage
      contextRef="c20211231"
      decimals="2"
      id="Fact_298fc5ad20a2442399af2cd8e8215ece"
      unitRef="U003">1</ions:AvailableForSaleSecuritiesDebtMaturitiesTotalPercentage>
    <ions:AvailableForSaleSecuritiesDebtMaturitiesWithinTwoYearsPercentage
      contextRef="c20211231"
      decimals="2"
      id="Fact_971b070bcf6846b8970847cdbaef1457"
      unitRef="U003">0.85</ions:AvailableForSaleSecuritiesDebtMaturitiesWithinTwoYearsPercentage>
    <ions:MaximumContractMaturityPeriodRange2
      contextRef="c20210101to20211231"
      id="Fact_e4aa3be8fcd040d0bcd0def824af337d">P2Y</ions:MaximumContractMaturityPeriodRange2>
    <ions:NumberOfPrivatelyHeldCompaniesInWhichEntityHasEquityInvestment
      contextRef="c20211231"
      decimals="INF"
      id="Fact_c487d989afb240aaae9be0536d4b8656"
      unitRef="U009">7</ions:NumberOfPrivatelyHeldCompaniesInWhichEntityHasEquityInvestment>
    <ions:NumberOfPubliclyHeldCompaniesInWhichEntityHasEquityInvestment
      contextRef="c20211231"
      decimals="INF"
      id="Fact_cc8fa179d30548a7b52fcdc75fe7eeee"
      unitRef="U009">3</ions:NumberOfPubliclyHeldCompaniesInWhichEntityHasEquityInvestment>
    <us-gaap:UnrealizedGainLossOnInvestmentsTableTextBlock
      contextRef="c20210101to20211231"
      id="Text_8334d44cad3443a9ab4f38e658200dff">
&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;The following is a summary of our investments (in thousands):&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;"&gt;


  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;

        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Amortized&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="6" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Gross Unrealized&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Estimated&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;December 31, 2021&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt; Cost&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Gains&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Losses&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Fair Value&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Available-for-sale securities:&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 52%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Corporate debt securities (1)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;383,870&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;728&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(226&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;384,372&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 52%; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Debt securities issued by U.S. government agencies&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;48,493&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;19&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(18&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;48,494&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 52%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Debt securities issued by the U.S. Treasury (1)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;45,424&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x2014;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(64&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;45,360&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 52%; padding-bottom: 2px; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Debt securities issued by states of the U.S. and political subdivisions of the states&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;134,770&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;45&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(37&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;134,778&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 52%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Total securities with a maturity of one year or less&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;612,557&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;792&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(345&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;613,004&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 52%; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Corporate debt securities&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;382,000&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;331&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(2,644&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;379,687&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 52%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Debt securities issued by U.S. government agencies&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;72,935&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x2014;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(561&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;72,374&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 52%; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Debt securities issued by the U.S. Treasury&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;137,635&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;139&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(500&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;137,274&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 52%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Debt securities issued by states of the U.S. and political subdivisions of the states&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;39,909&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;1&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(224&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;39,686&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 52%; padding-bottom: 2px; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Other municipal debt securities&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;6,136&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x2014;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(37&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;6,099&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 52%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Total securities with a maturity of more than one year&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;638,615&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;471&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(3,966&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;635,120&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 52%; padding-bottom: 2px; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Total available-for-sale securities&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;1,251,172&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;1,263&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(4,311&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;1,248,124&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 52%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Equity securities:&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 52%; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Total equity securities included in other current assets (2)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;11,897&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;7,145&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(837&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;18,205&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 52%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Total equity securities included in deposits and other assets (3)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;15,615&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;16,707&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x2014;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;32,322&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 52%; padding-bottom: 2px; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Total equity securities&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;27,512&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;23,852&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(837&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;50,527&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 52%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Total available-for-sale and equity securities&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;1,278,684&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;25,115&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(5,148&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;1,298,651&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;"&gt;


  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;

        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Amortized&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="6" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Gross Unrealized&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Estimated&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;December 31, 2020&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt; Cost&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Gains&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Losses&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Fair Value&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Available-for-sale securities:&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 52%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Corporate debt securities (1)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;514,182&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;2,194&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(41&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;516,335&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 52%; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Debt securities issued by U.S. government agencies&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;94,234&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;354&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(2&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;94,586&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 52%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Debt securities issued by the U.S. Treasury (1)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;307,576&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;233&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(9&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;307,800&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 52%; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Debt securities issued by states of the U.S. and political subdivisions of the states&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;104,271&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;196&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(12&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;104,455&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 52%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Other municipal debt securities&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;5,191&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x2014;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(7&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;5,184&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 52%; padding-bottom: 2px; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Total securities with a maturity of one year or less&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;1,025,454&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;2,977&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(71&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;1,028,360&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 52%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Corporate debt securities&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;325,079&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;4,941&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(40&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;329,980&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 52%; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Debt securities issued by U.S. government agencies&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;80,099&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;185&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(9&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;80,275&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 52%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Debt securities issued by the U.S. Treasury&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;50,318&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;383&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(4&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;50,697&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 52%; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Debt securities issued by states of the U.S. and political subdivisions of the states&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;31,779&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;91&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(16&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;31,854&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 52%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Other municipal debt securities&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;1,041&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x2014;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x2014;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;1,041&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 52%; padding-bottom: 2px; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Total securities with a maturity of more than one year&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;488,316&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;5,600&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(69&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;493,847&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 52%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Total available-for-sale securities&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;1,513,770&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;8,577&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(140&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;1,522,207&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 52%; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Equity securities:&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 52%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Total equity securities included in other current assets (2)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;4,712&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x2014;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(2,681&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;2,031&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 52%; padding-bottom: 2px; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Total equity securities included in deposits and other assets (3)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;15,062&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;15,938&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x2014;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;31,000&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 52%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Total equity securities&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;19,774&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;15,938&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(2,681&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;33,031&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 52%; padding-bottom: 4px; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Total available-for-sale and equity securities&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;1,533,544&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;24,515&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(2,821&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;1,555,238&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;________________&lt;/div&gt;

&lt;table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;"&gt;


  &lt;tr&gt;

    &lt;td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(1)&lt;/td&gt;

    &lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Includes investments classified
            as cash equivalents on our consolidated balance sheet.&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;"&gt;


  &lt;tr&gt;

    &lt;td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(2)&lt;/td&gt;

    &lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;
          &lt;div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Our equity securities included in other current
            assets consisted of our investments in publicly traded companies. We recognize publicly traded equity securities at fair value.&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;"&gt;


  &lt;tr&gt;

    &lt;td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(3)&lt;/td&gt;

    &lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;
          &lt;div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt;Our equity securities included in deposits and other assets consisted of our investments in privately held companies. We recognize our private company equity securities at&lt;/span&gt; cost minus
            impairments, plus or minus changes resulting from observable price changes in orderly transactions for the identical or similar investment of the same issuer&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt; on our consolidated balance sheet.&lt;/span&gt;&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;


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&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt;The following is a summary of our investments we
      considered to be temporarily impaired at&#160;&lt;/span&gt;December 31, 2021&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt;&#160;(in thousands). All of these investments have less than 12 months of temporary impairment. We believe that the decline in value of these securities is temporary and is primarily related to the change in market interest rates since
      purchase. We believe it is more likely than not that we will be able to hold our debt securities to maturity. Therefore, we anticipate full recovery of our debt securities&#x2019; amortized cost basis at maturity.&lt;/span&gt;&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;"&gt;


  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;

        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Number of&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Investments&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Estimated&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Fair Value&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Unrealized&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Losses&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Corporate debt securities&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;272&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;552,966&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(2,870&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 64%;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Debt securities issued by U.S. government agencies&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;15&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;114,338&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(579&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Debt securities issued by the U.S. Treasury&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;13&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;134,987&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(564&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 64%;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -11.2pt; margin-left: 11.2pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Debt securities issued by states of the U.S. and political subdivisions of the states&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;425&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;126,401&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(261&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Other municipal debt securities&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;2&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;6,099&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(37&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 64%; padding-bottom: 4px;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Total temporarily impaired securities&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;727&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;934,791&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(4,311&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;


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&lt;div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;3. Long-Term Obligations and Commitments&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;The carrying value of our long-term obligations was as follows (in thousands):&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;"&gt;


  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;

        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="6" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;December 31,&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;2021&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;2020&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;(as revised*)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 76%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;span style="text-indent: 0pt;"&gt;0.125 percent&lt;/span&gt; convertible senior notes&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;542,314&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;540,136&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 76%;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;span style="text-indent: 0pt;"&gt;1 percent&lt;/span&gt; convertible senior notes (1)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x2014;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;308,809&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 76%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;span style="text-indent: 0pt;"&gt;0 percent&lt;/span&gt; convertible senior notes&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;619,119&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x2014;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 76%;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Long-term mortgage debt&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;59,713&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;59,984&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 76%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Leases and other obligations&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;29,904&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;30,710&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 76%;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Total&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;1,251,050&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;939,639&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 76%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Less: current portion (1)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(3,526&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(316,110&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 76%; padding-bottom: 4px;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 18pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Total Long-Term Obligations&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;1,247,524&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;623,529&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;________________&lt;/div&gt;

&lt;table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;"&gt;


  &lt;tr&gt;

    &lt;td style="width: 18pt; vertical-align: top; align: right; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(1)&lt;/td&gt;

    &lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;
          &lt;div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;We classified the carrying value of
            our 1% Notes as a current liability on our consolidated balance sheet at December 31, 2020 because it matured in November 2021.&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;"&gt;


  &lt;tr&gt;

    &lt;td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;*&lt;/td&gt;

    &lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;We revised our 2020 amounts to reflect the simplified convertible instruments accounting guidance, which we adopted retrospectively. Refer to Note 1, &lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;"&gt;Organization and Significant Accounting Policies&lt;/span&gt;, for further information.&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Convertible Debt and Call Spread&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;"&gt;0 Percent
    Convertible Senior Notes and Call Spread&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;In April 2021, we completed a $632.5
    million offering of convertible senior notes. We used a portion of the net proceeds from the issuance of the 0% Notes to repurchase $247.9 million in principal of our 1% Notes for $257.0 million.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;At December 31, 2021,
    we had the following &lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;0%&lt;/span&gt; Notes outstanding (amounts in
    millions except interest rate and price per share data):&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;"&gt;


  &lt;tr&gt;

    &lt;td style="vertical-align: top; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: top; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;0%&lt;/span&gt; Notes&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 88%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Outstanding principal balance&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;632.5&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 88%;" valign="bottom"&gt;
          &lt;div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Unamortized debt issuance costs&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;13.4&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Maturity date&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: top; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;span style="-sec-ix-hidden:Fact_7dc5959ba24b47e092541cc149b2023c"&gt;April 2026&lt;/span&gt;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top;" valign="bottom"&gt;
          &lt;div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Interest rate&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: top;" valign="bottom"&gt;
          &lt;div style="text-align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;0 percent&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Effective interest rate&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: top; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;0.5 percent&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 88%;" valign="bottom"&gt;
          &lt;div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Conversion price per share&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;57.84&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 88%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Effective conversion price per share with call spread&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;76.39&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 88%;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Total shares of common stock subject to conversion&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;10.9&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 12pt;"&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;In conjunction with the April 2021 offering, we entered into a call spread transaction, which was comprised of purchasing
    note hedges and selling warrants, to minimize the impact of potential economic dilution upon conversion of our &lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;0%&lt;/span&gt; Notes by increasing the effective conversion price on our &lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;0%&lt;/span&gt; Notes. We increased our effective conversion price to $76.39
    with the same number of underlying shares as our &lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;0%&lt;/span&gt; Notes.
    The call spread cost us $46.9 million, of which $136.7
    million was for the note hedge purchase, offset by $89.8 million we received for selling the warrants. Similar to our &lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;0%&lt;/span&gt; Notes, our note hedges are subject to adjustment. Additionally, our note hedges
    are exercisable upon conversion of the &lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;0%&lt;/span&gt; Notes. The note
    hedges will expire upon maturity of the &lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;0%&lt;/span&gt; Notes, or April
    2026. The note hedges and warrants are separate transactions and are not part of the terms of our &lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;0%&lt;/span&gt; Notes. The holders of the &lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;0%&lt;/span&gt; Notes do not have any rights with respect to the note hedges and warrants.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;We recorded the amount we paid for the note hedges and the amount we received for the warrants in additional paid-in
    capital in our consolidated balance sheet. See our Call Spread accounting policy in Note 1, &lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;"&gt;Organization and&lt;/span&gt;&#160;&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;"&gt;Significant Accounting Policies&lt;/span&gt;, in the Notes to the Consolidated Financial Statements. We reassess our ability to continue to classify the note hedges and warrants in
    shareholders&#x2019; equity at each reporting period.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: left; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;"&gt;0.125 Percent
    Convertible Senior Notes and Call Spread&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;In December 2019, we entered into privately negotiated exchange and/or subscription agreements with certain new investors
    and certain holders of our existing 1% Notes to exchange $375.6 million of our 1% Notes for $439.3 million of our 0.125% Notes, and to issue $109.5 million of our 0.125% Notes.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;At December 31, 2021,
    we had the following 0.125% Notes outstanding with interest payable semi-annually (amounts in millions except interest rate and price per share
    data):&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;"&gt;


  &lt;tr&gt;

    &lt;td style="vertical-align: top; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: top; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;0.125%
            Notes&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 88%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Outstanding principal balance&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;548.8&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 88%;" valign="bottom"&gt;
          &lt;div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Unamortized debt issuance costs&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;6.5&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Maturity date&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: top; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;span style="-sec-ix-hidden:Fact_ef7fbbee87c14676a78b2a22d99ec0ae"&gt;December 2024&lt;/span&gt;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top;" valign="bottom"&gt;
          &lt;div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Interest rate&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: top;" valign="bottom"&gt;
          &lt;div style="text-align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;0.125 percent&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Effective interest rate&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: top; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;0.5 percent&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 88%;" valign="bottom"&gt;
          &lt;div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Conversion price per share&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;83.28&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 88%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Effective conversion price per share with call spread&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;123.38&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 88%;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Total shares of common stock subject to conversion&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;6.6&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 12pt;"&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt;In conjunction with the issuance of our &lt;/span&gt;0.125%&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt; Notes in December 2019, we entered into a call spread
      transaction, which was comprised of purchasing note hedges and selling warrants, to minimize the impact of potential economic dilution upon conversion of our &lt;/span&gt;0.125% Notes by increasing the effective conversion price on our 0.125% Notes&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt;. We increased our effective conversion price to $&lt;/span&gt;123.38&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt; with the same number of underlying shares as our &lt;/span&gt;0.125%&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt; Notes. The call spread cost us $&lt;/span&gt;52.6&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt; million, of which $&lt;/span&gt;108.7&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt; million was for the note hedge purchase, offset by $&lt;/span&gt;56.1&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt; million we received for selling the warrants. Similar to our &lt;/span&gt;0.125%
    Notes&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt;, our note hedges are subject to adjustment. Additionally, our note hedges are exercisable upon conversion of the &lt;/span&gt;0.125% Notes&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt;. The note hedges will expire upon maturity of the
    &lt;/span&gt;0.125% Notes&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt;, or December 2024. The note
      hedges and warrants are separate transactions and are not part of the terms of our &lt;/span&gt;0.125% Notes&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt;. The holders of the &lt;/span&gt;0.125% Notes&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt; do not have any rights with respect to the note hedges and warrants.&lt;/span&gt;&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;We recorded the amount we paid for the note hedges and the amount we received for the warrants in additional paid-in
    capital in our consolidated balance sheet. See our Call Spread accounting policy in Note 1, &lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;"&gt;Organization and&lt;/span&gt;&#160;&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;"&gt;Significant Accounting Policies&lt;/span&gt;, in the Notes to the Consolidated Financial Statements. We reassess our ability to continue to classify the note hedges and warrants in
    shareholders&#x2019; equity at each reporting period.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;"&gt;1 Percent
    Convertible Senior Notes&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;In November 2014, we completed a $500 million offering of convertible senior notes, which matured in 2021 and beared interest at 1 percent with interest payable semi-annually. In December 2016, we issued an additional $185.5 million of 1% Notes in exchange for the redemption of a portion of our previously outstanding 2.75% convertible senior notes, or 2.75% Notes. In December 2019, we exchanged a
    portion of our 1% Notes for new 0.125%
    Notes. As a result, the principal balance of 1% Notes was $309.9 million. Additionally, we recorded a $66.2 million non-cash loss on the early
    retirement of debt, reflecting the early retirement of a significant portion of our 1% Notes in December 2019. The non-cash loss on the early
    retirement of our debt is the difference between the amount paid to exchange our 1% Notes and the net carrying balance of the liability at the
    time that we completed the debt exchange.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;In April 2021, we repurchased $247.9 million in aggregate principal amount of our 1% Notes in privately negotiated
    transactions. As a result of the repurchase, we recognized an $8.6 million loss on early retirement of debt, reflecting the early retirement of a
    significant portion of our 1% Notes. The loss on the early retirement of our debt is the difference between the amount paid to retire our 1% Notes and the net carrying balance of the liability at the time that we retired the debt. We paid the remaining principal balance of our 1% Notes with $62.0 million of cash at maturity
    in November 2021.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: left; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;"&gt;Other Terms of Convertible Senior Notes&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;The 0% and 0.125% Notes are convertible under certain conditions, at the option of the note holders. We can settle conversions of the notes, at our election, in cash,
    shares of our common stock or a combination of both. We may not redeem the notes prior to maturity, and we do not have to provide a sinking fund for them. Holders of the notes may require us to purchase some or all of their notes upon the occurrence of
    certain fundamental changes, as set forth in the indentures governing the notes, at a purchase price equal to 100 percent of the principal
    amount of the notes to be purchased, plus any accrued and unpaid interest. The 1% Notes were subject to similar terms.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Our total interest expense for our outstanding senior convertible notes for the years ended December 31, 2021, 2020 and 2019 included $4.9 million, $3.2 million and $2.9 million, respectively, of
    non-cash interest expense related to the amortization of debt issuance costs for our convertible notes.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Financing Arrangements&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic; font-weight: bold;"&gt;Research and Development and Manufacturing Facilities&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;In July 2017, we purchased the building that houses our primary R&amp;amp;D facility for $79.4 million and our manufacturing facility for $14.0 million. We financed the purchase
    of these two facilities with mortgage debt of $60.4
    million in total. Our primary R&amp;amp;D facility mortgage has an interest rate of 3.88 percent. Our manufacturing facility mortgage has an
    interest rate of 4.20 percent. During the first five years of both mortgages, we are only required to make interest payments. We will begin making principal payments in 2022. Both mortgages mature in August 2027.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Maturity Schedules&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Annual debt and other obligation
    maturities, including fixed and determinable interest, at December 31, 2021 are as follows (in thousands):&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;"&gt;


  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 88%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;span style="text-indent: 0pt;"&gt;2022&lt;/span&gt;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;3,498&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 88%;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;span style="text-indent: 0pt;"&gt;2023&lt;/span&gt;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;4,180&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 88%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;span style="text-indent: 0pt;"&gt;2024&lt;/span&gt;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;4,180&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 88%;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;span style="text-indent: 0pt;"&gt;2025&lt;/span&gt;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;1,184,820&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 88%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;span style="text-indent: 0pt;"&gt;2026&lt;/span&gt;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;3,494&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 88%; padding-bottom: 2px;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Thereafter&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;57,439&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 88%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Subtotal&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;1,257,611&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 88%;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Less: current portion&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(3,526&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 88%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Less: fixed and determinable interest&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(15,498&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 88%;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Less: debt issuance costs&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(20,302&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 88%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Plus: lease liabilities&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;22,058&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 88%; padding-bottom: 2px;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Plus: other liabilities&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;7,181&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 88%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Total long-term debt&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;1,247,524&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;
</us-gaap:DebtDisclosureTextBlock>
    <us-gaap:ScheduleOfDebtInstrumentsTextBlock
      contextRef="c20210101to20211231"
      id="Text_487975f5bd5542cbb02179bbd1a60f54">
&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;The carrying value of our long-term obligations was as follows (in thousands):&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;"&gt;


  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;

        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="6" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;December 31,&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;2021&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;2020&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;(as revised*)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 76%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;span style="text-indent: 0pt;"&gt;0.125 percent&lt;/span&gt; convertible senior notes&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;542,314&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;540,136&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 76%;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;span style="text-indent: 0pt;"&gt;1 percent&lt;/span&gt; convertible senior notes (1)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x2014;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;308,809&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 76%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;span style="text-indent: 0pt;"&gt;0 percent&lt;/span&gt; convertible senior notes&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;619,119&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x2014;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 76%;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Long-term mortgage debt&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;59,713&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;59,984&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 76%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Leases and other obligations&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;29,904&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;30,710&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 76%;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Total&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;1,251,050&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;939,639&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 76%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Less: current portion (1)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(3,526&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(316,110&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 76%; padding-bottom: 4px;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 18pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Total Long-Term Obligations&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;1,247,524&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;623,529&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;________________&lt;/div&gt;

&lt;table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;"&gt;


  &lt;tr&gt;

    &lt;td style="width: 18pt; vertical-align: top; align: right; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(1)&lt;/td&gt;

    &lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;
          &lt;div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;We classified the carrying value of
            our 1% Notes as a current liability on our consolidated balance sheet at December 31, 2020 because it matured in November 2021.&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;
</us-gaap:ScheduleOfDebtInstrumentsTextBlock>
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      contextRef="c20211231_DebtInstrumentAxis_ConvertibleSeniorNotes0125PercentMember"
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      unitRef="U003">0.00125</us-gaap:DebtInstrumentInterestRateStatedPercentage>
    <us-gaap:DebtInstrumentInterestRateStatedPercentage
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    <us-gaap:ConvertibleDebt
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      decimals="-3"
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    <us-gaap:ConvertibleDebt
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      decimals="-3"
      id="Fact_65be5fa6a2434040beb0d9ae2a2ca4aa"
      unitRef="U001">540136000</us-gaap:ConvertibleDebt>
    <us-gaap:DebtInstrumentInterestRateStatedPercentage
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      decimals="2"
      id="Fact_678c9c8d08e84bc49b41f282f783fa1e"
      unitRef="U003">0.01</us-gaap:DebtInstrumentInterestRateStatedPercentage>
    <us-gaap:DebtInstrumentInterestRateStatedPercentage
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      decimals="2"
      id="Fact_d0d025675d994c9489fb7c521ed3ca93"
      unitRef="U003">0.01</us-gaap:DebtInstrumentInterestRateStatedPercentage>
    <us-gaap:ConvertibleDebt
      contextRef="c20211231_DebtInstrumentAxis_ConvertibleSeniorNotes1PercentMember"
      decimals="-3"
      id="Fact_cab8c72e622844b2bff548c7151f9645"
      unitRef="U001">0</us-gaap:ConvertibleDebt>
    <us-gaap:ConvertibleDebt
      contextRef="c20201231_DebtInstrumentAxis_ConvertibleSeniorNotes1PercentMember"
      decimals="-3"
      id="Fact_263762c2879f49e19df48df907a46cf1"
      unitRef="U001">308809000</us-gaap:ConvertibleDebt>
    <us-gaap:DebtInstrumentInterestRateStatedPercentage
      contextRef="c20211231_DebtInstrumentAxis_ConvertibleSeniorNotes0PercentMember"
      decimals="2"
      id="Fact_b968d0392956483cbbbe19532ac3d256"
      unitRef="U003">0</us-gaap:DebtInstrumentInterestRateStatedPercentage>
    <us-gaap:ConvertibleDebt
      contextRef="c20211231_DebtInstrumentAxis_ConvertibleSeniorNotes0PercentMember"
      decimals="-3"
      id="Fact_d2942608f57748bdabb18c2dc442d75b"
      unitRef="U001">619119000</us-gaap:ConvertibleDebt>
    <us-gaap:ConvertibleDebt
      contextRef="c20201231_DebtInstrumentAxis_ConvertibleSeniorNotes0PercentMember"
      decimals="-3"
      id="Fact_81ca00edf85442d7a959529afc711233"
      unitRef="U001">0</us-gaap:ConvertibleDebt>
    <us-gaap:LoansPayableToBank
      contextRef="c20211231"
      decimals="-3"
      id="Fact_7526ddee5b884532b24be01e4d495612"
      unitRef="U001">59713000</us-gaap:LoansPayableToBank>
    <us-gaap:LoansPayableToBank
      contextRef="c20201231"
      decimals="-3"
      id="Fact_1a31cb06bce14608b6b4bc53c537a2e8"
      unitRef="U001">59984000</us-gaap:LoansPayableToBank>
    <ions:LeasesAndOtherObligations
      contextRef="c20211231"
      decimals="-3"
      id="Fact_4f4ce1cf534445a182bc4dc79c4da3ed"
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    <ions:LeasesAndOtherObligations
      contextRef="c20201231"
      decimals="-3"
      id="Fact_14ee837947184542bf24c811e63d710b"
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    <ions:LongTermObligations
      contextRef="c20211231"
      decimals="-3"
      id="Fact_67f1e8de33db4b3ba71a251d6969a0e4"
      unitRef="U001">1251050000</ions:LongTermObligations>
    <ions:LongTermObligations
      contextRef="c20201231"
      decimals="-3"
      id="Fact_0db6c0acf39c4704b8b7fb0682124be0"
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    <ions:LongTermObligationsCurrent
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      decimals="-3"
      id="Fact_66f728e151b74fe99d367269b42506b7"
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    <ions:LongTermObligationsCurrent
      contextRef="c20201231"
      decimals="-3"
      id="Fact_6b303576d07b435ebdc0b94cf229a5a7"
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    <ions:LongTermObligationsNoncurrent
      contextRef="c20211231"
      decimals="-3"
      id="Fact_147209ef0e4d4ccf9a6541966995a76b"
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    <ions:LongTermObligationsNoncurrent
      contextRef="c20201231"
      decimals="-3"
      id="Fact_85488b1118b143d68b8dce7fa49d282e"
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      contextRef="c20201231_DebtInstrumentAxis_ConvertibleSeniorNotes1PercentMember"
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      decimals="-5"
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      contextRef="c20210430_DebtInstrumentAxis_ConvertibleSeniorNotes0PercentMember"
      decimals="2"
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      decimals="2"
      id="Fact_c8ba81cd84644a2189e187b26e13e6a6"
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    <us-gaap:RepaymentsOfConvertibleDebt
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      decimals="-5"
      id="Fact_afdcd3190e50476ea3eabe571179bfbb"
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&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;At December 31, 2021,
    we had the following &lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;0%&lt;/span&gt; Notes outstanding (amounts in
    millions except interest rate and price per share data):&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;"&gt;


  &lt;tr&gt;

    &lt;td style="vertical-align: top; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: top; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;0%&lt;/span&gt; Notes&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 88%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Outstanding principal balance&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;632.5&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 88%;" valign="bottom"&gt;
          &lt;div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Unamortized debt issuance costs&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;13.4&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Maturity date&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: top; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;span style="-sec-ix-hidden:Fact_7dc5959ba24b47e092541cc149b2023c"&gt;April 2026&lt;/span&gt;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top;" valign="bottom"&gt;
          &lt;div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Interest rate&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: top;" valign="bottom"&gt;
          &lt;div style="text-align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;0 percent&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Effective interest rate&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: top; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;0.5 percent&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 88%;" valign="bottom"&gt;
          &lt;div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Conversion price per share&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;57.84&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 88%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Effective conversion price per share with call spread&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;76.39&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 88%;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Total shares of common stock subject to conversion&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;10.9&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;


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&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;At December 31, 2021,
    we had the following 0.125% Notes outstanding with interest payable semi-annually (amounts in millions except interest rate and price per share
    data):&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;"&gt;


  &lt;tr&gt;

    &lt;td style="vertical-align: top; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: top; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;0.125%
            Notes&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 88%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Outstanding principal balance&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;548.8&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 88%;" valign="bottom"&gt;
          &lt;div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Unamortized debt issuance costs&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;6.5&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Maturity date&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: top; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;span style="-sec-ix-hidden:Fact_ef7fbbee87c14676a78b2a22d99ec0ae"&gt;December 2024&lt;/span&gt;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top;" valign="bottom"&gt;
          &lt;div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Interest rate&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: top;" valign="bottom"&gt;
          &lt;div style="text-align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;0.125 percent&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Effective interest rate&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: top; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;0.5 percent&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 88%;" valign="bottom"&gt;
          &lt;div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Conversion price per share&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;83.28&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 88%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Effective conversion price per share with call spread&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;123.38&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 88%;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Total shares of common stock subject to conversion&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;6.6&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;
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&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Annual debt and other obligation
    maturities, including fixed and determinable interest, at December 31, 2021 are as follows (in thousands):&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;"&gt;


  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 88%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;span style="text-indent: 0pt;"&gt;2022&lt;/span&gt;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;3,498&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 88%;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;span style="text-indent: 0pt;"&gt;2023&lt;/span&gt;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;4,180&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 88%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;span style="text-indent: 0pt;"&gt;2024&lt;/span&gt;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;4,180&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 88%;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;span style="text-indent: 0pt;"&gt;2025&lt;/span&gt;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;1,184,820&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 88%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;span style="text-indent: 0pt;"&gt;2026&lt;/span&gt;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;3,494&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 88%; padding-bottom: 2px;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Thereafter&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;57,439&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 88%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Subtotal&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;1,257,611&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 88%;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Less: current portion&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(3,526&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 88%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Less: fixed and determinable interest&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(15,498&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 88%;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Less: debt issuance costs&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(20,302&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 88%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Plus: lease liabilities&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;22,058&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 88%; padding-bottom: 2px;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Plus: other liabilities&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;7,181&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 88%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Total long-term debt&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;1,247,524&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;
</srt:ContractualObligationFiscalYearMaturityScheduleTableTextBlock>
    <us-gaap:ContractualObligationDueInNextTwelveMonths
      contextRef="c20211231"
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      id="Fact_d2eb54062a6d4f188ef1dbae3b8653d3"
      unitRef="U001">3498000</us-gaap:ContractualObligationDueInNextTwelveMonths>
    <us-gaap:ContractualObligationDueInSecondYear
      contextRef="c20211231"
      decimals="-3"
      id="Fact_c42e928b65cd45aa923675e567769ac7"
      unitRef="U001">4180000</us-gaap:ContractualObligationDueInSecondYear>
    <us-gaap:ContractualObligationDueInThirdYear
      contextRef="c20211231"
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      id="Fact_6b7eb3455bef4825bec5934f0ca8a9f2"
      unitRef="U001">4180000</us-gaap:ContractualObligationDueInThirdYear>
    <us-gaap:ContractualObligationDueInFourthYear
      contextRef="c20211231"
      decimals="-3"
      id="Fact_5163088d8dfb4bd8afb6a945c3e15b83"
      unitRef="U001">1184820000</us-gaap:ContractualObligationDueInFourthYear>
    <us-gaap:ContractualObligationDueInFifthYear
      contextRef="c20211231"
      decimals="-3"
      id="Fact_04194527fb664e52a3ac79595e34b654"
      unitRef="U001">3494000</us-gaap:ContractualObligationDueInFifthYear>
    <us-gaap:ContractualObligationDueAfterFifthYear
      contextRef="c20211231"
      decimals="-3"
      id="Fact_74f3f2a83bb64af5b0b4b21df7d35ef0"
      unitRef="U001">57439000</us-gaap:ContractualObligationDueAfterFifthYear>
    <us-gaap:ContractualObligation
      contextRef="c20211231"
      decimals="-3"
      id="Fact_41f58f8c96774a38af7b7c1cc41eabb9"
      unitRef="U001">1257611000</us-gaap:ContractualObligation>
    <ions:LongTermObligationsCurrent
      contextRef="c20211231"
      decimals="-3"
      id="Fact_bc879ac3c37f49de90a976632193e86e"
      unitRef="U001">3526000</ions:LongTermObligationsCurrent>
    <us-gaap:InterestPayableCurrentAndNoncurrent
      contextRef="c20211231"
      decimals="-3"
      id="Fact_ef9db53e88e14db9b13d2afa08b9cc23"
      unitRef="U001">15498000</us-gaap:InterestPayableCurrentAndNoncurrent>
    <us-gaap:DeferredFinanceCostsNet
      contextRef="c20211231"
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      id="Fact_97e59891cc4a4a90baf9d56b32982707"
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      contextRef="c20211231"
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    <ions:LongTermObligationsNoncurrent
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      decimals="-3"
      id="Fact_2e8033307b594b4f9b2e30ee6ba95bc3"
      unitRef="U001">1247524000</ions:LongTermObligationsNoncurrent>
    <us-gaap:LesseeOperatingLeasesTextBlock
      contextRef="c20210101to20211231"
      id="Text_816a383efe384026825a397c06709b4a">
&lt;div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Operating Leases&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;"&gt;Carlsbad Leases&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;We lease a facility adjacent to our manufacturing facility that has laboratory and office space that we use to support our
    manufacturing facility. We lease this space under a non-cancelable operating lease. In May 2020, we exercised our option to extend our lease, extending our lease term from June 2021 to August 2026. We have one remaining option to extend the lease for an additional five-year
    period.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;We also lease additional office spaces in Carlsbad. We lease these spaces under non-cancelable operating leases with
    initial terms ending in 2023 with options to extend each of the leases for one&#160;five-year period.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;"&gt;Boston Leases&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;We entered into an operating lease agreement for office space located in Boston, Massachusetts in the second quarter of
    2018. The lease commencement date was in August 2018 and we took occupancy in September 2018. We are leasing this space under a non-cancelable operating lease with an initial term ending after 123 months and an option to extend the lease for an additional five-year term. Under
    the lease agreement, we received a three-month free rent period, which commenced on August 15, 2018, and a tenant improvement allowance up to $3.8 million.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;In January 2022, we entered into a sublease agreement for our office space located in Boston, Massachusetts. The sublease commencement
    date was in January 2022 when the office space was ready for our tenant&#x2019;s occupancy. We are subleasing this space under a non-cancelable operating sublease with a sublease term ending 83 months following the sublease commencement date with no option to extend the sublease. Under the sublease agreement we provided a seven-month free rent period, which commenced on January 6, 2022. We will receive lease payments over the sublease term totaling $9.6 million.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;In September 2021, we entered into an operating lease agreement for another office space located in Boston, Massachusetts. The lease
    commencement date was in November 2021 when the office space was ready for our occupancy. We are leasing this space under a non-cancelable operating lease with an initial term ending 91 months following the lease commencement date and an option to extend the lease for &lt;span style="-sec-ix-hidden:Fact_75e2ca0ba9ea409188caefc97441d96a"&gt;an&lt;/span&gt;
    additional five-year term. Under the lease agreement, we will receive a seven-month free rent period, which commenced on November 1, 2021. Our lease payments over the initial term total $6.8 million. We recognized a right-of-use lease asset and lease liability in the fourth quarter of 2021 upon the lease commencement date.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;When we determined our lease term for our operating lease right-of-use assets and lease liabilities for these leases, we
    did not include the extension options for these leases in the original lease term.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Amounts related to our operating leases were as follows (dollar amounts in millions):&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;"&gt;


  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;

        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;At December 31, 2021&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 88%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Right-of-use operating lease assets (1)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;18.0&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 88%;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Operating lease liabilities (2)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;22.1&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Weighted average remaining lease term&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;6.6 years&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 88%;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Weighted average discount rate&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;6.0&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;%&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;________________&lt;/div&gt;

&lt;table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;"&gt;


  &lt;tr&gt;

    &lt;td style="width: 18pt; vertical-align: top; align: right; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(1)&lt;/td&gt;

    &lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;
          &lt;div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Included in &lt;span style="-sec-ix-hidden:Fact_f81ca57385a04657b8ecd0f06d505159"&gt;deposits and other assets&lt;/span&gt; on our consolidated balance sheet.&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;"&gt;


  &lt;tr&gt;

    &lt;td style="width: 18pt; vertical-align: top; align: right; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(2)&lt;/td&gt;

    &lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;
          &lt;div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Current portion of $2.6 million was included in &lt;span style="-sec-ix-hidden:Fact_b2b58e46aca04158b3b03811dd0a9c0f"&gt;current portion of long-term obligations&lt;/span&gt; on our consolidated balance sheet, with the difference included in &lt;span style="-sec-ix-hidden:Fact_9c37cb3853f74a4f821bbe4ed37a06ba"&gt;long-term obligations&lt;/span&gt;.&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 12pt;"&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;During the years ended December 31, 2021, 2020, and 2019 we paid $3.3 million, $3.8 million and $3.9 million of lease payments, which were included in
    operating activities in our consolidated statements of cash flows.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;As of December 31, 2021, the future payments for our operating lease liabilities are as follows (in thousands):&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;"&gt;


  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;

        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Operating&lt;/span&gt; &lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Leases&lt;/span&gt;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 88%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Year ending December 31,&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;$&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 88%;" valign="bottom"&gt;
          &lt;div style="text-align: justify; margin-left: 18.7pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;2022&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;4,075&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 88%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -0.2pt; margin-left: 18.7pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;span style="text-indent: 0pt;"&gt;2023&lt;/span&gt;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;4,314&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 88%;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -0.2pt; margin-left: 18.7pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;span style="text-indent: 0pt;"&gt;2024&lt;/span&gt;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;4,223&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 88%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; margin-left: 18.7pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;2025&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;4,062&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 88%;" valign="bottom"&gt;
          &lt;div style="text-align: justify; margin-left: 18.7pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;2026&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;3,778&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 88%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Thereafter&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;7,035&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 88%;" valign="bottom"&gt;
          &lt;div style="text-align: left; margin-left: 18.7pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Total minimum lease payments&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;27,487&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 88%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Less:&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 88%; padding-bottom: 2px;" valign="bottom"&gt;
          &lt;div style="text-align: left; margin-left: 18.7pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Imputed interest&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(5,429&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 88%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: left; margin-left: 36.7pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Total operating lease liabilities&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;22,058&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 12pt;"&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Rent expense was $3.4
    million, $3.7 million and $3.6 million
    for the years ended December 31, 2021, 2020
    and 2019, respectively. &lt;/div&gt;
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    <us-gaap:LesseeOperatingLeaseTermOfContract
      contextRef="c20211231_GeographicDistributionAxis_AnotherOfficeSpaceInBostonMember"
      id="Fact_f252e6bc1ca849dfb22869bd4a71369a">P91M</us-gaap:LesseeOperatingLeaseTermOfContract>
    <us-gaap:LesseeOperatingLeaseRenewalTerm
      contextRef="c20211231_GeographicDistributionAxis_AnotherOfficeSpaceInBostonMember"
      id="Fact_0db31532f59e4b6483e94032872c2c44">P5Y</us-gaap:LesseeOperatingLeaseRenewalTerm>
    <ions:LesseeOperatingLeasePeriodOfFreeRent
      contextRef="c20210101to20211231_GeographicDistributionAxis_AnotherOfficeSpaceInBostonMember"
      id="Fact_99931a7181e04c71bbd9180a5f64f952">P7M</ions:LesseeOperatingLeasePeriodOfFreeRent>
    <us-gaap:LesseeOperatingLeaseLiabilityPaymentsDue
      contextRef="c20211231_GeographicDistributionAxis_AnotherOfficeSpaceInBostonMember"
      decimals="-5"
      id="Fact_c350c485d2194852998ea1b496903ff5"
      unitRef="U001">6800000</us-gaap:LesseeOperatingLeaseLiabilityPaymentsDue>
    <ions:LesseeOperatingLeaseInformationTableTextBlock
      contextRef="c20210101to20211231"
      id="Text_e4fd6084d7e2468e95eebcfebd153735">
&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Amounts related to our operating leases were as follows (dollar amounts in millions):&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;"&gt;


  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;

        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;At December 31, 2021&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 88%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Right-of-use operating lease assets (1)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;18.0&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 88%;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Operating lease liabilities (2)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;22.1&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Weighted average remaining lease term&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;6.6 years&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 88%;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Weighted average discount rate&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;6.0&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;%&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;________________&lt;/div&gt;

&lt;table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;"&gt;


  &lt;tr&gt;

    &lt;td style="width: 18pt; vertical-align: top; align: right; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(1)&lt;/td&gt;

    &lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;
          &lt;div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Included in &lt;span style="-sec-ix-hidden:Fact_f81ca57385a04657b8ecd0f06d505159"&gt;deposits and other assets&lt;/span&gt; on our consolidated balance sheet.&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;"&gt;


  &lt;tr&gt;

    &lt;td style="width: 18pt; vertical-align: top; align: right; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(2)&lt;/td&gt;

    &lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;
          &lt;div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Current portion of $2.6 million was included in &lt;span style="-sec-ix-hidden:Fact_b2b58e46aca04158b3b03811dd0a9c0f"&gt;current portion of long-term obligations&lt;/span&gt; on our consolidated balance sheet, with the difference included in &lt;span style="-sec-ix-hidden:Fact_9c37cb3853f74a4f821bbe4ed37a06ba"&gt;long-term obligations&lt;/span&gt;.&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;
</ions:LesseeOperatingLeaseInformationTableTextBlock>
    <us-gaap:OperatingLeaseRightOfUseAsset
      contextRef="c20211231"
      decimals="-5"
      id="Fact_23749203f9514c17a3eb9047effcbc3f"
      unitRef="U001">18000000.0</us-gaap:OperatingLeaseRightOfUseAsset>
    <us-gaap:OperatingLeaseLiability
      contextRef="c20211231"
      decimals="-5"
      id="Fact_0bcc1def02bf4a9fae57dfb5f4021412"
      unitRef="U001">22100000</us-gaap:OperatingLeaseLiability>
    <us-gaap:OperatingLeaseWeightedAverageRemainingLeaseTerm1
      contextRef="c20211231"
      id="Fact_ccfd1bbd8568445fb43b6a1d85973cc7">P6Y7M6D</us-gaap:OperatingLeaseWeightedAverageRemainingLeaseTerm1>
    <us-gaap:OperatingLeaseWeightedAverageDiscountRatePercent
      contextRef="c20211231"
      decimals="3"
      id="Fact_0f6726aa9c174130a3010b4dad4799ef"
      unitRef="U003">0.060</us-gaap:OperatingLeaseWeightedAverageDiscountRatePercent>
    <us-gaap:OperatingLeaseLiabilityCurrent
      contextRef="c20211231"
      decimals="-5"
      id="Fact_9b0c762d64a740078d7920512d9fd9e9"
      unitRef="U001">2600000</us-gaap:OperatingLeaseLiabilityCurrent>
    <us-gaap:OperatingLeasePayments
      contextRef="c20210101to20211231"
      decimals="-5"
      id="Fact_826cead5743b4e90a9d8b807e97fe422"
      unitRef="U001">3300000</us-gaap:OperatingLeasePayments>
    <us-gaap:OperatingLeasePayments
      contextRef="c20200101to20201231"
      decimals="-5"
      id="Fact_297fcce7f2e44b348fe63e7be360cf7c"
      unitRef="U001">3800000</us-gaap:OperatingLeasePayments>
    <us-gaap:OperatingLeasePayments
      contextRef="c20190101to20191231"
      decimals="-5"
      id="Fact_50e928616e964a8c94f28d1e4409995c"
      unitRef="U001">3900000</us-gaap:OperatingLeasePayments>
    <us-gaap:LesseeOperatingLeaseLiabilityMaturityTableTextBlock
      contextRef="c20210101to20211231"
      id="Text_4ac550fe12b346a487d1639e48d94f8d">
&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;As of December 31, 2021, the future payments for our operating lease liabilities are as follows (in thousands):&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;"&gt;


  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;

        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Operating&lt;/span&gt; &lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Leases&lt;/span&gt;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 88%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Year ending December 31,&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;$&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 88%;" valign="bottom"&gt;
          &lt;div style="text-align: justify; margin-left: 18.7pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;2022&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;4,075&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 88%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -0.2pt; margin-left: 18.7pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;span style="text-indent: 0pt;"&gt;2023&lt;/span&gt;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;4,314&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 88%;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -0.2pt; margin-left: 18.7pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;span style="text-indent: 0pt;"&gt;2024&lt;/span&gt;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;4,223&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 88%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; margin-left: 18.7pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;2025&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;4,062&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 88%;" valign="bottom"&gt;
          &lt;div style="text-align: justify; margin-left: 18.7pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;2026&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;3,778&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 88%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Thereafter&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;7,035&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 88%;" valign="bottom"&gt;
          &lt;div style="text-align: left; margin-left: 18.7pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Total minimum lease payments&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;27,487&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 88%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Less:&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 88%; padding-bottom: 2px;" valign="bottom"&gt;
          &lt;div style="text-align: left; margin-left: 18.7pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Imputed interest&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(5,429&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 88%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: left; margin-left: 36.7pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Total operating lease liabilities&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;22,058&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;
</us-gaap:LesseeOperatingLeaseLiabilityMaturityTableTextBlock>
    <us-gaap:LesseeOperatingLeaseLiabilityPaymentsDueNextTwelveMonths
      contextRef="c20211231"
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      unitRef="U001">4075000</us-gaap:LesseeOperatingLeaseLiabilityPaymentsDueNextTwelveMonths>
    <us-gaap:LesseeOperatingLeaseLiabilityPaymentsDueYearTwo
      contextRef="c20211231"
      decimals="-3"
      id="Fact_4609f99ef9604c9aae3baed51a3c3fed"
      unitRef="U001">4314000</us-gaap:LesseeOperatingLeaseLiabilityPaymentsDueYearTwo>
    <us-gaap:LesseeOperatingLeaseLiabilityPaymentsDueYearThree
      contextRef="c20211231"
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      id="Fact_d11239309f5945a3891ef526d1491daa"
      unitRef="U001">4223000</us-gaap:LesseeOperatingLeaseLiabilityPaymentsDueYearThree>
    <us-gaap:LesseeOperatingLeaseLiabilityPaymentsDueYearFour
      contextRef="c20211231"
      decimals="-3"
      id="Fact_43a6c7550e004272b7f9ca99a8ba22d8"
      unitRef="U001">4062000</us-gaap:LesseeOperatingLeaseLiabilityPaymentsDueYearFour>
    <us-gaap:LesseeOperatingLeaseLiabilityPaymentsDueYearFive
      contextRef="c20211231"
      decimals="-3"
      id="Fact_74899d789ebf4c2ebccd545b74c63e21"
      unitRef="U001">3778000</us-gaap:LesseeOperatingLeaseLiabilityPaymentsDueYearFive>
    <us-gaap:LesseeOperatingLeaseLiabilityPaymentsDueAfterYearFive
      contextRef="c20211231"
      decimals="-3"
      id="Fact_3931369a624044a9b1905cb93b92544f"
      unitRef="U001">7035000</us-gaap:LesseeOperatingLeaseLiabilityPaymentsDueAfterYearFive>
    <us-gaap:LesseeOperatingLeaseLiabilityPaymentsDue
      contextRef="c20211231"
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      id="Fact_3603a725690b46dda9be3db4e21043c4"
      unitRef="U001">27487000</us-gaap:LesseeOperatingLeaseLiabilityPaymentsDue>
    <us-gaap:LesseeOperatingLeaseLiabilityUndiscountedExcessAmount
      contextRef="c20211231"
      decimals="-3"
      id="Fact_7af8c05d1850481699607948c91a7946"
      unitRef="U001">5429000</us-gaap:LesseeOperatingLeaseLiabilityUndiscountedExcessAmount>
    <us-gaap:OperatingLeaseLiability
      contextRef="c20211231"
      decimals="-3"
      id="Fact_5bc4a22d2bca49aca884201dc1170194"
      unitRef="U001">22058000</us-gaap:OperatingLeaseLiability>
    <us-gaap:OperatingLeaseExpense
      contextRef="c20210101to20211231"
      decimals="-5"
      id="Fact_b625c294a3bd434f8c74620b51e1ea20"
      unitRef="U001">3400000</us-gaap:OperatingLeaseExpense>
    <us-gaap:OperatingLeaseExpense
      contextRef="c20200101to20201231"
      decimals="-5"
      id="Fact_37e7125f4da2437a81d1b7f1853e4554"
      unitRef="U001">3700000</us-gaap:OperatingLeaseExpense>
    <us-gaap:OperatingLeaseExpense
      contextRef="c20190101to20191231"
      decimals="-5"
      id="Fact_a6f37ce5e1654e67b6bfb04f2bfaa94b"
      unitRef="U001">3600000</us-gaap:OperatingLeaseExpense>
    <us-gaap:StockholdersEquityNoteDisclosureTextBlock
      contextRef="c20210101to20211231"
      id="Text_334061329e6345ae91c6341ea13083ef">
&lt;div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;4. Stockholders&lt;/span&gt;&#x2019;&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt; Equity&lt;/span&gt;&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Preferred Stock&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;We are authorized to issue up to 15 million shares of &#x201c;blank check&#x201d; Preferred Stock. As of December 31, 2021, there
    were no shares of Preferred Stock outstanding. We have designated Series C Junior Participating Preferred Stock but have no issued or outstanding shares as of December 31, 2021.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Common Stock&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;At December 31, 2021
    and 2020, we had 300 million
    shares of common stock authorized, of which 141.2 million and 140.4 million were issued and outstanding, respectively. As of December 31, 2021,
    total common shares reserved for future issuance were 46.2 million.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;During the years ended December 31, 2021, 2020 and 2019, we issued 1.1 million, 1.7 million and 3.1 million shares of common stock, respectively, for stock option
    exercises, vesting of restricted stock units, and ESPP purchases. We received net proceeds from these transactions of $11.6 million, $52.0 million and $119.7 million in 2021, 2020 and 2019, respectively.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Share Repurchase Program&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;In September 2019, our board of directors approved a share repurchase program of up to $125 million of our common stock. In 2019, we repurchased 535,000
    shares for $34.4 million. In the first quarter of 2020, we repurchased an additional 1.5 million shares for $90.5 million.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Stock Plans&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;"&gt;1989 Stock Option Plan&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;In June 1989, our Board of Directors adopted, and the stockholders subsequently approved, a stock option plan that, as
    amended, provides for the issuance of non-qualified and incentive stock options for the purchase of up to 20.0 million shares of common stock to
    our employees, directors, and consultants. The plan expires in January 2024. The 1989 Plan does not allow us to grant stock bonuses or restricted stock awards and prohibits us from repricing any options outstanding under the plan unless our
    stockholders approve the repricing. Options vest over a four-year period, with 25percent exercisable at the end of one year from the date of the grant and the
    balance vesting ratably, on a monthly basis, thereafter and have a term of seven years. At December 31, 2021, a total of 28 thousand options were outstanding, of which
    options to purchase 28 thousand shares were exercisable, and 49 thousand shares were available for future grant under the 1989 Plan.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: -18pt; margin-left: 54pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;"&gt;2011 Equity Incentive Plan&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;In March 2011, our Board of Directors adopted, and the stockholders subsequently approved, a stock option plan that
    provides for the issuance of stock options, stock appreciation rights, restricted stock awards, restricted stock unit awards, and performance cash awards to our employees, directors, and consultants. In June 2015, May 2017 and June 2019, after
    receiving approval from our stockholders, we amended our 2011 Equity Incentive Plan, or&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt; 2011 Plan,&lt;/span&gt; to increase the total number of shares reserved for issuance. We
    increased the shares available under our 2011 Equity Incentive Plan from 5.5 million to 11.0 million in June 2015, from 11.0 million to 16.0 million in May 2017 and from 16.0 million to 23.0 million in June 2019. In the second quarter of 2021, after receiving approval from our stockholders, we amended our &lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;2011 Plan. The amendment increased the total number of shares of common stock authorized for issuance under the 2011 Plan from &lt;/span&gt;23.0&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt; million to &lt;/span&gt;29.7&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt; million and added a fungible share counting ratio whereby the share reserve will be reduced by &lt;/span&gt;1.7&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt; shares for each share of common stock issued pursuant to a full value award (i.e., RSU or PRSU) and increased by
    &lt;/span&gt;1.7&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt; shares for each share of common stock returning from a
      full value award. &lt;/span&gt;The plan expires in June 2031. The 2011 Plan does not allow us to reduce the exercise price of any outstanding stock options or stock appreciation rights or cancel any outstanding stock options or stock appreciation rights
    that have an exercise price or strike price greater than the current fair market value of the common stock in exchange for cash or other stock awards unless our stockholders approve such action. Currently we anticipate awarding only stock options, RSU
    and PRSU awards to our employees, directors and consultants. Options vest over a four-year period, with 25 percent exercisable at the end of one year from the date of the grant
    and the balance vesting ratably, on a monthly basis, thereafter and have a term of seven years. Options granted after December 31, 2021 have a
    term of ten years. We have granted restricted stock unit awards to our employees under the 2011 Plan which vest annually over a four-year period. At December 31, 2021, a
    total of 12.8 million options were outstanding, of which 8.3 million were exercisable, 2.5 million restricted stock unit awards were
    outstanding, and 8.5 million shares were available for future grant under the 2011 Plan.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Under the 2011 Plan, we may issue a stock award with additional acceleration of vesting and exercisability upon or after a
    change in control. In the absence of such provisions, no such acceleration will occur. The stock options and restricted stock unit awards we issued to Dr. Stanley T. Crooke in his former role as chief executive officer and certain stock options and
    restricted stock unit awards we issued to B. Lynne Parshall in her former role as chief operating officer have accelerated vesting upon a change of control, as defined in the 2011 Plan. In addition, we implemented a change of control and severance
    benefit plan that provides for change of control and severance benefits to our executive officers, including our chief executive officer and chief financial officer. If we terminate one of our executive officers or if an executive officer resigns for good reason during the period that begins three months before and ends twelve months following a change in control of the
    company, the impacted executive officers&#x2019; stock options and RSUs vesting will accelerate for options and RSUs outstanding as of the termination date.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: -18pt; margin-left: 54pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;"&gt;2020 Equity Incentive Plan&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;In connection with the Akcea Merger in October 2020, we
      assumed the unallocated portion of the available share reserve under the Akcea 2015 Equity Incentive Plan. In December 2020, we amended and restated the Akcea 2015 equity plan, including renaming the plan as the Ionis Pharmaceuticals, Inc. 2020
      Equity Incentive Plan, or 2020 Plan. The 2020 Plan provided for the issuance of up to &lt;/span&gt;2.6&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt; million shares of our Common Stock to our employees, directors and consultants who were employees of Akcea prior to the Akcea Merger. &lt;/span&gt;&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt;In the second quarter of 2021, our Compensation Committee approved an amendment to the 2020 Plan. The amendment decreased the total number of shares of common stock authorized for issuance under the 2020 Plan from
      approximately &lt;/span&gt;2.6&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt; million to &lt;/span&gt;1.6&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt; million. We assumed the 2020 Plan in connection with Ionis&#x2019;
      reacquisition of all of the outstanding shares of Akcea Therapeutics, Inc. as part of the Akcea Merger.&lt;/span&gt;&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;The plan expires in December 2025. The 2020 Plan does not allow us to reduce the exercise price of any outstanding stock
    options or stock appreciation rights or cancel any outstanding stock options or stock appreciation rights that have an exercise price or strike price greater than the current fair market value of the common stock in exchange for cash or other stock
    awards unless our stockholders approve such action. Currently we anticipate awarding only stock options and RSU awards to our eligible employees, directors and consultants. Options vest over a four-year period, with 25 percent exercisable at the end of one year from the date of the grant and the balance vesting ratably, on a monthly basis, thereafter and have a term of seven years. Options granted after December 31, 2021 have a term of ten years.
    We have granted restricted stock unit awards to our employees under the 2020 Plan which vest annually over a four-year period. At December 31, 2021, a total of 0.2 million
    options were outstanding, of which none were exercisable, 0.1 million restricted stock unit awards were outstanding, and 1.3 million shares were
    available for future grant under the 2020 Plan.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Under the 2020 Plan, we may issue a stock award with additional acceleration of vesting and exercisability upon or after a
    change in control. In the absence of such provisions, no such acceleration will occur.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: left; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;"&gt;Corporate Transactions and Change in Control under 2011 and 2020 Plans&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;In the event of certain significant corporate transactions, our Board of Directors has the discretion to take one or more
    of the following actions with respect to outstanding stock awards under the 2011 and 2020 Plans:&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;"&gt;


  &lt;tr&gt;

    &lt;td style="width: 36pt;"/&gt;

    &lt;td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x25cf;&lt;/td&gt;

    &lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;arrange for assumption, continuation, or substitution of a stock award by a surviving or acquiring entity (or its parent company);&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;"&gt;


  &lt;tr&gt;

    &lt;td style="width: 36pt;"/&gt;

    &lt;td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x25cf;&lt;/td&gt;

    &lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;arrange for the assignment of any reacquisition or repurchase rights applicable to any shares of our common stock issued pursuant to a stock award to the
            surviving or acquiring corporation (or its parent company);&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;"&gt;


  &lt;tr&gt;

    &lt;td style="width: 36pt;"/&gt;

    &lt;td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x25cf;&lt;/td&gt;

    &lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;accelerate the vesting and exercisability of a stock award followed by the termination of the stock award;&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;"&gt;


  &lt;tr&gt;

    &lt;td style="width: 36pt;"/&gt;

    &lt;td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x25cf;&lt;/td&gt;

    &lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;arrange for the lapse of any reacquisition or repurchase rights applicable to any shares of our common stock issued pursuant to a stock award;&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;"&gt;


  &lt;tr&gt;

    &lt;td style="width: 36pt;"/&gt;

    &lt;td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x25cf;&lt;/td&gt;

    &lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;cancel or arrange for the cancellation of a stock award, to the extent not vested or not exercised prior to the effective date of the corporate
            transaction, in exchange for cash consideration, if any, as the Board, in its sole discretion, may consider appropriate; and&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;"&gt;


  &lt;tr&gt;

    &lt;td style="width: 36pt;"/&gt;

    &lt;td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x25cf;&lt;/td&gt;

    &lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;arrange for the surrender of a stock award in exchange for a payment equal to the excess of (a) the value of the property the holder of the stock award
            would have received upon the exercise of the stock award, over (b) any exercise price payable by such holder in connection with such exercise.&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;"&gt;2002 Non-Employee Directors&#x2019; Stock Option Plan&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;In September 2001, our Board of Directors adopted, and the stockholders subsequently approved, an amendment and
    restatement of the 1992 Non-Employee Directors&#x2019; Stock Option Plan, which provides for the issuance of non-qualified stock options and restricted stock units to our non-employee directors. The name of the resulting plan is the 2002 Non-Employee
    Directors&#x2019; Stock Option Plan, or the 2002 Plan. In June 2015, after receiving approval from our stockholders, we amended our 2002 Plan to increase the total number of shares reserved for issuance from 1.2 million to 2.0 million. In June 2020, after receiving approval from our
    stockholders, we further amended our 2002 Plan. &lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;The amendments included:&lt;/span&gt;&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;"&gt;


  &lt;tr&gt;

    &lt;td style="width: 36pt;"/&gt;

    &lt;td style="width: 18pt; vertical-align: top; align: right; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x25cf;&lt;/td&gt;

    &lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;
          &lt;div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt;An increase to the total number of shares reserved for issuance under the
              plan from &lt;/span&gt;2.0&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt; million to &lt;/span&gt;2.8&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt; million shares;&lt;/span&gt;&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;"&gt;


  &lt;tr&gt;

    &lt;td style="width: 36pt;"/&gt;

    &lt;td style="width: 18pt; vertical-align: top; align: right; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x25cf;&lt;/td&gt;

    &lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;A reduction to the amount of the automatic awards under the plan;&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;"&gt;


  &lt;tr&gt;

    &lt;td style="width: 36pt;"/&gt;

    &lt;td style="width: 18pt; vertical-align: top; align: right; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x25cf;&lt;/td&gt;

    &lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;A revision to the vesting schedule of new awards granted; and&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;"&gt;


  &lt;tr&gt;

    &lt;td style="width: 36pt;"/&gt;

    &lt;td style="width: 18pt; vertical-align: top; align: right; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x25cf;&lt;/td&gt;

    &lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;
          &lt;div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;An extension of the term of the plan.&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Options under this plan expire 10 years from the date of grant. At December 31, 2021, a total of 1.0 million options were outstanding, of which 0.8
    million were exercisable, 0.1 million restricted stock unit awards were outstanding, and 0.7 million shares were available for future grant under the 2002 Plan.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: -18pt; margin-left: 54pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;"&gt;Employee Stock Purchase Plan&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;In June 2009, our Board of Directors adopted, and the stockholders subsequently approved, the amendment and restatement of
    the ESPP and we reserved an additional 150,000 shares of common stock for issuance thereunder. In each of the subsequent years until 2019, we
    reserved an additional 150,000 shares of common stock for the ESPP resulting in a total of 3.2 million shares authorized under the plan as of December 31, 2021. The ESPP
    permits full-time employees to purchase common stock through payroll deductions (which cannot exceed 10percent of each employee&#x2019;s compensation)
    at the lower of 85percent of fair market value at the beginning of the purchase period or the end of each purchase period. Under the amended
    and restated ESPP, employees must hold the stock they purchase for a minimum of six months from the date of purchase. During 2021, employees purchased and we issued to employees 0.07
    million shares under the ESPP at a weighted average price of $39.26 per share. At December 31, 2021, there were 0.6 million shares available for purchase under the
    ESPP.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Stock Option Activity&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;The following table summarizes the stock option activity under our stock plans for the year ended December 31, 2021 (in thousands, except per share and contractual life data):&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;"&gt;


  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;

        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Number&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;of Shares&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Weighted&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Average Exercise&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Price Per Share&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Average&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Remaining&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Contractual Term&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;(Years)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Aggregate&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Intrinsic&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Value&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;span style="text-indent: 0pt;"&gt;Outstanding at December 31, 2020&lt;/span&gt;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;12,439&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;54.11&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 18pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Granted&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;3,382&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;53.07&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 18pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Exercised&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(219&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;38.69&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 18pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Cancelled/forfeited/expired&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(1,513&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; padding-bottom: 2px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;54.65&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 52%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;span style="text-indent: 0pt;"&gt;Outstanding at December 31, 2021&lt;/span&gt;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;14,089&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;54.04&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;3.89&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;1,131&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 52%; padding-bottom: 4px;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;span style="text-indent: 0pt;"&gt;Exercisable at December 31, 2021&lt;/span&gt;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;9,175&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;53.65&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;2.94&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;1,067&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 12pt;"&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;The weighted-average estimated fair values of options granted were $24.35, $29.43 and $28.76 for the years ended December 31, 2021, 2020 and 2019, respectively. The total intrinsic value of options
    exercised during the years ended December 31, 2021, 2020 and 2019 were $2.5 million, $15.5 million and $83.8 million, respectively, which we determined as of the date of exercise. The amount of cash received from the exercise of stock options was $8.5 million, $43.7 million and $105.9 million for the years ended December 31, 2021, 2020 and 2019, respectively. For the year
    ended December 31, 2021, the weighted-average fair value of options exercised was $50.13. As of December 31, 2021, total unrecognized compensation cost related to
    non-vested stock options was $49.6 million. We expect to recognize this cost over a weighted average period of 1.1 years. We will adjust the total unrecognized compensation cost for future changes in estimated forfeitures.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Restricted Stock Unit Activity&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;The following table summarizes the RSU activity for the year ended December 31, 2021 (in thousands, except per share data):&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;"&gt;


  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;

        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Number&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;of Shares&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Weighted Average&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Grant Date Fair&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Value Per Share&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 76%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;span style="text-indent: 0pt;"&gt;Non-vested at December 31, 2020&lt;/span&gt;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;2,374&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;58.81&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 76%;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 18pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Granted&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;1,548&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;57.69&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 76%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 18pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Vested&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(834&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;57.47&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 76%; padding-bottom: 2px;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 18pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Cancelled/forfeited&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(411&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;59.24&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 76%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;span style="text-indent: 0pt;"&gt;Non-vested at December 31, 2021&lt;/span&gt;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;2,677&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;58.51&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 12pt;"&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;For the years ended December 31, 2021, 2020 and 2019, the weighted-average grant date fair value of RSUs granted was $57.69, $60.86 and $60.23 per RSU, respectively. As of
    December 31, 2021, total unrecognized compensation cost related to RSUs was $57.0 million. We expect to recognize this cost over a weighted average period of 1.2
    years. We will adjust the total unrecognized compensation cost for future changes in estimated forfeitures.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Stock-based Compensation Expense and Valuation Information&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;The following table summarizes stock-based compensation expense for the years ended December 31, 2021, 2020 and 2019 (in thousands):&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;"&gt;


  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;

        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="10" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Year Ended December 31,&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;2021&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;2020&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;2019&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Cost of sales&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;456&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;1,991&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;438&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 64%;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Research, development and patent&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;87,522&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;115,584&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;95,348&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Selling, general and administrative&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;32,700&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;112,542&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;50,788&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 64%; padding-bottom: 4px;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Total&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;120,678&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;230,117&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;146,574&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;div style="text-align: justify; font-family: 'Times New Roman', Times, serif; font-size: 12pt;"&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;In October 2020, as part of the Akcea Merger, Akcea&#x2019;s outstanding equity awards vested under Akcea&#x2019;s Plan. As a result, in
    the fourth quarter of 2020, we recognized all unrecognized stock-based compensation ($59.3 million) under Akcea&#x2019;s Plan. See Note 7, &lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;"&gt;Akcea Merger&lt;/span&gt;, in the Notes to the Consolidated Financial Statements for further details.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;In the third quarter of 2019, &lt;/span&gt;three&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt; Akcea executive officers terminated their employment and entered into
      separation agreements with Akcea. As a result, in the third quarter of 2019, Akcea reversed $&lt;/span&gt;19.1&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt; million of stock-based compensation expense it had previously recognized related to the executive officers&#x2019; stock options and RSUs that were no longer going to vest.&lt;/span&gt;&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: -18pt; margin-left: 54pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;"&gt;Determining Fair Value&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;"&gt;Valuation.&lt;/span&gt; We
    measure stock-based compensation expense for equity-classified awards, principally related to stock options, RSUs, PRSUs and stock purchase rights under the ESPP at the grant date, based on the estimated fair value of the award and we recognize the
    expense over the employee&#x2019;s requisite service period. We value RSUs based on the market price of our common stock on the date of grant. See Note 1, &lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;"&gt;Organization
      and Significant Accounting Policies&lt;/span&gt;, in the Notes to the Consolidated Financial Statements for further details on how we determine the fair value of PRSUs.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;We use the Black-Scholes model to estimate the fair value of stock options granted and stock purchase rights under our
    ESPP. The expected term of stock options granted represents the period of time that we expect them to be outstanding. We estimate the expected term of stock options granted based on actual and projected exercise patterns. We recognize compensation
    expense for stock options granted, RSUs, PRSUs and stock purchase rights under the ESPP using the accelerated multiple-option approach. Under the accelerated multiple-option approach (also known as the graded-vesting method), we recognize compensation
    expense over the requisite service period for each separately vesting tranche of the award as though the award were in substance multiple awards, which results in the expense being front-loaded over the vesting period.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;For the years ended December 31, 2021, 2020 and 2019, we used the following weighted-average assumptions in our Black-Scholes calculations:&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;"&gt;Ionis Employee Stock Options:&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;"&gt;


  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;

        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="10" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Year Ended December 31,&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;2021&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;2020&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;2019&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Risk-free interest rate&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;0.6&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;%&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;1.5&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;%&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;2.3&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;%&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 64%;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Dividend yield&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;0.0&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;%&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;0.0&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;%&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;0.0&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;%&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Volatility&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;54.0&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;%&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;58.6&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;%&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;60.3&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;%&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Expected life&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom;" valign="bottom"&gt;
          &lt;div style="text-align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;4.9 years&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom;" valign="bottom"&gt;
          &lt;div style="text-align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;4.7 years&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom;" valign="bottom"&gt;
          &lt;div style="text-align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;4.8 years&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;"&gt;Ionis Board of Director Stock Options:&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;"&gt;


  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;

        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="10" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Year Ended December 31,&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;2021&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;2020&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;2019&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Risk-free interest rate&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;1.2&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;%&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;0.5&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;%&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;1.9&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;%&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 64%;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Dividend yield&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;0.0&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;%&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;0.0&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;%&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;0.0&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;%&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Volatility&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;55.9&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;%&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;57.6&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;%&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;60.7&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;%&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Expected life&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom;" valign="bottom"&gt;
          &lt;div style="text-align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;7.3 years&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom;" valign="bottom"&gt;
          &lt;div style="text-align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;6.7 years&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom;" valign="bottom"&gt;
          &lt;div style="text-align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;6.6 years&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: left; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 12pt;"&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: left; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;"&gt;Ionis ESPP:&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;"&gt;


  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;

        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="10" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Year Ended December 31,&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;2021&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;2020&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;2019&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Risk-free interest rate&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;0.1&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;%&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;0.8&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;%&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;2.4&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;%&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 64%;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Dividend yield&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;0.0&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;%&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;0.0&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;%&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;0.0&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;%&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Volatility&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;42.4&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;%&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;47.9&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;%&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;45.6&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;%&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Expected life&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom;" valign="bottom"&gt;
          &lt;div style="text-align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;6 months&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom;" valign="bottom"&gt;
          &lt;div style="text-align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;6 months&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom;" valign="bottom"&gt;
          &lt;div style="text-align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;6 months&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 12pt;"&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;"&gt;Risk-Free Interest Rate.&lt;/span&gt;
    We base the risk-free interest rate assumption on observed interest rates appropriate for the term of our stock option plans or ESPP.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;"&gt;Dividend Yield.&lt;/span&gt; We
    base the dividend yield assumption on our history and expectation of dividend payouts. We have not paid dividends in the past and do not expect to in the future.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;"&gt;Volatility.&lt;/span&gt; We use
    an average of the historical stock price volatility of our stock for the Black-Scholes model. We computed the historical stock volatility based on the expected term of the awards.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;"&gt;Expected Life. &lt;/span&gt;The
    expected term of stock options we have granted represents the period of time that we expect them to be outstanding. We estimated the expected term of options we have granted based on actual and projected exercise patterns.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;"&gt;Forfeitures.&lt;/span&gt; We
    reduce stock-based compensation expense for estimated forfeitures. We estimate forfeitures at the time of grant and revise, if necessary, in subsequent periods if actual forfeitures differ from those estimates. We estimate forfeitures based on
    historical experience. &lt;/div&gt;
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&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;The following table summarizes the stock option activity under our stock plans for the year ended December 31, 2021 (in thousands, except per share and contractual life data):&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;"&gt;


  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;

        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Number&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;of Shares&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Weighted&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Average Exercise&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Price Per Share&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Average&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Remaining&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Contractual Term&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;(Years)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Aggregate&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Intrinsic&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Value&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;span style="text-indent: 0pt;"&gt;Outstanding at December 31, 2020&lt;/span&gt;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;12,439&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;54.11&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 18pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Granted&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;3,382&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;53.07&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 18pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Exercised&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(219&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;38.69&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 18pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Cancelled/forfeited/expired&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(1,513&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; padding-bottom: 2px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;54.65&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 52%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;span style="text-indent: 0pt;"&gt;Outstanding at December 31, 2021&lt;/span&gt;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;14,089&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;54.04&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;3.89&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;1,131&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 52%; padding-bottom: 4px;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;span style="text-indent: 0pt;"&gt;Exercisable at December 31, 2021&lt;/span&gt;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;9,175&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;53.65&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;2.94&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;1,067&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;
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    <us-gaap:ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsOutstandingNumber
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    <us-gaap:ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsOutstandingWeightedAverageExercisePrice
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&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;The following table summarizes the RSU activity for the year ended December 31, 2021 (in thousands, except per share data):&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;"&gt;


  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;

        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Number&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;of Shares&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Weighted Average&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Grant Date Fair&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Value Per Share&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 76%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;span style="text-indent: 0pt;"&gt;Non-vested at December 31, 2020&lt;/span&gt;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;2,374&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;58.81&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 76%;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 18pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Granted&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;1,548&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;57.69&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 76%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 18pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Vested&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(834&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;57.47&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 76%; padding-bottom: 2px;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 18pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Cancelled/forfeited&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(411&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;59.24&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 76%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;span style="text-indent: 0pt;"&gt;Non-vested at December 31, 2021&lt;/span&gt;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;2,677&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;58.51&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;
</us-gaap:ScheduleOfSharebasedCompensationRestrictedStockAndRestrictedStockUnitsActivityTableTextBlock>
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&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;The following table summarizes stock-based compensation expense for the years ended December 31, 2021, 2020 and 2019 (in thousands):&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;"&gt;


  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;

        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="10" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Year Ended December 31,&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;2021&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;2020&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;2019&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Cost of sales&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;456&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;1,991&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;438&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 64%;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Research, development and patent&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;87,522&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;115,584&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;95,348&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Selling, general and administrative&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;32,700&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;112,542&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;50,788&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 64%; padding-bottom: 4px;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Total&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;120,678&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;230,117&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;146,574&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;
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&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;"&gt;Ionis Employee Stock Options:&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;"&gt;


  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;

        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="10" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Year Ended December 31,&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;2021&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;2020&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;2019&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Risk-free interest rate&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;0.6&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;%&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;1.5&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;%&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;2.3&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;%&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 64%;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Dividend yield&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;0.0&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;%&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;0.0&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;%&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;0.0&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;%&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Volatility&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;54.0&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;%&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;58.6&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;%&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;60.3&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;%&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Expected life&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom;" valign="bottom"&gt;
          &lt;div style="text-align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;4.9 years&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom;" valign="bottom"&gt;
          &lt;div style="text-align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;4.7 years&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom;" valign="bottom"&gt;
          &lt;div style="text-align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;4.8 years&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;"&gt;Ionis Board of Director Stock Options:&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;"&gt;


  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;

        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="10" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Year Ended December 31,&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;2021&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;2020&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;2019&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Risk-free interest rate&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;1.2&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;%&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;0.5&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;%&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;1.9&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;%&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 64%;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Dividend yield&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;0.0&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;%&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;0.0&lt;/div&gt;
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          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;%&lt;/div&gt;
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    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;0.0&lt;/div&gt;
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    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;%&lt;/div&gt;
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  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Volatility&lt;/div&gt;
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    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;55.9&lt;/div&gt;
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    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;%&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;57.6&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;%&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;60.7&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;%&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Expected life&lt;/div&gt;
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    &lt;td colspan="1" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom;" valign="bottom"&gt;
          &lt;div style="text-align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;7.3 years&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom;" valign="bottom"&gt;
          &lt;div style="text-align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;6.7 years&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom;" valign="bottom"&gt;
          &lt;div style="text-align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;6.6 years&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;


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&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: left; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;"&gt;Ionis ESPP:&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;"&gt;


  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;

        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="10" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Year Ended December 31,&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;2021&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;2020&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;2019&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Risk-free interest rate&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;0.1&lt;/div&gt;
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    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;%&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;0.8&lt;/div&gt;
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    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;%&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;2.4&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;%&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 64%;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Dividend yield&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;0.0&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;%&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;0.0&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;%&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;0.0&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;%&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Volatility&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;42.4&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;%&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;47.9&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;%&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;45.6&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;%&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Expected life&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom;" valign="bottom"&gt;
          &lt;div style="text-align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;6 months&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom;" valign="bottom"&gt;
          &lt;div style="text-align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;6 months&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom;" valign="bottom"&gt;
          &lt;div style="text-align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;6 months&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;


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&lt;div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;5. Income Taxes&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Income (loss) before income taxes is comprised of (in thousands):&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;"&gt;


  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;

        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="10" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Year Ended December 31,&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;2021&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;2020&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;2019&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;(as revised*)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;(as revised*)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;United States&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(29,966&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(137,222&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;336,277&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 64%; padding-bottom: 2px;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Foreign&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;818&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;2,670&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;2,489&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 64%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Income (loss) before income taxes&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(29,148&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(134,552&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;338,766&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 12pt;"&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Our income tax expense (benefit) was as follows (in thousands):&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;"&gt;


  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;

        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="10" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Year Ended December 31,&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;2021&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;2020&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;2019&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;(as revised*)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;(as revised*)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Current:&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Federal&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(200&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(837&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;35,861&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 64%;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;State&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(690&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;3,782&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;14,329&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Foreign&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;339&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;518&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;413&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 64%;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Total current income tax expense (benefit)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(551&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;3,463&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;50,603&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 64%;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Deferred:&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Federal&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x2014;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;341,728&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;904&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 64%; padding-bottom: 2px;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;State&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x2014;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x2014;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x2014;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Total deferred income tax benefit&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x2014;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;341,728&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;904&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 64%; padding-bottom: 4px;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Total income tax expense (benefit)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(551&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;345,191&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;51,507&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 12pt;"&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Our expense (benefit) for income taxes differs from the amount computed by applying the U.S. federal
    statutory rate to income (loss) before taxes. The sources and tax effects of the differences are as follows (in thousands):&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;"&gt;


  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;

        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="22" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Year Ended December 31,&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="6" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;2021&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="6" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;2020&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="6" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;2019&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="6" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="6" style="vertical-align: bottom;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;(as revised*)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="6" style="vertical-align: bottom;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;(as revised*)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="6" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="6" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="6" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Pre-tax income (loss)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(29,148&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(134,552&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;338,766&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 28%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Statutory rate&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(6,121&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;21.0&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;%&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(28,256&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;21.0&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;%&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;71,141&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;21.0&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;%&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 28%;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;State income tax net of federal benefit&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;4,278&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(14.7&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)%&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(37,705&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;28.0&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;%&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;49,000&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;14.5&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;%&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 28%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Foreign&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;143&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(0.5&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)%&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;49&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;0.0&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;%&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;340&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;0.1&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;%&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 28%;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Net change in valuation allowance&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;2,885&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(9.9&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)%&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;460,898&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(342.5&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)%&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(37,314&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(11.0&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)%&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 28%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Loss on debt transactions&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;262&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(0.9&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)%&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x2014;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x2014;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;9,911&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;2.9&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;%&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 28%;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Impact from outside basis differences&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x2014;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x2014;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x2014;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x2014;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(16,344&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(4.8&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)%&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 28%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Tax credits&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(23,198&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;79.6&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;%&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(18,774&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;14.0&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;%&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(22,296&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(6.6&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)%&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 28%;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Deferred tax true-up&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(24&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;0.1&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;%&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(206&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;0.2&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;%&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;646&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;0.2&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;%&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 28%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Tax rate change&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;12,838&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(44.0&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)%&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(32,951&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;24.5&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;%&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;1,248&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;0.4&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;%&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 28%;" valign="bottom"&gt;
          &lt;div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Non-deductible compensation&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;5,085&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(17.4&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)%&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;7,931&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(5.9&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)%&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;3,361&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;1.0&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;%&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 28%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Other non-deductible items&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;84&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(0.3&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)%&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;193&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(0.1&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)%&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;329&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;0.1&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;%&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 28%;" valign="bottom"&gt;
          &lt;div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Stock-based compensation&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;4,720&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(16.2&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)%&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;17,435&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(13.0&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)%&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(4,837&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(1.4&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)%&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 28%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Foreign-derived intangible income benefit&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x2014;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x2014;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x2014;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x2014;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(2,071&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(0.6&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)%&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 28%;" valign="bottom"&gt;
          &lt;div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Impacts from Akcea Merger&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x2014;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x2014;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(22,032&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;16.4&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;%&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x2014;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x2014;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 28%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Other&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(1,503&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;5.1&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;%&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(1,391&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;0.9&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;%&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(1,607&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(0.6&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)%&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 28%; padding-bottom: 4px;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Effective rate&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(551&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;1.9&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;%&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;345,191&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(256.5&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)%&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;51,507&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;15.2&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;%&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 12pt;"&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Deferred income taxes reflect the net tax effects of temporary differences between the carrying amounts of assets and
    liabilities for financial reporting purposes and the amounts used for income tax purposes.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Significant components of our deferred tax assets and liabilities as of December 31, 2021 and 2020 are as follows (in thousands):&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;"&gt;


  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;

        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="6" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Year Ended December 31,&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;2021&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;2020&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;(as revised*)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Deferred Tax Assets:&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 76%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Net operating loss carryovers&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;85,600&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;83,681&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 76%;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Tax credits&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;269,538&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;245,746&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 76%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Deferred revenue&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;104,330&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;124,452&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 76%;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Stock-based compensation&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;86,611&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;80,055&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 76%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Intangible and capital assets&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;92,542&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;98,443&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 76%;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Convertible debt&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;45,681&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;22,395&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 76%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Interest expense limitation&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;6,996&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x2014;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 76%; padding-bottom: 2px;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Other&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;15,048&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;13,402&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 76%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Total deferred tax assets&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;706,346&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;668,174&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 76%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 76%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Deferred Tax Liabilities:&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 76%;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Fixed assets&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(3,303&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(3,611&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 76%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Other&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(5,270&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(5,808&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 76%;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Net deferred tax asset&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;697,773&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;658,755&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 76%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Valuation allowance&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(697,773&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(658,755&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 76%; padding-bottom: 4px;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Total net deferred tax assets and liabilities&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x2014;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x2014;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;"&gt;


  &lt;tr&gt;

    &lt;td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;*&lt;/td&gt;

    &lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;We revised our 2020 and 2019 amounts to reflect the simplified convertible instruments accounting guidance, which we adopted retrospectively. Refer to
            Note 1, &lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;"&gt;Organization and Significant Accounting Policies&lt;/span&gt;, for further information.&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;We evaluate our deferred tax assets regularly to determine whether adjustments to the valuation allowance are appropriate
    due to changes in facts or circumstances, such as changes in expected future pre-tax earnings, tax law, interactions with taxing authorities and developments in case law. In making this evaluation, we rely on our recent history of pre-tax earnings. Our
    material assumptions are our forecasts of future pre-tax earnings and the nature and timing of future deductions and income represented by the deferred tax assets and liabilities, all of which involve the exercise of significant judgment. Although we
    believe our estimates are reasonable, we are required to use significant judgment in determining the appropriate amount of valuation allowance recorded against our deferred tax assets.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Ionis and Akcea filed separate U.S. federal income tax returns from the date of Akcea&#x2019;s IPO in 2017 through October 12,
    2020, the date on which we completed the Akcea Merger. As a result of the Akcea Merger, Ionis and Akcea now file a consolidated U.S. federal income tax return, and we now assess our U.S. federal and state valuation allowance requirements on a
    consolidated basis.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;We assessed our valuation allowance requirements and recorded a valuation allowance of $341 million against all of Ionis&#x2019; U.S. federal net deferred tax assets in the fourth quarter of 2020, due to uncertainties related to our ability to realize
    the tax benefits associated with these assets. We based this determination largely on Akcea rejoining the Ionis consolidated U.S. federal tax group in the fourth quarter of 2020. Due to Akcea&#x2019;s historical and projected financial statement losses, and
    the expected negative impact this will have on Ionis&#x2019; consolidated taxable income, we are uncertain if we will generate sufficient consolidated pre-tax income in future periods to realize the Ionis deferred tax benefits. We also expect that Ionis&#x2019;
    pre-tax income in future periods will be lower due to significant investments in research and development associated with our pipeline of wholly owned medicines. We now maintain a valuation allowance against all our consolidated U.S. federal and state
    net deferred tax assets.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Our valuation allowance increased by $39 million from December 31, 2020 to December 31, 2021. The increase was primarily related to increases in our deferred tax assets for tax credits and convertible debt offset against a decrease in our
    deferred tax asset for deferred revenue.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;At December 31, 2021,
    we had federal and state, primarily California, tax net operating loss carryforwards of $271.5 million and $333.8 million, respectively. Our federal tax loss carryforwards are available indefinitely. Our California tax loss carryforwards will begin to expire in 2031. At December 31, 2021, we also had federal and California research and development tax credit carryforwards of $225.5 million and $99.7 million, respectively. Our federal research and development tax
    credit carryforwards will begin to expire in 2034. Our California research and development tax credit carryforwards are available indefinitely.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Utilization of the net operating loss and tax credit carryforwards may be subject to an annual limitation due to the ownership change
    limitations provided by the Internal Revenue Code of 1986, as amended, and similar state provisions. The annual limitation may result in the expiration of net operating losses and credits before utilization.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;We analyze filing positions in all U.S. federal, state and foreign jurisdictions where we file income tax returns, and all open tax years
    in these jurisdictions to determine if we have any uncertain tax positions on any of our income tax returns. We recognize the impact of an uncertain tax position on an income tax return at the largest amount that the relevant taxing authority is
    more-likely-than not to sustain upon audit. We do not recognize uncertain income tax positions if they have less than 50 percent likelihood of the applicable tax authority sustaining our position.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;The following table summarizes our gross unrecognized tax benefits &lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt;(in thousands):&lt;/span&gt;&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;"&gt;


  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;

        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="10" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Year Ended December 31,&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;2021&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;2020&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;2019&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Beginning balance of unrecognized tax benefits&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;54,163&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;69,784&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;68,301&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 64%;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Decrease for prior period tax positions&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(695&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(24,154&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(867&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Increase for prior period tax positions&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;263&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;7,023&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;736&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 64%; padding-bottom: 2px;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Increase for current period tax positions&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;1,354&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;1,510&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;1,614&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 64%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Ending balance of unrecognized tax benefits&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;55,085&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;54,163&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;69,784&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 12pt;"&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Included in the balance of unrecognized tax benefits at December 31, 2021, 2020 and 2019 was $6.2 million, $6.4 million and $0.4 million respectively, that if we recognized, could impact our effective tax rate, subject to our remaining valuation allowance.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;We do not foresee any material changes to our gross unrecognized tax benefits within the next twelve months.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;We recognize interest and/or penalties related to income tax matters in income tax expense. During the year ended December
    31, 2021 and 2020, we recognized $0.5
    million and $0.3 million, respectively, of accrued interest and penalties related to gross unrecognized tax benefits. We did not record any accrued interest and penalties for the years ended December 31, 2019.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;We are subject to taxation in the U.S. and various state and foreign jurisdictions. Our tax years for 1999 through 2020
    are subject to examination by the U.S. federal, state and foreign tax authorities.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt;We do not provide for a U.S. income tax
      liability and foreign withholding taxes on undistributed foreign earnings of our foreign subsidiaries as we consider those earnings to be permanently reinvested. It is not practicable for us to calculate the amount of unrecognized deferred tax
      liabilities associated with these earnings&lt;/span&gt;.&lt;/div&gt;
</us-gaap:IncomeTaxDisclosureTextBlock>
    <us-gaap:ScheduleOfIncomeBeforeIncomeTaxDomesticAndForeignTableTextBlock
      contextRef="c20210101to20211231"
      id="Text_7281bd0eb54443b994694c659a6a8f66">
&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Income (loss) before income taxes is comprised of (in thousands):&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;"&gt;


  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;

        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="10" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Year Ended December 31,&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;2021&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;2020&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;2019&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;(as revised*)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;(as revised*)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;United States&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(29,966&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(137,222&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;336,277&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 64%; padding-bottom: 2px;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Foreign&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;818&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;2,670&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;2,489&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 64%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Income (loss) before income taxes&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(29,148&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(134,552&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;338,766&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;
</us-gaap:ScheduleOfIncomeBeforeIncomeTaxDomesticAndForeignTableTextBlock>
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      contextRef="c20210101to20211231"
      decimals="-3"
      id="Fact_1154d9477ea5403c89bcaba61b591e79"
      unitRef="U001">-29966000</us-gaap:IncomeLossFromContinuingOperationsBeforeIncomeTaxesDomestic>
    <us-gaap:IncomeLossFromContinuingOperationsBeforeIncomeTaxesDomestic
      contextRef="c20200101to20201231"
      decimals="-3"
      id="Fact_74d3abad4f744e0aa68801acc3a6ed6b"
      unitRef="U001">-137222000</us-gaap:IncomeLossFromContinuingOperationsBeforeIncomeTaxesDomestic>
    <us-gaap:IncomeLossFromContinuingOperationsBeforeIncomeTaxesDomestic
      contextRef="c20190101to20191231"
      decimals="-3"
      id="Fact_8977ca2c8272434794efd8259c5f22b7"
      unitRef="U001">336277000</us-gaap:IncomeLossFromContinuingOperationsBeforeIncomeTaxesDomestic>
    <us-gaap:IncomeLossFromContinuingOperationsBeforeIncomeTaxesForeign
      contextRef="c20210101to20211231"
      decimals="-3"
      id="Fact_70ca994a31be49619caefe5e71de1587"
      unitRef="U001">818000</us-gaap:IncomeLossFromContinuingOperationsBeforeIncomeTaxesForeign>
    <us-gaap:IncomeLossFromContinuingOperationsBeforeIncomeTaxesForeign
      contextRef="c20200101to20201231"
      decimals="-3"
      id="Fact_8425f2adaf6948cdb4db61cdf7def1fc"
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      contextRef="c20190101to20191231"
      decimals="-3"
      id="Fact_15eeca6092a14a5c9b839eb716ea8ae4"
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    <us-gaap:IncomeLossFromContinuingOperationsBeforeIncomeTaxesExtraordinaryItemsNoncontrollingInterest
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      decimals="-3"
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      decimals="-3"
      id="Fact_9fd05fd89e164623ad7d51c758cf30c6"
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    <us-gaap:IncomeLossFromContinuingOperationsBeforeIncomeTaxesExtraordinaryItemsNoncontrollingInterest
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      decimals="-3"
      id="Fact_225bd758b4d047a9b56b2a1266e8768e"
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    <us-gaap:ScheduleOfComponentsOfIncomeTaxExpenseBenefitTableTextBlock
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      id="Text_d123dff19b9e4823b03cc17efdea0755">
&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Our income tax expense (benefit) was as follows (in thousands):&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;"&gt;


  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;

        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="10" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Year Ended December 31,&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;2021&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;2020&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;2019&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;(as revised*)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;(as revised*)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Current:&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Federal&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(200&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(837&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;35,861&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 64%;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;State&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(690&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;3,782&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;14,329&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Foreign&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;339&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;518&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;413&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 64%;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Total current income tax expense (benefit)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(551&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;3,463&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;50,603&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 64%;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Deferred:&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Federal&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x2014;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;341,728&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;904&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 64%; padding-bottom: 2px;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;State&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x2014;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x2014;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x2014;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Total deferred income tax benefit&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x2014;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;341,728&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;904&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 64%; padding-bottom: 4px;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Total income tax expense (benefit)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(551&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;345,191&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;51,507&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;
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      decimals="-3"
      id="Fact_72e6d39ff1da4d90b52e886f5e5ff672"
      unitRef="U001">51507000</us-gaap:IncomeTaxExpenseBenefit>
    <us-gaap:ScheduleOfEffectiveIncomeTaxRateReconciliationTableTextBlock
      contextRef="c20210101to20211231"
      id="Text_51a6178b5d104096a200807a70958787">
&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Our expense (benefit) for income taxes differs from the amount computed by applying the U.S. federal
    statutory rate to income (loss) before taxes. The sources and tax effects of the differences are as follows (in thousands):&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;"&gt;


  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;

        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="22" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Year Ended December 31,&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="6" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;2021&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="6" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;2020&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="6" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;2019&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="6" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="6" style="vertical-align: bottom;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;(as revised*)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="6" style="vertical-align: bottom;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;(as revised*)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="6" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="6" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="6" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Pre-tax income (loss)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(29,148&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(134,552&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;338,766&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 28%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Statutory rate&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(6,121&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;21.0&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;%&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(28,256&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;21.0&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;%&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;71,141&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;21.0&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;%&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 28%;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;State income tax net of federal benefit&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;4,278&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(14.7&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)%&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(37,705&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;28.0&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;%&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;49,000&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;14.5&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;%&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 28%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Foreign&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;143&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(0.5&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)%&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;49&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;0.0&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;%&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;340&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;0.1&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;%&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 28%;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Net change in valuation allowance&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;2,885&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(9.9&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)%&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;460,898&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(342.5&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)%&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(37,314&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(11.0&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)%&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 28%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Loss on debt transactions&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;262&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(0.9&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)%&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x2014;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x2014;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;9,911&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;2.9&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;%&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 28%;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Impact from outside basis differences&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x2014;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x2014;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x2014;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x2014;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(16,344&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(4.8&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)%&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 28%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Tax credits&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(23,198&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;79.6&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;%&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(18,774&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;14.0&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;%&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(22,296&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(6.6&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)%&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 28%;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Deferred tax true-up&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(24&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;0.1&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;%&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(206&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;0.2&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;%&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;646&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;0.2&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;%&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 28%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Tax rate change&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;12,838&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(44.0&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)%&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(32,951&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;24.5&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;%&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;1,248&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;0.4&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;%&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 28%;" valign="bottom"&gt;
          &lt;div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Non-deductible compensation&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;5,085&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(17.4&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)%&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;7,931&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(5.9&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)%&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;3,361&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;1.0&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;%&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 28%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Other non-deductible items&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;84&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(0.3&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)%&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;193&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(0.1&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)%&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;329&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;0.1&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;%&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 28%;" valign="bottom"&gt;
          &lt;div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Stock-based compensation&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;4,720&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(16.2&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)%&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;17,435&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(13.0&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)%&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(4,837&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(1.4&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)%&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 28%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Foreign-derived intangible income benefit&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x2014;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x2014;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x2014;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x2014;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(2,071&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(0.6&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)%&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 28%;" valign="bottom"&gt;
          &lt;div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Impacts from Akcea Merger&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x2014;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x2014;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(22,032&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;16.4&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;%&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x2014;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x2014;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 28%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Other&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(1,503&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;5.1&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;%&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(1,391&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;0.9&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;%&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(1,607&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(0.6&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)%&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 28%; padding-bottom: 4px;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Effective rate&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(551&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;1.9&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;%&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" valign="bottom"&gt;
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&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Significant components of our deferred tax assets and liabilities as of December 31, 2021 and 2020 are as follows (in thousands):&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;"&gt;


  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;

        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="6" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Year Ended December 31,&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;2021&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;2020&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;(as revised*)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Deferred Tax Assets:&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 76%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Net operating loss carryovers&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;85,600&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;83,681&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 76%;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Tax credits&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;269,538&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;245,746&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 76%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Deferred revenue&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;104,330&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;124,452&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 76%;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Stock-based compensation&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;86,611&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;80,055&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 76%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Intangible and capital assets&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;92,542&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;98,443&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 76%;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Convertible debt&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;45,681&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;22,395&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 76%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Interest expense limitation&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;6,996&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x2014;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 76%; padding-bottom: 2px;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Other&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;15,048&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;13,402&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 76%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Total deferred tax assets&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;706,346&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;668,174&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 76%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 76%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Deferred Tax Liabilities:&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 76%;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Fixed assets&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(3,303&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(3,611&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 76%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Other&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(5,270&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(5,808&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 76%;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Net deferred tax asset&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;697,773&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;658,755&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 76%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Valuation allowance&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(697,773&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(658,755&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 76%; padding-bottom: 4px;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Total net deferred tax assets and liabilities&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x2014;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x2014;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;"&gt;


  &lt;tr&gt;

    &lt;td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;*&lt;/td&gt;

    &lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;We revised our 2020 and 2019 amounts to reflect the simplified convertible instruments accounting guidance, which we adopted retrospectively. Refer to
            Note 1, &lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;"&gt;Organization and Significant Accounting Policies&lt;/span&gt;, for further information.&lt;/div&gt;
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&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;The following table summarizes our gross unrecognized tax benefits &lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt;(in thousands):&lt;/span&gt;&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;"&gt;


  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;

        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="10" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Year Ended December 31,&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;2021&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;2020&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;2019&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Beginning balance of unrecognized tax benefits&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;54,163&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;69,784&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;68,301&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 64%;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Decrease for prior period tax positions&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(695&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(24,154&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(867&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Increase for prior period tax positions&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;263&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;7,023&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;736&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 64%; padding-bottom: 2px;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Increase for current period tax positions&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;1,354&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;1,510&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;1,614&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 64%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Ending balance of unrecognized tax benefits&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;55,085&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;54,163&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;69,784&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;


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&lt;div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;6. Collaborative Arrangements and Licensing Agreements&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Strategic Partnership&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;"&gt;Biogen&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;We have several strategic collaborations with Biogen focused on using antisense technology to advance the treatment of
    neurological disorders. These collaborations combine our expertise in creating antisense medicines with Biogen&#x2019;s expertise in developing therapies for neurological disorders. We developed and licensed to Biogen SPINRAZA, our approved medicine to treat
    people with spinal muscular atrophy, or SMA. We and Biogen are currently developing nine investigational medicines to treat neurodegenerative
    diseases under these collaborations, including medicines in development to treat people with ALS, SMA, AS, Alzheimer&#x2019;s disease&lt;sub&gt;&#160;&lt;/sub&gt;and Parkinson&#x2019;s disease. In addition to these medicines, our collaborations with Biogen include a substantial
    research pipeline that addresses a broad range of neurological diseases. From inception through December 2021, we have received more than $3.1 billion from our Biogen collaborations.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: left; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic; font-weight: bold;"&gt;Spinal Muscular Atrophy Collaborations&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: left; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;"&gt;SPINRAZA&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt;In January 2012, we entered into a
      collaboration agreement with Biogen to develop and commercialize SPINRAZA, an RNA-targeted therapy for the treatment of SMA.&lt;/span&gt;&#160;&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt;From inception through
      December 2021, we earned more than $&lt;/span&gt;1.6&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt;
      billion in total revenue under our SPINRAZA collaboration, including nearly $&lt;/span&gt;1.2&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt; billion in revenue from SPINRAZA royalties and more than $&lt;/span&gt;435&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt; million in R&amp;amp;D revenue. We are receiving tiered royalties ranging from &lt;/span&gt;11 percent&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt; to &lt;/span&gt;15 percent&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt; on net sales of SPINRAZA. We have exclusively in-licensed patents related to SPINRAZA from Cold Spring Harbor Laboratory and the University of Massachusetts. We pay Cold Spring Harbor
      Laboratory and the University of Massachusetts a low single digit royalty on net sales of SPINRAZA. Biogen is responsible for all global development, regulatory and commercialization activities and costs for SPINRAZA. We completed our performance
      obligations under our collaboration in 2016&lt;/span&gt;.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;"&gt;New antisense medicines for the treatment of SMA&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt;In December 2017, we entered into a
      collaboration agreement with Biogen to &lt;/span&gt;identify &lt;span style="background-color: #FBFBFB; font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;new antisense medicines for the treatment of SMA&lt;/span&gt;&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt;. &lt;/span&gt;&lt;span style="background-color: #FBFBFB; font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt;Biogen has the option to license therapies arising out of
      this collaboration following the completion of preclinical studies. Upon licensing, Biogen &lt;/span&gt;&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt;will be responsible for global development, regulatory and
      commercialization activities and costs for such therapies&lt;/span&gt;&lt;span style="background-color: #FBFBFB; font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt;. Under the collaboration agreement, we received a &lt;/span&gt;$25 million&lt;span style="background-color: #FBFBFB; font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt; upfront payment in the &lt;/span&gt;&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt;fourth&lt;/span&gt;&lt;span style="background-color: #FBFBFB; font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt; quarter of &lt;/span&gt;&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt;2017&lt;/span&gt;&lt;span style="background-color: #FBFBFB; font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt;. &lt;/span&gt;&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt;In December 2021, we earned a $&lt;/span&gt;60&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt; million license fee payment when Biogen exercised its option to license ION306. &lt;/span&gt;&lt;span style="background-color: #FBFBFB; font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt;We will receive development and regulatory milestone payments from Biogen if new medicines advance towards marketing approval. &lt;/span&gt;&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt;In total over the term of our collaboration, we are eligible to receive up to $&lt;/span&gt;1.2&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt; billion in license fees, milestone payments and other payments, including up to $&lt;/span&gt;555&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt; million in payments if Biogen advances ION306, which includes up to $&lt;/span&gt;45&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt; million for the achievement of development milestones, up to $&lt;/span&gt;110&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt; million for the achievement of regulatory milestones and up
      to $&lt;/span&gt;400&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt; million for the achievement of
      sales milestones. In addition, we are eligible to receive tiered royalties &lt;/span&gt;&lt;span style="background-color: #FBFBFB; font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt;from the mid-teens to &lt;/span&gt;&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt;mid-&lt;/span&gt;20 percent&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt; range &lt;/span&gt;&lt;span style="background-color: #FBFBFB; font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt;on net sales.&lt;/span&gt;&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt; We will achieve the next payment of up to $&lt;/span&gt;45&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt; millionfor the initiation of a Phase 3 trial under this collaboration. &lt;/span&gt;&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;At the commencement of this collaboration, we identified one performance obligation, which was to perform R&amp;amp;D services for Biogen. We determined the transaction price to be the $25 million upfront payment we received when we entered into the collaboration. We allocated the transaction price to our single performance obligation. In the fourth quarter of 2019, we
    completed our R&amp;amp;D services performance obligation under this collaboration. We recognized revenue as we performed services based on our effort to satisfy our performance obligation relative to the total effort expected to satisfy our performance
    obligation. We completed our performance obligation earlier than we previously estimated, as a result, we recognized $8.3 million of additional
    revenue in the fourth quarter of 2019.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;In the fourth quarter of 2021, we identified another performance obligation upon Biogen&#x2019;s license of ION306 because the license we granted
    to Biogen is distinct from our other performance obligations. We recognized the $60 million license fee for ION306 as revenue at that time
    because Biogen had full use of the license without any continuing involvement from us. Additionally, we did not have any further performance obligations related to the license after we delivered it to Biogen. Biogen is solely responsible for the costs
    and expenses related to the development, manufacturing and potential future commercialization of ION306 following the option exercise. We do not have any remaining performance obligations under this collaboration.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic; font-weight: bold;"&gt;Neurology Collaborations&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: left; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;"&gt;2018 Strategic Neurology&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt;In April 2018, we and Biogen entered into a
      strategic collaboration to develop novel antisense medicines for a broad range of neurological diseases and entered into a SPA. As part of the collaboration, Biogen gained exclusive rights to the use of our antisense technology to develop therapies
      for these diseases for &lt;/span&gt;10&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt; years. We are
      responsible for the identification of antisense drug candidates based on selected medicines&lt;/span&gt;. Biogen is responsible for conducting IND-enabling toxicology studies for the selected medicine. &lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt;Biogen will have the option to license the selected medicine &lt;/span&gt;after it completes the IND-enabling toxicology study. &lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt;If Biogen exercises its option to license a medicine, it will assume global development, regulatory and commercialization responsibilities and costs for that medicine.&lt;/span&gt;&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;span style="background-color: #FBFBFB; font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;In the &lt;/span&gt;second&lt;span style="background-color: #FBFBFB; font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt; quarter of &lt;/span&gt;2018&lt;span style="background-color: #FBFBFB; font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;, we received &lt;/span&gt;$1 billion from Biogen, comprised of $625 million
    to purchase our stock at an approximately 25 percent cash premium and $375 million in an upfront payment. &lt;span style="background-color: #FBFBFB; font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;We are eligible to receive up to $&lt;/span&gt;270&lt;span style="background-color: #FBFBFB; font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt; million in milestone payments for each medicine
      that achieves marketing approval. &lt;/span&gt;In addition, we are eligible to receive tiered royalties &lt;span style="background-color: #FBFBFB; font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;up to the &lt;/span&gt;20 percent range &lt;span style="background-color: #FBFBFB; font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;on net sales.&lt;/span&gt;&#160;&lt;span style="background-color: #FBFBFB; font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;W&lt;/span&gt;e are currently advancing nine
    programs under this collaboration and from inception through December 2021, we have received nearly $1.1 billion in payments under this
    collaboration. We will achieve the next payment of $7.5 million if Biogen designates or advances another program&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;under this collaboration. &lt;/span&gt;&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt;At the commencement of this collaboration, &lt;/span&gt;we
    identified one performance obligation, which was to perform R&amp;amp;D services for Biogen.&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt; We determined our transaction price to be $&lt;/span&gt;552&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt; million, comprised of $&lt;/span&gt;375&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt; million from the upfront payment and $&lt;/span&gt;177&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt; million for the premium paid by Biogen for its purchase of our common stock.&lt;/span&gt; We determined the fair value of the premium we received by using the stated premium in the SPA and applying a lack of marketability
    discount. We included a lack of marketability discount in our valuation of the premium because Biogen received restricted shares of our common stock. We allocated the transaction price to our single performance obligation.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;From inception through December 2021, we have included $616 million &lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt;in payments in the transaction price for our R&amp;amp;D services performance obligation
      under this collaboration, including $&lt;/span&gt;23&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt;
      million of milestone payments we achieved in 2021 and $&lt;/span&gt;11&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt; million of milestone payments we achieved in 2020. These milestone payments did not create new performance obligations because they are part of our original R&amp;amp;D services performance obligation. Therefore, we included these
      amounts in our transaction price for our R&amp;amp;D services performance obligation in the period we achieved the milestone payment. We are recognizing revenue for our R&amp;amp;D services performance obligation as we perform services based on our effort to
      satisfy our performance obligation relative to our total effort expected to satisfy our performance obligation. We currently estimate we will satisfy our performance obligation at the end of the contractual term in June 2028.&lt;/span&gt;&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: left; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;"&gt;2013 Strategic Neurology&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;In September 2013, we and Biogen entered into a long-term strategic relationship focused on applying antisense technology
    to advance the treatment of neurodegenerative diseases. As part of the collaboration, Biogen gained exclusive rights to the use of our antisense technology to develop therapies for neurological diseases and has the option to license medicines resulting
    from this collaboration. We will usually be responsible for drug discovery and early development of antisense medicines and Biogen has the option to license antisense medicines after Phase 2 proof-of-concept. In October 2016, we expanded our
    collaboration to include additional research activities we will perform. If Biogen exercises its option to license a medicine, it will assume global development, regulatory and commercialization responsibilities and costs for that medicine. We are
    currently advancing six investigational medicines in development under this collaboration, including &lt;span style="-sec-ix-hidden:Fact_864d03b225ca4f548971b12e6b3ad3d0"&gt;a&lt;/span&gt; medicine for Parkinson&#x2019;s disease (ION859), three medicines for ALS
    (tofersen, IONIS-C9&lt;sub&gt;Rx&lt;/sub&gt; and ION541), &lt;span style="-sec-ix-hidden:Fact_7b05dc571fcb46f8bbbe0db51a44d460"&gt;a&lt;/span&gt; medicine for multiple system atrophy (ION464) and &lt;span style="-sec-ix-hidden:Fact_33617a5e2de04e8688f1a06dd038ea29"&gt;a&lt;/span&gt; medicine for an undisclosed target. In the fourth quarter of 2018, Biogen exercised its option to license our most advanced ALS medicine, tofersen, our medicine in Phase 3
    development for SOD1 ALS. As a result, Biogen is now responsible for global development, regulatory and commercialization activities and costs for tofersen.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Under the terms of the agreement, we received an upfront payment of $100 million and are eligible to receive milestone payments, license fees and royalty payments for all medicines developed under this collaboration, with the specific amounts dependent upon the
    modality of the molecule advanced by Biogen. For each antisense molecule that is chosen for drug discovery and development under this collaboration, we are eligible to receive up to approximately $260 million in a license fee and milestone payments per program. The $260 million per
    program consists of approximately $60 million in development milestones, including amounts related to the cost of clinical trials, and up to $130 million in milestone payments if Biogen achieves pre-specified regulatory milestones. In addition, we are eligible to receive tiered royalties up to the
    mid-teens on net sales from any antisense medicines developed under this collaboration. From inception through December 2021, we have received over $280
    million in upfront fees, milestone payments and other payments under this collaboration. We will achieve the next payment of up to $70 million if
    Biogen licenses a medicine under this collaboration.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;At the commencement of our 2013 strategic neurology collaboration, we identified one performance obligation, which was to perform R&amp;amp;D services for Biogen. At inception, we determined the transaction price to be the $100 million upfront payment we received and allocated it to our single performance obligation. As we achieve milestone payments for our R&amp;amp;D services, we
    include these amounts in our transaction price for our R&amp;amp;D services performance obligation. We recognized revenue for our R&amp;amp;D services performance obligation based on our effort to satisfy our performance obligation relative to our total effort
    expected to satisfy our performance obligation&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt;. &lt;/span&gt;In the third quarter of 2019, we updated our estimate of the total effort we expect to expend to
    satisfy our performance obligation. As a result, we recorded a cumulative catch up adjustment of $16.5 million to decrease revenue in the third
    quarter of 2019. During 2020, we completed our remaining&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt; research and development services and recognized the remaining revenue related to this performance
      obligation. &lt;/span&gt;From inception through the completion of our R&amp;amp;D services performance obligation in 2020, we included $145 million in
    total payments in the transaction price for our R&amp;amp;D services performance obligation.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt;Under this collaboration, we have also
      generated additional payments that we concluded were not part of our R&amp;amp;D services performance obligation. We recognized each of these payments in full in the respective quarter we generated the payment because we did not have any performance
      obligations for the respective payment. For example, in the second quarter of 2021, we earned a &lt;/span&gt;$10&#160;&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt;million milestone payment when Biogen advanced ION541, which we recognized in full because we did not have any performance obligations related to this milestone payment.&lt;/span&gt;&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;"&gt;2012 Neurology&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 35.3pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;In December 2012, we and Biogen entered into a collaboration agreement to develop and commercialize novel antisense
    medicines to treat neurodegenerative diseases. We are responsible for the development of each of the medicines through the completion of the initial Phase 2 clinical study for such medicine. Biogen has the option to license a medicine from each of the
    programs through the completion of the first Phase 2 study for each program. Under this collaboration, we are currently advancing IONIS-MAPT&lt;sub&gt;Rx&lt;/sub&gt; for Alzheimer&#x2019;s disease and ION582 for AS. If Biogen exercises its option to license a medicine,
    it will assume global development, regulatory and commercialization responsibilities and costs for that medicine. In the fourth quarter of 2019, Biogen exercised its option to license IONIS-MAPT&lt;sub&gt;Rx&lt;/sub&gt;. We are responsible for completing the Phase
    1/2 in study patients with mild AD and a one-year long-term extension study. Biogen will have responsibility for global development, regulatory
    and commercialization activities and costs for IONIS-MAPT&lt;sub&gt;Rx&lt;/sub&gt;.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt;Under the terms of the agreement, we received
      an upfront payment of $&lt;/span&gt;30&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt; million. Over the
      term of the collaboration, we are eligible to receive up to $&lt;/span&gt;210&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt; million in a license fee and milestone payments per program, plus a mark-up on the cost estimate of the Phase 1 and 2 studies. The $&lt;/span&gt;210&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt; million per program consists of up to $&lt;/span&gt;10&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt; million in development milestone payments, plus a mark-up on the cost estimate of the Phase 1 and
      2 studies and up to $&lt;/span&gt;130&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt; million in
      milestone payments if Biogen achieves pre-specified regulatory milestones. In addition, we are eligible to receive tiered royalties up to the mid-teens on net sales of any medicines resulting from each of the &lt;/span&gt;three&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt; programs. From inception through December 2021, we have
      received $&lt;/span&gt;155&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt; million in payments under
      this collaboration, including $&lt;/span&gt;19.5&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt; million
      we received from Biogen for achieving milestones for advancing &lt;/span&gt;IONIS-MAPT&lt;sub&gt;Rx&lt;/sub&gt;&lt;sub style="color: #000000;"&gt;&#160;&lt;/sub&gt;&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt;during 2020. We will
      achieve the next payment of $&lt;/span&gt;25&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt;&#160;&lt;/span&gt;million
    if Biogen advances a medicine under this collaboration.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Under our collaboration, we determined we had a performance obligation to perform R&amp;amp;D services. We allocated $40 million in total payments to the transaction price for our R&amp;amp;D services performance obligation. In the third quarter of 2019, we completed our
    R&amp;amp;D services performance obligation when we designated a development candidate and Biogen accepted the development candidate. Biogen&#x2019;s decision to accept the development candidate was not within our control. We were recognizing revenue as we
    performed services based on our effort to satisfy our performance obligation relative to the total effort expected to satisfy our performance obligation. Because Biogen accepted the development candidate earlier than when we were previously estimating,
    we recognized $6.3 million of accelerated revenue in the third quarter of 2019.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;When we commenced development for IONIS-MAPT&lt;sub&gt;Rx&lt;/sub&gt; we identified our development work as a separate performance obligation. We are
    recognizing our IONIS-MAPT&lt;sub&gt;Rx&lt;/sub&gt; development performance obligation based on the percentage of completion. From inception through December 2021, we have included $57 million in the transaction price for our IONIS-MAPT&lt;sub&gt;Rx&lt;/sub&gt; development performance obligation, including $19.5 million milestone payments we earned from Biogen in 2020 when we advanced IONIS-MAPT&lt;sub&gt;Rx&lt;/sub&gt;. We currently estimate we will satisfy our performance obligation in 2022.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;In the fourth quarter of 2019, we identified another performance obligation upon Biogen&#x2019;s license of IONIS-MAPT&lt;sub&gt;Rx&lt;/sub&gt; because the
    license we granted to Biogen is distinct from our other performance obligations. We recognized the $45 million license fee for IONIS-MAPT&lt;sub&gt;Rx&lt;/sub&gt;
    as revenue at that time because Biogen had full use of the license without any continuing involvement from us. Additionally, we did not have any further performance obligations related to the license after we delivered it to Biogen.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;In the fourth quarter of 2021, we &lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt;earned a $&lt;/span&gt;10&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt; million milestone payment when Biogen advanced ION582, which
      we recognized in full because we did not have any performance obligations related to this milestone payment.&lt;/span&gt;&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;During the years ended December 31, 2021, 2020 and 2019, we earned the following revenue from our relationship with Biogen (in millions, except percentage amounts):&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;"&gt;


  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;

        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="10" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Year Ended December 31,&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;2021&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;2020&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;2019&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -27pt; margin-left: 27pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;SPINRAZA royalties (commercial revenue)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;267.8&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;286.6&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;293.0&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 64%; padding-bottom: 2px;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;R&amp;amp;D revenue&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;161.0&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;122.0&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;180.6&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: left; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Total revenue from our relationship with Biogen&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;428.8&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;408.6&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;473.6&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 64%;" valign="bottom"&gt;
          &lt;div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Percentage of total revenue&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;53&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;%&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;56&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;%&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;42&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;%&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 12pt;"&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt;Our &lt;/span&gt;consolidated balance sheet at
    December 31&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt;, &lt;/span&gt;2021&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt; and &lt;/span&gt;2020&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt; included deferred revenue of $&lt;/span&gt;407.5&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt; million and $&lt;/span&gt;465.8&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt; million, respectively, related to our relationship with Biogen.&lt;/span&gt;&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Joint Development and Commercialization Arrangement&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;"&gt;AstraZeneca&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;"&gt;Eplontersen Collaboration&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;In December 2021, we entered into a joint development and commercialization agreement with AstraZeneca to develop and
    commercialize eplontersen for the treatment of ATTR. We are jointly developing and preparing to commercialize eplontersen with AstraZeneca in the U.S. We granted AstraZeneca exclusive rights to commercialize eplontersen outside the U.S., except certain
    countries in Latin America. Under the terms of the agreement, we received a $200 million upfront payment. We are eligible to receive up to $485 million in development and approval milestones, and up to $2.9
    billion in sales-related milestone payments. The agreement also includes territory-specific development, commercial and medical affairs cost-sharing provisions. In addition, we are eligible to receive up to mid-20 percent royalties for sales in the U.S. and tiered royalties up to the high teens for sales outside the U.S.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;We evaluated our eplontersen collaboration under ASC 808 and identified four material components: (i) the license we granted to AstraZeneca in 2021, (ii) the co-development activities that we and AstraZeneca will perform, (iii) the co-commercialization
    activities that we and AstraZeneca will perform and (iv) the co-medical affairs activities that we and AstraZeneca will perform.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;We determined that we had a vendor-customer relationship within the scope of ASC 606 for the license we granted to
    AstraZeneca and as a result we had one performance obligation.&#160; For our sole performance obligation, we determined the transaction price was the
    $200 million upfront payment we received. We recognized the upfront payment in full in 2021 because we did not have any remaining performance
    obligations after we delivered the license to AstraZeneca.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;We also concluded that the co-development activities, the co-commercialization activities and the co-medical affairs
    activities are within the scope of ASC 808 because we and AstraZeneca are active participants exposed to the risks and benefits of the activities under the collaboration.&#160; AstraZeneca will pay 55 percent of the costs associated with the ongoing global Phase 3 development program. As we will continue to lead the Phase 3 development program, we will recognize as revenue the 55 percent of cost-share funding AstraZeneca is responsible for in the same period we incur the related development expenses. As AstraZeneca is responsible
    for the majority of the commercial and medical affairs costs in the U.S. and all costs associated with bringing eplontersen to market outside the U.S., we will recognize cost-share funding we receive from AstraZeneca related to these activities as a
    reduction of our commercial and medical affairs expenses.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;We will achieve the next payment of up to $50 million upon the first regulatory approval under this collaboration. Through December 2021, we have generated $200 million in payments under this collaboration.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Research and Development Partners&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;"&gt;AstraZeneca&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;In addition to our collaboration for eplontersen, we have two other collaborations with AstraZeneca. One is focused on the treatment of
    cardiovascular, renal and metabolic diseases and the &lt;span style="-sec-ix-hidden:Fact_e7c38e1898fc4f72b5cb9e5bb0749c53"&gt;other&lt;/span&gt; is focused on the treatment of oncology diseases. We and AstraZeneca are currently
    developing six medicines under these collaborations, including medicines in development to treat people with ATTR amyloidosis, cardiovascular
    disease, a genetically associated form of kidney disease, &lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;NASH and cancer&lt;/span&gt;. From inception through December 2021, we have received more than $386 million from our AstraZeneca research and
    development collaborations.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;"&gt;Cardiovascular, Renal and Metabolic Diseases Collaboration&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;In July 2015, we and AstraZeneca formed a collaboration to discover and develop antisense therapies for treating
    cardiovascular, renal and metabolic diseases. Under our collaboration, AstraZeneca has licensed five medicines from us. AstraZeneca is
    responsible for global development, regulatory and commercialization activities and costs for each of the medicines it has licensed from us.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Under the terms of the agreement, we received a $65 million upfront payment. We are eligible to receive license fees and milestone payments of up to more than $5.5 billion as medicines under this collaboration advance, including up to $1.1 billion
    for the achievement of development milestones, up to $2.9 billion for regulatory milestones and up to $1.5 billion for commercial milestones. In addition, we are eligible to receive tiered royalties up to the low teens on net sales from any product that AstraZeneca successfully
    commercializes under this collaboration agreement. We will achieve the next payment of $10 million under this collaboration if AstraZeneca
    advances a medicine under this collaboration&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;.&lt;/span&gt; From inception through December 2021, we have received over $282 million in an upfront fee, license fees, milestone payments, and other payments under this collaboration, including $30 million we earned in 2021 when AstraZeneca licensed a target for a metabolic disease and $10
    million we earned in 2021 when AstraZeneca advanced a target for a metabolic disease.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;At the commencement of this collaboration, we identified one performance obligation, which was to perform R&amp;amp;D services for AstraZeneca. We determined the transaction price to be the $65 million upfront payment we received and we allocated it to our single performance obligation. We recognized revenue for our R&amp;amp;D services performance obligation as we performed services
    based on our effort to satisfy this performance obligation relative to our total effort expected to satisfy our performance obligation. We&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt; completed our
      performance obligation in&lt;/span&gt; the fourth quarter of 2021. As we achieve milestone payments for our R&amp;amp;D services, we include these amounts in our transaction price for our R&amp;amp;D services performance obligation. From inception through December&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt; 2021&lt;/span&gt;, we have included $90 million in payments
    in the transaction price for our R&amp;amp;D services performance obligation.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Under this collaboration, we have also generated additional payments that we concluded were not part of our R&amp;amp;D
    services performance obligation. We recognized each of these payments in full in the respective quarter we generated the payment because the payments were distinct and we did not have any performance obligations for the respective payment. For example,
    in the fourth quarter of 2021, we earned a $30 million license fee when AstraZeneca licensed a target for a metabolic disease. We recognized the
    license fee as revenue at that time because AstraZeneca had full use of the license without any continuing involvement from us. Additionally, we did not have any further performance obligations related to the license after we delivered it to
    AstraZeneca.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: left; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;"&gt;Oncology Collaboration&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;In December 2012, we entered into a collaboration agreement with AstraZeneca to discover and develop antisense medicines
    to treat cancer. We and AstraZeneca also established an oncology research program. In 2020, AstraZeneca licensed ION736, an investigational medicine in development targeting FOXP3 for the treatment of cancer. AstraZeneca is responsible for global
    development, regulatory and commercialization activities and costs for ION736.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt;Under the terms of this agreement, we
      received $&lt;/span&gt;31&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt; million in upfront payments.
      We are eligible to receive milestone payments and license fees up to $&lt;/span&gt;160&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt; million under this collaboration, including up to $&lt;/span&gt;42&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt; million for the achievement of development milestones and up to $&lt;/span&gt;105&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt; million for the achievement of regulatory milestones. In addition, we are eligible to receive tiered royalties up to the low teens on net sales from any product that AstraZeneca
      successfully commercializes under this collaboration agreement. From inception through December 2021, we have received over $&lt;/span&gt;141&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt; million in upfront fees, milestone payments, and other payments under this oncology collaboration, including $&lt;/span&gt;13&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt; million we earned when AstraZeneca licensed&lt;/span&gt; ION736 in 2020. We &lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt;will achieve the next payment of $&lt;/span&gt;12&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt; million if AstraZeneca advances ION736 in development.&lt;/span&gt;&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;We completed all of the performance obligations we identified under this collaboration in the first quarter of 2018.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt;Under this collaboration, we have also
      generated additional payments that we concluded were not part of other performance obligations discussed above. We recognized each of these payments in full in the respective quarter we generated the payment because the payments were distinct and we
      did not have any performance obligations for the respective payment. In 2020, we earned a $&lt;/span&gt;13&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt; million license fee when AstraZeneca licensed ION736&lt;/span&gt; because AstraZeneca had full use of the license without any continuing involvement from us.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;During the years ended December 31, 2021, 2020 and 2019, we earned the following revenue from our relationship with AstraZeneca (in millions, except percentage amounts):&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;"&gt;


  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;

        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="10" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Year Ended December 31,&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;2021&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;2020&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;2019&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -27pt; margin-left: 27pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;R&amp;amp;D revenue&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;254.6&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;88.0&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;28.1&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 64%;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Percentage of total revenue&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;31&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;%&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;12&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;%&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;3&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;%&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 12pt;"&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt;We did &lt;/span&gt;no&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt;t have any deferred revenue from our relationship with
      AstraZeneca at December 31, 2021. Our &lt;/span&gt;consolidated balance sheet at &lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt;December 31, &lt;/span&gt;2020&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt; included deferred revenue of $&lt;/span&gt;10.0&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt; million from our relationship with AstraZeneca.&lt;/span&gt;&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: left; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;"&gt;Bayer&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
    &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;In May 2015, we entered into an exclusive license agreement with Bayer to develop and commercialize IONIS-FXI&lt;sub&gt;Rx&lt;/sub&gt;
      for the prevention of thrombosis. We were responsible for completing a Phase 2 study of IONIS-FXI&lt;sub&gt;Rx&lt;/sub&gt; in people with end-stage renal disease on hemodialysis. Under the terms of the agreement, we received a $100 million upfront payment in the second quarter of 2015. In February 2017, we amended our agreement with Bayer to advance IONIS-FXI&lt;sub&gt;Rx&lt;/sub&gt; and to
      initiate development of fesomersen, which Bayer licensed. In conjunction with the decision to advance these programs, we received a $75 million
      payment from Bayer. In October 2019, Bayer decided it would advance fesomersen following positive clinical results. Bayer is now responsible for all global development, regulatory and commercialization activities and costs for the FXI program.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;We are eligible to receive up to $385 million in license fees, milestone payments and other payments, including up to $125
    million for the achievement of development milestones and up to $110 million for the achievement of sales milestones. In addition, we are
    eligible to receive tiered royalties in the low to high 20 percent range on gross margins of both medicines combined. From inception through
    December 2021, we have received over $191 million from this collaboration. We will achieve the next payment of $20 million if Bayer initiates a Phase 3 study for the FXI program.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;At the commencement of this collaboration, we identified three performance obligations, the license of IONIS-FXI&lt;sub&gt;Rx&lt;/sub&gt;, R&amp;amp;D services and delivery of API, all of which we completed in 2016.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;In February 2017, when we amended our collaboration with Bayer, we identified two new performance obligations&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt;, &lt;/span&gt;one&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt; for the license of fesomersen and &lt;/span&gt;one&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt; for R&amp;amp;D services&lt;/span&gt;. We determined the transaction price to be the $75 million payment. We allocated $64.9 million to
    &lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt;the license of fesomersen based on its estimated relative stand-alone selling price and recognized the associated revenue upon our delivery of the license in
      the first quarter of 2017. We allocated $&lt;/span&gt;10.1&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt; million to our R&amp;amp;D services performance obligation based on an estimated relative stand-alone selling price. &lt;/span&gt;We recognized revenue for our R&amp;amp;D services performance obligation as we performed services based on our effort to
    satisfy our performance obligation relative to our total effort expected to satisfy our performance obligation. We completed our obligation in the third quarter of 2019.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;In the fourth quarter of 2019, we earned a $10 million milestone payment when Bayer decided it would advance fesomersen. We recognized this milestone payment in full in the fourth quarter of 2019 because we did not have any performance
    obligations related to this milestone payment.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;During the years ended December 31, 2021, 2020 and 2019, we earned the following revenue from our relationship with Bayer (in millions, except percentage amounts):&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;"&gt;


  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;

        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="10" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Year Ended December 31,&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;2021&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;2020&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;2019&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -27pt; margin-left: 27pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;R&amp;amp;D revenue&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;1.1&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;3.2&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;14.3&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 64%;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Percentage of total revenue&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;0&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;%&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;0&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;%&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;1&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;%&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 12pt;"&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Our consolidated balance sheet at December 31, 2021 included an &lt;span style="-sec-ix-hidden:Fact_613e73fd93424660870569ffe2993ea8"&gt;insignificant&lt;/span&gt; amount of deferred revenue related to our relationship with Bayer. We did not
    have any deferred revenue from our relationship with Bayer at December 31, 2020.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;"&gt;GSK&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;In March 2010, we entered into an alliance with GSK using our antisense drug discovery platform to discover and develop
    new medicines against targets for serious and rare diseases, including infectious diseases and some conditions causing blindness. Under the terms of the agreement, we received upfront payments of $35 million. Our collaboration with GSK currently includes two medicines targeting
    hepatitis B virus, or HBV: bepirovirsen and IONIS-HBV-L&lt;sub&gt;Rx&lt;/sub&gt;. We designed these medicines to reduce the production of viral proteins associated with HBV infection. In the third quarter of 2019, following positive Phase 2 results, GSK licensed
    our HBV program. GSK is responsible for all global development, regulatory and commercialization activities and costs for the HBV program.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Under our agreement, if GSK successfully develops these medicines and achieves pre-agreed sales targets, we could receive
    license fees and milestone payments of more than $260 million, including up to $47.5 million for the achievement of development milestones, up to $120 million for the
    achievement of regulatory milestones and up to $70 million for the achievement of sales milestones. In addition, we are eligible to receive
    tiered royalties up to the mid-teens on net sales from any product that GSK successfully commercializes under this alliance. From inception through December 2021, we have received more than $190 million in payments under this alliance with GSK. We will achieve the next payment of $15
    million if GSK initiates a Phase 3 study of a medicine under this program.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt;We completed our R&amp;amp;D services performance
      obligations under our collaboration in the first quarter of 2015. &lt;/span&gt;We identified a new performance obligation when we granted GSK the license of the HBV program and assigned related intellectual property rights in the third quarter of 2019
    because the license was distinct from our other performance obligations. We recognized the $25 million license fee for the HBV program as revenue
    at that time because GSK had full use of the license without any continuing involvement from us. Additionally, we did not have any further performance obligations related to the license after we delivered it to GSK.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;We do not have any remaining performance obligations under our collaboration with GSK; however, we can still earn additional payments and
    royalties as GSK advances the HBV program.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;During the years ended December 31, 2021, 2020 and 2019, we earned the following revenue from our relationship with GSK (in millions, except percentage amounts):&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;"&gt;


  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;

        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="10" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Year Ended December 31,&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;2021&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;2020&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;2019&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -27pt; margin-left: 27pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;R&amp;amp;D revenue&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x2014;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;0.2&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;25.4&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 64%;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Percentage of total revenue&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x2014;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;0&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;%&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;2&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;%&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;div style="text-align: justify; font-family: 'Times New Roman', Times, serif; font-size: 12pt;"&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;We did not
    have any deferred revenue from our relationship with GSK at December 31, 2021 and 2020.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;"&gt;Novartis&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt;In January 2017, we initiated a collaboration
      with Novartis to develop and commercialize pelacarsen and olezarsen.&lt;/span&gt;&lt;sub style="color: #000000;"&gt;&#160;&lt;/sub&gt;We received a $75 million
    upfront payment in the first quarter of 2017. &lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt;In the first quarter of 2019, Novartis licensed pelacarsen&lt;/span&gt; and we earned a $150 million license fee. Novartis is responsible for conducting and funding future development and regulatory activities for pelacarsen, including a global
    Phase 3 cardiovascular outcomes study that Novartis initiated in the fourth quarter 2019.&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt;&#160;&lt;/span&gt;In connection with Novartis&#x2019; license of pelacarsen, we and
    Novartis established a more definitive framework under which the companies would negotiate the co-commercialization of pelacarsen in selected markets. Included in this framework is an option by which Novartis could solely commercialize pelacarsen in
    exchange for Novartis paying us increased sales milestone payments based on sales of pelacarsen.&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt;&#160;When Novartis decided to not exercise its option for &lt;/span&gt;olezarsen,
    we retained rights to develop and commercialize olezarsen.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Under the collaboration, we are eligible to receive up to $675 million in milestone payments, including $25 million for the achievement of a
    development milestone, up to $290 million for the achievement of regulatory milestones and up to $360 million for the achievement of sales milestones. &lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt;From inception through December
      2021, we have received nearly $&lt;/span&gt;425&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt; million
      in upfront payments, milestone payments, license fees and other payments from this collaboration. &lt;/span&gt;We are also eligible to receive tiered royalties in the mid-teens to low 20 percent range on net sales of pelacarsen. In August 2021, we earned a $25 million
    milestone payment from Novartis when Novartis achieved 50 percent enrollment in the Lp(a) HORIZON Phase 3 cardiovascular outcome study of
    pelacarsen. We recognized the milestone payment in full in the third quarter of 2021 because we did not have any remaining performance obligations related to the milestone payment. &lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt;We&lt;/span&gt;&lt;span style="background-color: #FBFBFB; font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt; will achieve the next payment of up to $&lt;/span&gt;75&lt;span style="background-color: #FBFBFB; font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt; million if Novartis advances regulatory activities for
      pelacarsen.&lt;/span&gt;&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;In conjunction with this collaboration, we entered into a SPA with Novartis. As part of the SPA, Novartis purchased 1.6 million shares of our common stock for $100
    million in the first quarter of 2017.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;At the commencement of this collaboration, we identified four separate performance obligations:&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;"&gt;


  &lt;tr&gt;

    &lt;td style="width: 36pt;"/&gt;

    &lt;td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x25cf;&lt;/td&gt;

    &lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;
          &lt;div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;R&amp;amp;D services for pelacarsen;&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;"&gt;


  &lt;tr&gt;

    &lt;td style="width: 36pt;"/&gt;

    &lt;td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x25cf;&lt;/td&gt;

    &lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;
          &lt;div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;R&amp;amp;D services for olezarsen;&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;"&gt;


  &lt;tr&gt;

    &lt;td style="width: 36pt;"/&gt;

    &lt;td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x25cf;&lt;/td&gt;

    &lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;
          &lt;div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;API for pelacarsen; and&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;"&gt;


  &lt;tr&gt;

    &lt;td style="width: 36pt;"/&gt;

    &lt;td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x25cf;&lt;/td&gt;

    &lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;
          &lt;div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;API for olezarsen.&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;We determined that the R&amp;amp;D services for each medicine and the API for each medicine were distinct performance obligations.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;We determined our transaction price to be $108.4
    million, comprised of the following:&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;"&gt;


  &lt;tr&gt;

    &lt;td style="width: 36pt;"/&gt;

    &lt;td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x25cf;&lt;/td&gt;

    &lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;
          &lt;div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$75 million from the upfront payment;&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;"&gt;


  &lt;tr&gt;

    &lt;td style="width: 36pt;"/&gt;

    &lt;td style="width: 18pt; vertical-align: top; align: right; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x25cf;&lt;/td&gt;

    &lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;
          &lt;div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$28.4 million for the premium paid by Novartis for its purchase
            of our common stock at a premium in the first quarter of 2017; and&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;"&gt;


  &lt;tr&gt;

    &lt;td style="width: 36pt;"/&gt;

    &lt;td style="width: 18pt; vertical-align: top; align: right; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x25cf;&lt;/td&gt;

    &lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;
          &lt;div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$5.0 million for the potential premium Novartis would have paid
            if they purchased our common stock in the future.&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;We allocated the transaction price based on the estimated stand-alone selling price of each performance obligation as follows:&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;"&gt;


  &lt;tr&gt;

    &lt;td style="width: 36pt;"/&gt;

    &lt;td style="width: 18pt; vertical-align: top; align: right; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x25cf;&lt;/td&gt;

    &lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;
          &lt;div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt;$&lt;/span&gt;64.0&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt; million for the R&amp;amp;D services for pelacarsen;&lt;/span&gt;&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;"&gt;


  &lt;tr&gt;

    &lt;td style="width: 36pt;"/&gt;

    &lt;td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x25cf;&lt;/td&gt;

    &lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$40.1 million for the R&amp;amp;D services for &lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;olezarsen&lt;/span&gt;; &lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;"&gt;


  &lt;tr&gt;

    &lt;td style="width: 36pt;"/&gt;

    &lt;td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x25cf;&lt;/td&gt;

    &lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$1.5&lt;/span&gt; million for the delivery of pelacarsen API; and&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;"&gt;


  &lt;tr&gt;

    &lt;td style="width: 36pt;"/&gt;

    &lt;td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x25cf;&lt;/td&gt;

    &lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$2.8&lt;/span&gt; million for the delivery of olezarsen API.&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;We completed our R&amp;amp;D services performance obligations for olezarsen and pelacarsen&lt;sub&gt;&#160;&lt;/sub&gt;in 2019. As such, we recognized all
    revenue we allocated to the olezarsen and pelacarsen&lt;sub&gt;&#160;&lt;/sub&gt;R&amp;amp;D services as of the end of 2019.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt;We recognized revenue related to the R&amp;amp;D
      services for pelacarsen and olezarsen performance obligations as we performed services &lt;/span&gt;based on our effort to satisfy our performance obligations relative to our total effort expected to satisfy our performance obligations&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt;.&lt;/span&gt;&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;During the years ended December 31, 2021, 2020 and 2019, we earned the following revenue from our
    relationship with Novartis (in millions, except percentage amounts):&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;"&gt;


  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;

        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="10" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Year Ended December 31,&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;2021&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;2020&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;2019&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -27pt; margin-left: 27pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;R&amp;amp;D revenue&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;25.5&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;1.0&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;187.4&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 64%;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Percentage of total revenue&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;3&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;%&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;0&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;%&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;17&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;%&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 12pt;"&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;We did not
    have any deferred revenue from our relationship with Novartis at December 31, 2021 and 2020.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;"&gt;Roche&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="text-align: left; margin-left: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;"&gt;Huntington&#x2019;s Disease&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
    &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;In April 2013, we formed an alliance with Hoffman-La Roche Inc. and F. Hoffmann-La Roche Ltd., collectively Roche, to
      develop treatments for HD based on our antisense technology. Under the agreement, we discovered and developed tominersen, an investigational medicine targeting HTT protein. We developed tominersen through completion of our Phase 1/2 clinical study in
      people with early stage HD. In the fourth quarter of 2017, upon completion of the Phase 1/2 study, Roche exercised its option to license tominersen. Roche is responsible for all global development, regulatory and commercialization activities and
      costs for tominersen.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Under the terms of the agreement, we received an upfront payment of $30 million in April 2013 and an additional $3 million payment in 2017. We are eligible
    to receive up to $365 million in a license fee and milestone payments including up to $70 million for the achievement of development milestones, up to $170 million for the
    achievement of regulatory milestones and up to $80 million for the achievement of sales milestones. In addition, we are eligible to receive up to
    $136.5 million in milestone payments for each additional medicine successfully developed. We are also eligible to receive tiered royalties up to
    the mid-teens on net sales of any product resulting from this alliance. From inception through December 2021, we have received $150 million in upfront fees, milestone payments and license fees under this collaboration. We will achieve the next payment of $15 million if Roche advances tominersen into registration.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;At the commencement of this collaboration, we identified one performance obligation, which was to perform R&amp;amp;D services for Roche. We determined the transaction price to be the $30 million upfront payment we received and allocated it to our single performance obligation. As we achieved milestone payments for our R&amp;amp;D services, we included these amounts in our
    transaction price for our R&amp;amp;D services performance obligation. We recognized revenue for our R&amp;amp;D services performance obligation over our period of performance, which ended in the third quarter of 2017.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Under this collaboration, we have also generated additional payments that we concluded were not part of our R&amp;amp;D
    services performance obligation. We recognized each of these payments in full in the respective quarter in which we generated the payment because the payments were distinct and we did not have any performance obligations for the respective payment. In
    2019, we earned $35 million in milestone payments when Roche dosed the first patient in the Phase 3 study of tominersen.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;In January 2022, &lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt;Roche announced it is
      actively preparing to initiate a new Phase 2 study of tominersen in patients with HD. Post-hoc analyses from the GENERATION HD1 study suggested tominersen may benefit younger adult patients with lower disease burden&lt;/span&gt;. In March 2021, Roche
    decided to discontinue dosing in the Phase 3 GENERATION HD1 study of tominersen in patients with manifest HD based on the results of a pre-planned review of data from the Phase 3 study conducted by an unblinded iDMC. We do not have any remaining
    performance obligations related to tominersen under this collaboration with Roche; however, we can still earn additional payments and royalties as Roche advances tominersen.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: left; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;"&gt;&lt;span style="background-color: #FBFBFB; font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;IONIS-FB-L&lt;/span&gt;&lt;sub&gt;&lt;span style="background-color: #FBFBFB;"&gt;Rx&lt;/span&gt;&lt;/sub&gt;&lt;span style="background-color: #FBFBFB; font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt; for Complement-Mediated Diseases&lt;/span&gt;&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt;In October 2018, we entered into a
      collaboration agreement with Roche to&lt;/span&gt;&lt;span style="background-color: #FBFBFB; font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt; develop IONIS-FB-L&lt;/span&gt;&lt;sub style="color: #000000;"&gt;Rx&lt;/sub&gt;&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt; for the treatment of complement-mediated diseases. We are currently conducting Phase 2 studies in &lt;/span&gt;two&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt; disease indications for &lt;/span&gt;&lt;span style="background-color: #FBFBFB; font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt;IONIS-FB-L&lt;/span&gt;&lt;sub style="color: #000000;"&gt;Rx&lt;/sub&gt;&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt;, &lt;/span&gt;one&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt; for the treatment of patients with GA, the advanced stage
      of dry AMD, and a &lt;/span&gt;&lt;span style="-sec-ix-hidden:Fact_04500eaf787641bfbd86183ba9891b89"&gt;second&lt;/span&gt;&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt; for the treatment
      of patients with IgA nephropathy. &lt;/span&gt;Roche&lt;span style="background-color: #FBFBFB; font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt; has the option to license IONIS-FB-L&lt;/span&gt;&lt;sub style="color: #000000;"&gt;&lt;span style="background-color: #FBFBFB;"&gt;Rx&lt;/span&gt;&lt;/sub&gt;&lt;span style="background-color: #FBFBFB; font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt; at the completion of these studies. Upon licensing, &lt;/span&gt;Roche &lt;span style="background-color: #FBFBFB; font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt;will be responsible for global development, regulatory and commercialization activities and costs.&lt;/span&gt;&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;span style="background-color: #FBFBFB; font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt;Under the terms of
      this agreement, we received a &lt;/span&gt;$75 million&lt;span style="background-color: #FBFBFB; font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt; upfront payment in the fourth quarter of 2018. We are eligible to receive more than &lt;/span&gt;$680 million&lt;span style="background-color: #FBFBFB; font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt; in development, regulatory and sales milestone payments and license fees. In addition, we are also eligible to receive tiered royalties
      from the high teens to &lt;/span&gt;20 percent&lt;span style="background-color: #FBFBFB; font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt; on net sales. &lt;/span&gt;&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt;From inception through December &lt;/span&gt;2021&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt;, we have received $&lt;/span&gt;75&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt; million in upfront fees, milestone payments and license fees under this collaboration. &lt;/span&gt;&lt;span style="background-color: #FBFBFB; font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt;We will achieve the next payment of $&lt;/span&gt;20&lt;span style="background-color: #FBFBFB; font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt; million if we further advance &lt;/span&gt;the Phase 2 study in patients with dry AMD&lt;span style="background-color: #FBFBFB; font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt;.&lt;/span&gt;&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;At the commencement of this collaboration, we identified one performance obligation, which was to perform R&amp;amp;D services for Roche. We determined the transaction price to be the $75 million upfront payment we received and allocated it to our single performance obligation. We are recognizing revenue for our R&amp;amp;D services performance obligation as we perform services
    based on our effort to satisfy our performance obligation relative to our total effort expected to satisfy our performance obligation. During the fourth quarter of 2020, we &lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt;updated our estimate of the total effort we expected to expend to satisfy our performance obligation under this collaboration.&lt;/span&gt;&#160;&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt;In the
      fourth quarter of 2020, we recorded a cumulative catch up adjustment of $&lt;/span&gt;9.2&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt; million to decrease revenue because we updated our total cost estimate to complete the Phase 2 study of &lt;/span&gt;&lt;span style="background-color: #FBFBFB; font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt;IONIS-FB-L&lt;/span&gt;&lt;sub style="color: #000000;"&gt;&lt;span style="background-color: #FBFBFB;"&gt;Rx &lt;/span&gt;&lt;/sub&gt;&lt;span style="background-color: #FBFBFB; font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt;for
      the &lt;/span&gt;&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt;treatment of patients with GA. &lt;/span&gt;We&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt; currently
      estimate we will satisfy our performance obligation in &lt;/span&gt;the fourth quarter of 2023.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;During the years ended December 31, 2021, 2020 and 2019, we earned the following revenue from our relationship with Roche (in millions, except percentage amounts):&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;"&gt;


  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;

        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="10" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Year Ended December 31,&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;2021&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;2020&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;2019&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -27pt; margin-left: 27pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;R&amp;amp;D revenue&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;17.2&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;5.9&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;57.0&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 64%;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Percentage of total revenue&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;2&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;%&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;1&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;%&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;5&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;%&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 12pt;"&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt;Our &lt;/span&gt;consolidated balance sheet at &lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt;December 31, &lt;/span&gt;2021&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt; and &lt;/span&gt;2020&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt; included deferred revenue of $&lt;/span&gt;31.6&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt; million and $&lt;/span&gt;47.2&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt;
      million related to our relationship with Roche, respectively.&lt;/span&gt;&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Commercialization Partnerships&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: left; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;"&gt;Swedish Orphan Biovitrum AB (Sobi)&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;We began commercializing TEGSEDI and WAYLIVRA in Europe in January 2021 and TEGSEDI in North America in April 2021 through
    distribution agreements with Sobi. Under our agreements, we are responsible for supplying finished goods inventory to Sobi and Sobi is responsible for selling each medicine to the end customer. In exchange, we earn a distribution fee on net sales from
    Sobi for each medicine.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: left; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;"&gt;PTC Therapeutics&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt;In August 2018, we entered into an exclusive
      license agreement with PTC Therapeutics to commercialize TEGSEDI and WAYLIVRA in Latin America and certain Caribbean countries. Under the license agreement, we are eligible to receive royalties from PTC in the mid-&lt;/span&gt;20 percent&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt; range on net sales for each medicine. &lt;/span&gt;In
    December 2021, we started receiving royalties from PTC for TEGSEDI sales&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt;.&lt;/span&gt;&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Technology Enhancement Collaboration&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: left; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic; font-weight: bold;"&gt;Bicycle License Agreement&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;In December 2020, we entered into a collaboration agreement with Bicycle and obtained an option to license its peptide technology to
    potentially increase the delivery capabilities of our LICA medicines. In July 2021, we paid $42 million when we exercised our option to license
    Bicycle&#x2019;s technology, which included an equity investment in Bicycle. As part of our stock purchase, we entered into a lockup agreement with Bicycle that restricts our ability to trade our Bicycle shares for one year. In 2021, we recorded a $7.2 million equity investment for the
    shares we received in Bicycle. We recognized the remaining $34.8 million as R&amp;amp;D expense in 2021. From inception through December 31, 2021, we
    have paid Bicycle $46.6 million under this collaboration agreement.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Other Agreements&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
    &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;"&gt;Alnylam Pharmaceuticals, Inc.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
    &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Under the terms of our agreement with Alnylam, we co-exclusively (with ourselves) licensed to Alnylam our patent estate
      relating to antisense motifs and mechanisms and oligonucleotide chemistry for double-stranded RNAi therapeutics, with Alynylam having the exclusive right to grant platform sublicenses for double-stranded RNAi. In exchange for such rights, Alynylam
      gave us a technology access fee, participation in fees from Alnylam&#x2019;s partnering programs, as well as future milestone and royalty payments from Alnylam. We retained exclusive rights to our patents for single-stranded antisense therapeutics and for a
      limited number of double-stranded RNAi therapeutic targets and all rights to single-stranded RNAi, or ssRNAi, therapeutics. In turn, Alnylam nonexclusively licensed to us its patent estate relating to antisense motifs and mechanisms and
      oligonucleotide chemistry to research, develop and commercialize single-stranded antisense therapeutics, ssRNAi therapeutics, and to research double-stranded RNAi compounds. We also received a license to develop and commercialize double-stranded RNAi
      therapeutics targeting a limited number of therapeutic targets on a nonexclusive basis. Additionally, in 2015, we and Alnylam entered into an alliance in which we cross-licensed intellectual property. Under this alliance, we and Alnylam each obtained
      exclusive license rights to four therapeutic programs. Alnylam granted us an exclusive, royalty-bearing license to its chemistry, RNA targeting mechanism and target-specific intellectual property for oligonucleotides against four targets, including
      FXI and Apo(a) and two other targets. In exchange, we granted Alnylam an exclusive, royalty-bearing license to our chemistry, RNA targeting mechanism and target-specific intellectual property for oligonucleotides against four other targets. Alnylam
      also granted us a royalty-bearing, non-exclusive license to new platform technology arising from May 2014 through April 2019 for single-stranded antisense therapeutics. In turn, we granted Alnylam a royalty-bearing, non-exclusive license to new
      platform technology arising from May 2014 through April 2019 for double-stranded RNAi therapeutics.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;In the fourth quarter 2020, we completed an arbitration process with Alnylam. The arbitration panel awarded us $41.2 million for payments owed to us by Alnylam related to Alnylam&#x2019;s agreement with Sanofi Genzyme. We recognized the $41.2 million payment from Alnylam as revenue in the fourth quarter of 2020 because we did not have any performance obligations for the respective payment.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
    &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;During the years ended December 31, &lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;2021&lt;/span&gt;, &lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;2020&lt;/span&gt; and &lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;2019&lt;/span&gt;, we
      earned the following revenue from our relationship with Alnylam (in millions, except percentage amounts):&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
    &lt;/div&gt;

&lt;table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;"&gt;


  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;

        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="10" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Year Ended December 31,&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;2021&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;2020&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;2019&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -27pt; margin-left: 27pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;R&amp;amp;D revenue&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x2014;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;47.9&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;24.1&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 64%;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Percentage of total revenue&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x2014;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;7&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;%&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;2&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;%&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 12pt;"&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;We did not
    have any deferred revenue from our relationship with Alnylam at December 31, 2021 and 2020.&lt;/div&gt;
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&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;During the years ended December 31, 2021, 2020 and 2019, we earned the following revenue from our relationship with Biogen (in millions, except percentage amounts):&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;"&gt;


  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;

        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="10" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Year Ended December 31,&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;2021&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;2020&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;2019&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -27pt; margin-left: 27pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;SPINRAZA royalties (commercial revenue)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;267.8&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;286.6&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;293.0&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 64%; padding-bottom: 2px;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;R&amp;amp;D revenue&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;161.0&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;122.0&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;180.6&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: left; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Total revenue from our relationship with Biogen&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;428.8&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;408.6&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;473.6&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 64%;" valign="bottom"&gt;
          &lt;div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Percentage of total revenue&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;53&lt;/div&gt;
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&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;During the years ended December 31, 2021, 2020 and 2019, we earned the following revenue from our relationship with AstraZeneca (in millions, except percentage amounts):&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;"&gt;


  &lt;tr&gt;

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        &lt;/td&gt;

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          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Year Ended December 31,&lt;/div&gt;
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    &lt;td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

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          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;2021&lt;/div&gt;
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          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;2020&lt;/div&gt;
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          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;2019&lt;/div&gt;
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  &lt;/tr&gt;

  &lt;tr&gt;

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          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;254.6&lt;/div&gt;
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    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;88.0&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;28.1&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 64%;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Percentage of total revenue&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;31&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;%&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;12&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;%&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;3&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;%&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;
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      id="Fact_abb5e5bfab0742a594537d03e99e580c"
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      id="Fact_671c15f958d449e1b0996ae26fb02f7f"
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      decimals="-6"
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&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;During the years ended December 31, 2021, 2020 and 2019, we earned the following revenue from our relationship with Bayer (in millions, except percentage amounts):&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;"&gt;


  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;

        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="10" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Year Ended December 31,&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;2021&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;2020&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;2019&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -27pt; margin-left: 27pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;R&amp;amp;D revenue&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;1.1&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;3.2&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;14.3&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 64%;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Percentage of total revenue&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;0&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;%&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;0&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;%&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;1&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;%&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;
</us-gaap:SchedulesOfConcentrationOfRiskByRiskFactorTextBlock>
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&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;During the years ended December 31, 2021, 2020 and 2019, we earned the following revenue from our relationship with GSK (in millions, except percentage amounts):&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;"&gt;


  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;

        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

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          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Year Ended December 31,&lt;/div&gt;
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  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

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          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;2021&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;2020&lt;/div&gt;
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    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

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          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;2019&lt;/div&gt;
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  &lt;/tr&gt;

  &lt;tr&gt;

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          &lt;div style="text-align: left; text-indent: -27pt; margin-left: 27pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;R&amp;amp;D revenue&lt;/div&gt;
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    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
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          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x2014;&lt;/div&gt;
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    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
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    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;0.2&lt;/div&gt;
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    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
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          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;25.4&lt;/div&gt;
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    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

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    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

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    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
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    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;
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    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

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    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;%&lt;/div&gt;
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    <ions:RevenueFromContractWithCustomerTransactionPrice
      contextRef="c20170331_ProductOrServiceAxis_PelacarsenActivePharmaceuticalIngredientMember_TypeOfArrangementAxis_NovartisCollaborationMember"
      decimals="-5"
      id="Fact_b3744373869c4288908b09e14ce88277"
      unitRef="U001">1500000</ions:RevenueFromContractWithCustomerTransactionPrice>
    <ions:RevenueFromContractWithCustomerTransactionPrice
      contextRef="c20170331_ProductOrServiceAxis_OlezarsenActivePharmaceuticalIngredientMember_TypeOfArrangementAxis_NovartisCollaborationMember"
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      id="Fact_060f939deb0d4433a9dd740934afd81c"
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&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;During the years ended December 31, 2021, 2020 and 2019, we earned the following revenue from our
    relationship with Novartis (in millions, except percentage amounts):&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;"&gt;


  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;

        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="10" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Year Ended December 31,&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;2021&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;2020&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;2019&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -27pt; margin-left: 27pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;R&amp;amp;D revenue&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;25.5&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;1.0&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;187.4&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 64%;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Percentage of total revenue&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;3&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;%&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;0&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;%&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;17&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;%&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;
</us-gaap:SchedulesOfConcentrationOfRiskByRiskFactorTextBlock>
    <us-gaap:RevenueFromContractWithCustomerExcludingAssessedTax
      contextRef="c20210101to20211231_ProductOrServiceAxis_ResearchAndDevelopmentRevenueUnderCollaborativeAgreementsMember_TypeOfArrangementAxis_NovartisCollaborationMember"
      decimals="-5"
      id="Fact_34a7cbc53ddb475aaaa8bcec238b44ce"
      unitRef="U001">25500000</us-gaap:RevenueFromContractWithCustomerExcludingAssessedTax>
    <us-gaap:RevenueFromContractWithCustomerExcludingAssessedTax
      contextRef="c20200101to20201231_ProductOrServiceAxis_ResearchAndDevelopmentRevenueUnderCollaborativeAgreementsMember_TypeOfArrangementAxis_NovartisCollaborationMember"
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      contextRef="c20190101to20191231_ProductOrServiceAxis_ResearchAndDevelopmentRevenueUnderCollaborativeAgreementsMember_TypeOfArrangementAxis_NovartisCollaborationMember"
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      unitRef="U001">187400000</us-gaap:RevenueFromContractWithCustomerExcludingAssessedTax>
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      id="Fact_1f40d9d87ee4435c83ab9656d281b655"
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      contextRef="c20190101to20191231_ConcentrationRiskByBenchmarkAxis_RevenueFromContractWithCustomerMember_ConcentrationRiskByTypeAxis_CustomerConcentrationRiskMember_TypeOfArrangementAxis_NovartisCollaborationMember"
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      contextRef="c20201231_TypeOfArrangementAxis_NovartisCollaborationMember"
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    <ions:UpfrontPaymentReceived
      contextRef="c20130401to20130430_TypeOfArrangementAxis_RocheCollaborationHuntingtonsDiseaseMember"
      decimals="-6"
      id="Fact_9f09a173393d49bc818e79aacee84764"
      unitRef="U001">30000000</ions:UpfrontPaymentReceived>
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      contextRef="c20170101to20171231_TypeOfArrangementAxis_RocheCollaborationHuntingtonsDiseaseMember"
      decimals="-6"
      id="Fact_8432cd12b85e48c6b111a7bdcb5f2ac8"
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      contextRef="c20211231_TypeOfArrangementAxis_RocheCollaborationHuntingtonsDiseaseMember"
      decimals="-6"
      id="Fact_d8d42ebb32dc46b7895c83156cf73607"
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      contextRef="c20211231_TypeOfArrangementAxis_RocheCollaborationHuntingtonsDiseaseMember"
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      contextRef="c20211231_TypeOfArrangementAxis_RocheCollaborationHuntingtonsDiseaseMember"
      decimals="-6"
      id="Fact_884490256579410c93629768255d304a"
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      contextRef="c20211231_TypeOfArrangementAxis_RocheCollaborationHuntingtonsDiseaseMember"
      decimals="-6"
      id="Fact_a9fce437f8684220b259d8408d43875f"
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      contextRef="c20211231_TypeOfArrangementAxis_RocheCollaborationHuntingtonsDiseaseMember"
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      id="Fact_67793d8d7c8843aba2b236e8d909758e"
      unitRef="U001">136500000</ions:MaximumAmountOfPaymentReceivableForEachAdditionalMedicineDeveloped>
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      contextRef="c20211231_TypeOfArrangementAxis_RocheCollaborationHuntingtonsDiseaseMember"
      decimals="-6"
      id="Fact_3aa74885781e415aa4fe5dd8e04e1eda"
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      contextRef="c20211231_TypeOfArrangementAxis_RocheCollaborationHuntingtonsDiseaseMember"
      decimals="-6"
      id="Fact_cb403b59db80408fb4a9b96e8393b762"
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      contextRef="c20130430_TypeOfArrangementAxis_RocheCollaborationHuntingtonsDiseaseMember"
      decimals="INF"
      id="Fact_efae3e04708b4937bacd7fa2bb5963f7"
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      contextRef="c20210101to20211231_TypeOfArrangementAxis_RocheCollaborationIonisFbLForComplementMediatedDiseasesMember"
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      decimals="-6"
      id="Fact_c786e47ad0b540fbb376640b5b6b6aba"
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      decimals="-6"
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      id="Fact_468a8db7e8de46a69b5ee7a0575f664d"
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    <ions:RevenueFromContractWithCustomerTransactionPrice
      contextRef="c20181031_TypeOfArrangementAxis_RocheCollaborationIonisFbLForComplementMediatedDiseasesMember"
      decimals="-6"
      id="Fact_64f9009b51e54bc8a818455d38bda2ae"
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    <us-gaap:RevenueFromContractWithCustomerExcludingAssessedTax
      contextRef="c20201001to20201231_TypeOfArrangementAxis_RocheCollaborationIonisFbLForComplementMediatedDiseasesMember"
      decimals="-5"
      id="Fact_0c806f7d3c2b4f6d9c6f41c84e900bd0"
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&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;During the years ended December 31, 2021, 2020 and 2019, we earned the following revenue from our relationship with Roche (in millions, except percentage amounts):&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;"&gt;


  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;

        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="10" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Year Ended December 31,&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;2021&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;2020&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;2019&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -27pt; margin-left: 27pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;R&amp;amp;D revenue&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;17.2&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;5.9&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;57.0&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 64%;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Percentage of total revenue&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;2&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;%&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;1&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;%&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;5&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;%&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;
</us-gaap:SchedulesOfConcentrationOfRiskByRiskFactorTextBlock>
    <us-gaap:RevenueFromContractWithCustomerExcludingAssessedTax
      contextRef="c20210101to20211231_ProductOrServiceAxis_ResearchAndDevelopmentRevenueUnderCollaborativeAgreementsMember_TypeOfArrangementAxis_RocheCollaborationMember"
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      id="Fact_fb8913807e664ded9db727de95b93bfc"
      unitRef="U001">17200000</us-gaap:RevenueFromContractWithCustomerExcludingAssessedTax>
    <us-gaap:RevenueFromContractWithCustomerExcludingAssessedTax
      contextRef="c20200101to20201231_ProductOrServiceAxis_ResearchAndDevelopmentRevenueUnderCollaborativeAgreementsMember_TypeOfArrangementAxis_RocheCollaborationMember"
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      id="Fact_43d5265cf6164fce9ca88f18b5897dc3"
      unitRef="U001">5900000</us-gaap:RevenueFromContractWithCustomerExcludingAssessedTax>
    <us-gaap:RevenueFromContractWithCustomerExcludingAssessedTax
      contextRef="c20190101to20191231_ProductOrServiceAxis_ResearchAndDevelopmentRevenueUnderCollaborativeAgreementsMember_TypeOfArrangementAxis_RocheCollaborationMember"
      decimals="-5"
      id="Fact_20872827ad6c4817bcf759078e23498f"
      unitRef="U001">57000000.0</us-gaap:RevenueFromContractWithCustomerExcludingAssessedTax>
    <us-gaap:ConcentrationRiskPercentage1
      contextRef="c20210101to20211231_ConcentrationRiskByBenchmarkAxis_RevenueFromContractWithCustomerMember_ConcentrationRiskByTypeAxis_CustomerConcentrationRiskMember_TypeOfArrangementAxis_RocheCollaborationMember"
      decimals="2"
      id="Fact_50cff48cda6946bc87457fee3925e81c"
      unitRef="U003">0.02</us-gaap:ConcentrationRiskPercentage1>
    <us-gaap:ConcentrationRiskPercentage1
      contextRef="c20200101to20201231_ConcentrationRiskByBenchmarkAxis_RevenueFromContractWithCustomerMember_ConcentrationRiskByTypeAxis_CustomerConcentrationRiskMember_TypeOfArrangementAxis_RocheCollaborationMember"
      decimals="2"
      id="Fact_cf5ca05dc07c4448bdda2353f8ed8769"
      unitRef="U003">0.01</us-gaap:ConcentrationRiskPercentage1>
    <us-gaap:ConcentrationRiskPercentage1
      contextRef="c20190101to20191231_ConcentrationRiskByBenchmarkAxis_RevenueFromContractWithCustomerMember_ConcentrationRiskByTypeAxis_CustomerConcentrationRiskMember_TypeOfArrangementAxis_RocheCollaborationMember"
      decimals="2"
      id="Fact_6490dfcad60e494083f50ae6646f73e4"
      unitRef="U003">0.05</us-gaap:ConcentrationRiskPercentage1>
    <us-gaap:ContractWithCustomerLiability
      contextRef="c20211231_TypeOfArrangementAxis_RocheCollaborationMember"
      decimals="-5"
      id="Fact_5ff4d7b8efd14d4a81981ea0cfa0cf58"
      unitRef="U001">31600000</us-gaap:ContractWithCustomerLiability>
    <us-gaap:ContractWithCustomerLiability
      contextRef="c20201231_TypeOfArrangementAxis_RocheCollaborationMember"
      decimals="-5"
      id="Fact_a38902f403274142aedd7c7ed42e8214"
      unitRef="U001">47200000</us-gaap:ContractWithCustomerLiability>
    <ions:RoyaltyPercentageReceivedOnNetSalesOfEachMedicineFromCollaborationPartner
      contextRef="c20210101to20211231_TypeOfArrangementAxis_PtcTherapeuticsCollaborationMember"
      decimals="2"
      id="Fact_570d071a48d248dbb4cd460b720cd572"
      unitRef="U003">0.20</ions:RoyaltyPercentageReceivedOnNetSalesOfEachMedicineFromCollaborationPartner>
    <ions:PaymentsMadeUnderCollaborationAgreement
      contextRef="c20210701to20210731_TypeOfArrangementAxis_BicycleCollaborationMember"
      decimals="-6"
      id="Fact_5f30af4db40c410198d4adf0cf56a2ac"
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    <ions:LockUpAgreementTermOfTradingRestriction
      contextRef="c20210101to20211231_TypeOfArrangementAxis_BicycleCollaborationMember"
      id="Fact_3b6f7ff3760d482699aca63514d611a3">P1Y</ions:LockUpAgreementTermOfTradingRestriction>
    <ions:InvestmentInEquitySecuritiesFvNi
      contextRef="c20210101to20211231_TypeOfArrangementAxis_BicycleCollaborationMember"
      decimals="-5"
      id="Fact_c4984ca504f041ad810726dda263687c"
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    <us-gaap:ResearchAndDevelopmentExpense
      contextRef="c20210101to20211231_TypeOfArrangementAxis_BicycleCollaborationMember"
      decimals="-5"
      id="Fact_f54d6f5ead044550b599ce90b22d6d17"
      unitRef="U001">34800000</us-gaap:ResearchAndDevelopmentExpense>
    <ions:CumulativePaymentsMade
      contextRef="c20211231_TypeOfArrangementAxis_BicycleCollaborationMember"
      decimals="-5"
      id="Fact_2ffb576dcfe749bd9031d801899bcdcb"
      unitRef="U001">46600000</ions:CumulativePaymentsMade>
    <us-gaap:LitigationSettlementAmountAwardedFromOtherParty
      contextRef="c20201001to20201231_TypeOfArrangementAxis_AlnylamCollaborationMember"
      decimals="-5"
      id="Fact_dfb16bacc6b94e7989aea7d88eebed5b"
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    <us-gaap:RevenueFromContractWithCustomerExcludingAssessedTax
      contextRef="c20201001to20201231_TypeOfArrangementAxis_AlnylamCollaborationMember"
      decimals="-5"
      id="Fact_397eed8f6b004e30bfacdacc310446cf"
      unitRef="U001">41200000</us-gaap:RevenueFromContractWithCustomerExcludingAssessedTax>
    <us-gaap:SchedulesOfConcentrationOfRiskByRiskFactorTextBlock
      contextRef="c20210101to20211231_TypeOfArrangementAxis_AlnylamPharmaceuticalsIncMember"
      id="Text_0f88f578e1cc4bc5928904be72a89aac">
&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;During the years ended December 31, &lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;2021&lt;/span&gt;, &lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;2020&lt;/span&gt; and &lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;2019&lt;/span&gt;, we
      earned the following revenue from our relationship with Alnylam (in millions, except percentage amounts):&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
    &lt;/div&gt;

&lt;table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;"&gt;


  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;

        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="10" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Year Ended December 31,&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;2021&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;2020&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;2019&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -27pt; margin-left: 27pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;R&amp;amp;D revenue&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x2014;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;47.9&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;24.1&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 64%;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Percentage of total revenue&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x2014;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;7&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;%&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;2&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;%&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;
</us-gaap:SchedulesOfConcentrationOfRiskByRiskFactorTextBlock>
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      contextRef="c20210101to20211231_ProductOrServiceAxis_ResearchAndDevelopmentRevenueUnderCollaborativeAgreementsMember_TypeOfArrangementAxis_AlnylamCollaborationMember"
      decimals="-6"
      id="Fact_45285d7fd8354da4a078a4a11aba04ee"
      unitRef="U001">0</us-gaap:RevenueFromContractWithCustomerExcludingAssessedTax>
    <us-gaap:RevenueFromContractWithCustomerExcludingAssessedTax
      contextRef="c20200101to20201231_ProductOrServiceAxis_ResearchAndDevelopmentRevenueUnderCollaborativeAgreementsMember_TypeOfArrangementAxis_AlnylamCollaborationMember"
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      id="Fact_234485bc14344d888b7bed969bbbb34c"
      unitRef="U001">47900000</us-gaap:RevenueFromContractWithCustomerExcludingAssessedTax>
    <us-gaap:RevenueFromContractWithCustomerExcludingAssessedTax
      contextRef="c20190101to20191231_ProductOrServiceAxis_ResearchAndDevelopmentRevenueUnderCollaborativeAgreementsMember_TypeOfArrangementAxis_AlnylamCollaborationMember"
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    <us-gaap:ConcentrationRiskPercentage1
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      decimals="2"
      id="Fact_ab0a985934234f8bb07ff855cb4f906d"
      unitRef="U003">0.07</us-gaap:ConcentrationRiskPercentage1>
    <us-gaap:ConcentrationRiskPercentage1
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    <us-gaap:ContractWithCustomerLiability
      contextRef="c20201231_TypeOfArrangementAxis_AlnylamCollaborationMember"
      decimals="-6"
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&lt;div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;7. Akcea Merger&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;"&gt;Purchase Price and Direct Transaction Costs Accounting for the Akcea Merger&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;In October 2020, we reacquired the shares of Akcea&#x2019;s common stock we did not own, increasing our ownership from 76 percent to 100 percent. Under the purchase
    agreement, we purchased 24.8 million shares at $18.15
    per share, resulting in a total purchase price of $450.6 million.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;To reflect our 100 percent
    ownership, we accounted for the increase in our ownership by eliminating the noncontrolling interest adjustment in stockholders&#x2019; equity in accordance with the Consolidation accounting guidance (ASC Topic 810). We recognized the difference between the
    purchase price and the adjustment to noncontrolling interest in stockholders&#x2019; equity as additional-paid-in capital. Refer to our &lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;"&gt;Statement of
      Stockholders&#x2019; Equity&lt;/span&gt; for detailed amounts.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;We accounted for the transaction costs related to the Akcea Merger as a direct charge to stockholders&#x2019; equity. We incurred
    $40.6 million of direct transaction costs from the Akcea Merger, primarily comprised of banking and legal fees.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;"&gt;Equity Award Payouts related to the Akcea Merger&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt;In October 2020, as part of the Akcea Merger,
      Ionis cancelled all of Akcea&#x2019;s equity awards. In exchange for the cancelled awards, if eligible under the terms of the Akcea Merger, we paid holder&#x2019;s a cash payment. We paid $&lt;/span&gt;18.15&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt; for each outstanding RSU. For each outstanding option with an exercise price less than $&lt;/span&gt;18.15&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt;, we paid $&lt;/span&gt;18.15&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt; less the exercise price. As a result, we paid out $&lt;/span&gt;53.4&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt; million in the fourth quarter of 2020 related to Akcea&#x2019;s
      cancelled equity awards. We accounted for these payments as part of the transaction costs recorded to stockholders&#x2019; equity in the fourth quarter of 2020. &lt;/span&gt;Because we did not replace the Akcea awards, we recognized all unrecognized non-cash
    stock-based compensation ($59.3 million) under Akcea&#x2019;s Plan in our statement of operations in the post-merger period in the fourth quarter of
    2020.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;"&gt;Severance and Retention Costs related to the Akcea Merger&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;As a result of the Akcea Merger, we incurred severance and retention expenses of $27.0 million. During 2021 and 2020, we recorded $11.7 million and $15.3 million of severance and retention related costs in operating expenses, respectively. As of December 31, 2021, we have recognized all severance and
    retention costs related to the Akcea Merger.&lt;/div&gt;

&lt;div style="text-align: justify;"&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;The following table summarizes the severance and retention expenses related to the Akcea Merger that we recognized for the periods indicated (in
    millions):&lt;/div&gt;

&lt;div style="text-align: justify;"&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;"&gt;


  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;

        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Year Ended&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;December 31, 2021&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: top; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Year Ended&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;December 31, 2020&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 76%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;R&amp;amp;D expenses&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;5.1&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;3.9&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 76%; padding-bottom: 2px;" valign="bottom"&gt;
          &lt;div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;SG&amp;amp;A expenses&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;6.6&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;11.4&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 76%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Total&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;11.7&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;15.3&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;The following table summarizes the severance and retention reserve amounts related to the Akcea Merger that we included in
    accrued compensation for the period indicated (in millions):&lt;/div&gt;

&lt;div style="text-align: justify;"&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;"&gt;


  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;

        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Year Ended&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;December 31, 2021&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 88%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Beginning balance as of January 1, 2021&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;14.7&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 88%;" valign="bottom"&gt;
          &lt;div style="text-align: left; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Amount expensed during the year&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;13.5&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 88%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: left; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Reserve adjustments during the year&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(1.8&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 88%;" valign="bottom"&gt;
          &lt;div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Net amount expensed during the year&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;11.7&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 88%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Amounts paid during the year&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(26.4&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 88%; padding-bottom: 4px;" valign="bottom"&gt;
          &lt;div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Ending balance as of December 31, 2021&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x2014;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 12pt;"&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: left; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;The reserve adjustments during the period primarily related to forfeitures of severance and retention payments as a result of employee
    terminations before they earned the amounts.&lt;/div&gt;
</us-gaap:MinorityInterestDisclosureTextBlock>
    <us-gaap:MinorityInterestOwnershipPercentageByParent
      contextRef="c20200930_OwnershipAxis_AkceaTherapeuticsIncMember"
      decimals="2"
      id="Fact_b6feac506d324b98951f0933ce40dd67"
      unitRef="U003">0.76</us-gaap:MinorityInterestOwnershipPercentageByParent>
    <us-gaap:MinorityInterestOwnershipPercentageByParent
      contextRef="c20201031_OwnershipAxis_AkceaTherapeuticsIncMember"
      decimals="2"
      id="Fact_33b44fc190674e72a94a538abf61155f"
      unitRef="U003">1</us-gaap:MinorityInterestOwnershipPercentageByParent>
    <ions:ConsolidationLessThanWhollyOwnedSubsidiaryParentOwnershipInterestChangesPurchaseOfInterestByParentShares
      contextRef="c20201001to20201031_OwnershipAxis_AkceaTherapeuticsIncMember"
      decimals="-5"
      id="Fact_24aa2fc2d1384378a728edf162abb8fb"
      unitRef="U002">24800000</ions:ConsolidationLessThanWhollyOwnedSubsidiaryParentOwnershipInterestChangesPurchaseOfInterestByParentShares>
    <ions:ConsolidationLessThanWhollyOwnedSubsidiaryParentOwnershipInterestChangesPurchaseOfInterestByParentPricePerShare
      contextRef="c20201001to20201031_OwnershipAxis_AkceaTherapeuticsIncMember"
      decimals="2"
      id="Fact_fa704d2a69a948088d5d227df198df4e"
      unitRef="U004">18.15</ions:ConsolidationLessThanWhollyOwnedSubsidiaryParentOwnershipInterestChangesPurchaseOfInterestByParentPricePerShare>
    <us-gaap:ConsolidationLessThanWhollyOwnedSubsidiaryParentOwnershipInterestChangesPurchaseOfInterestByParent
      contextRef="c20201001to20201031_OwnershipAxis_AkceaTherapeuticsIncMember"
      decimals="-5"
      id="Fact_2e6fddec0b5647c1862613421ea983f3"
      unitRef="U001">450600000</us-gaap:ConsolidationLessThanWhollyOwnedSubsidiaryParentOwnershipInterestChangesPurchaseOfInterestByParent>
    <us-gaap:MinorityInterestOwnershipPercentageByParent
      contextRef="c20201031_OwnershipAxis_AkceaTherapeuticsIncMember"
      decimals="2"
      id="Fact_43cd203825e04ef79c3027298eeb9ffa"
      unitRef="U003">1</us-gaap:MinorityInterestOwnershipPercentageByParent>
    <us-gaap:BusinessAcquisitionCostOfAcquiredEntityTransactionCosts
      contextRef="c20201231_OwnershipAxis_AkceaTherapeuticsIncMember"
      decimals="-5"
      id="Fact_0884cfbdf1684305809ccf99311b4099"
      unitRef="U001">40600000</us-gaap:BusinessAcquisitionCostOfAcquiredEntityTransactionCosts>
    <ions:CashPurchasePriceOfEquityAwards
      contextRef="c20201001to20201231_OwnershipAxis_AkceaTherapeuticsIncMember"
      decimals="2"
      id="Fact_638c1e20e6404ff4aa52f098c6deb05d"
      unitRef="U004">18.15</ions:CashPurchasePriceOfEquityAwards>
    <ions:CashPurchasePriceOfEquityAwards
      contextRef="c20201001to20201231_OwnershipAxis_AkceaTherapeuticsIncMember"
      decimals="2"
      id="Fact_b89bdecf0fa14315963911cf431521b4"
      unitRef="U004">18.15</ions:CashPurchasePriceOfEquityAwards>
    <ions:CashPurchasePriceOfEquityAwards
      contextRef="c20201001to20201231_OwnershipAxis_AkceaTherapeuticsIncMember"
      decimals="2"
      id="Fact_99ca9852ab9f4ad6ae3ea6c3a7b75b3b"
      unitRef="U004">18.15</ions:CashPurchasePriceOfEquityAwards>
    <ions:PaymentsForCancelledEquityAwards
      contextRef="c20201001to20201231_OwnershipAxis_AkceaTherapeuticsIncMember"
      decimals="-5"
      id="Fact_aab524f795c14b308413d9edfc049700"
      unitRef="U001">53400000</ions:PaymentsForCancelledEquityAwards>
    <us-gaap:EmployeeServiceShareBasedCompensationNonvestedAwardsTotalCompensationCostNotYetRecognizedShareBasedAwardsOtherThanOptions
      contextRef="c20201031_OwnershipAxis_AkceaTherapeuticsIncMember"
      decimals="-5"
      id="Fact_46135659ff5e45719f62bc97882f97ae"
      unitRef="U001">59300000</us-gaap:EmployeeServiceShareBasedCompensationNonvestedAwardsTotalCompensationCostNotYetRecognizedShareBasedAwardsOtherThanOptions>
    <ions:RestructuringReserveRestructuringChargesNetOfReserveAdjustments
      contextRef="c20200101to20211231_RestructuringCostAndReserveAxis_AkceaMergerMember"
      decimals="-5"
      id="Fact_9dc8f2fc62ba4f10b141ceb5929b5e78"
      unitRef="U001">27000000.0</ions:RestructuringReserveRestructuringChargesNetOfReserveAdjustments>
    <ions:RestructuringReserveRestructuringChargesNetOfReserveAdjustments
      contextRef="c20210101to20211231_RestructuringCostAndReserveAxis_AkceaMergerMember"
      decimals="-5"
      id="Fact_17e8057efb034b5e9a107d550fa5913d"
      unitRef="U001">11700000</ions:RestructuringReserveRestructuringChargesNetOfReserveAdjustments>
    <ions:RestructuringReserveRestructuringChargesNetOfReserveAdjustments
      contextRef="c20200101to20201231_RestructuringCostAndReserveAxis_AkceaMergerMember"
      decimals="-5"
      id="Fact_c4276bcb84694590920af5733a7570a2"
      unitRef="U001">15300000</ions:RestructuringReserveRestructuringChargesNetOfReserveAdjustments>
    <us-gaap:ConsolidationLessThanWhollyOwnedSubsidiaryParentOwnershipInterestEffectsOfChangesNetTextBlock
      contextRef="c20210101to20211231"
      id="Text_ce395f00571c40dd848de2c896322ca4">
&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;The following table summarizes the severance and retention expenses related to the Akcea Merger that we recognized for the periods indicated (in
    millions):&lt;/div&gt;

&lt;div style="text-align: justify;"&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;"&gt;


  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;

        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Year Ended&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;December 31, 2021&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: top; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Year Ended&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;December 31, 2020&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 76%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;R&amp;amp;D expenses&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;5.1&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;3.9&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 76%; padding-bottom: 2px;" valign="bottom"&gt;
          &lt;div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;SG&amp;amp;A expenses&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;6.6&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;11.4&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 76%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Total&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;11.7&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;15.3&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;The following table summarizes the severance and retention reserve amounts related to the Akcea Merger that we included in
    accrued compensation for the period indicated (in millions):&lt;/div&gt;

&lt;div style="text-align: justify;"&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;"&gt;


  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;

        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Year Ended&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;December 31, 2021&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 88%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Beginning balance as of January 1, 2021&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;14.7&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 88%;" valign="bottom"&gt;
          &lt;div style="text-align: left; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Amount expensed during the year&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;13.5&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 88%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: left; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Reserve adjustments during the year&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(1.8&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 88%;" valign="bottom"&gt;
          &lt;div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Net amount expensed during the year&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;11.7&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 88%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Amounts paid during the year&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(26.4&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 88%; padding-bottom: 4px;" valign="bottom"&gt;
          &lt;div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Ending balance as of December 31, 2021&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x2014;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;


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&lt;div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;8. Severance and Retention Costs related to our
    Restructured Operations&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;"&gt;Restructured European Operations&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt;In the fourth quarter of 2020, &lt;/span&gt;we
    entered into a distribution agreement with Sobi to commercialize TEGSEDI and WAYLIVRA in Europe. Under the distribution agreement, Sobi took over all material distribution operations at the end of January 2021. &lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt;We remain the marketing authorization holder for TEGSEDI and WAYLIVRA in Europe. We will continue to maintain limited European operations including regulatory, manufacturing, and the
      management of relationships with key opinion leaders. We will also continue to lead the TEGSEDI and WAYLIVRA global commercial strategy.&lt;/span&gt;&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;As a result of this change, we incurred severance and retention expenses of $14.2 million. During 2021 and 2020, we recorded $1.7 million and $12.5 million of severance and retention related costs in operating expenses, respectively. As of December 31, 2021, we have recognized all severance and
    retention costs related to this agreement.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;The following table summarizes the
    severance and retention expenses related to our restructured European operations that we recognized for the periods indicated (in millions):&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;"&gt;


  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;

        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Year Ended&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;December 31, 2021&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: top; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Year Ended&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;December 31, 2020&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 76%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;R&amp;amp;D expenses&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;0.6&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;4.2&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 76%; padding-bottom: 2px;" valign="bottom"&gt;
          &lt;div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;SG&amp;amp;A expenses&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;1.1&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;8.3&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 76%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Total&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;1.7&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;12.5&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;The following table summarizes the severance and retention reserve amounts related to our restructured European operations
    that we included in accrued compensation for the period indicated (in millions):&lt;/div&gt;

&lt;div style="text-align: justify;"&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;"&gt;


  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;

        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Year Ended&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;December 31, 2021&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 88%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Beginning balance as of January 1, 2021&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;12.4&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 88%;" valign="bottom"&gt;
          &lt;div style="text-align: left; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Amount expensed during the year&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;2.6&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 88%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: left; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Reserve adjustments during the year&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(0.9&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 88%;" valign="bottom"&gt;
          &lt;div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Net amount expensed during the year&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;1.7&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 88%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Amounts paid during the year&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(14.1&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 88%; padding-bottom: 4px;" valign="bottom"&gt;
          &lt;div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Ending balance as of December 31, 2021&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x2014;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;div style="text-align: left;"&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: left; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;The reserve adjustments during the period primarily related to tax expense adjustments.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;"&gt;Restructured North American TEGSEDI Operations&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;In April 2021, we entered into a distribution agreement with Sobi for TEGSEDI in North America. Under the terms of the
    distribution agreement, we will retain the marketing authorizations for TEGSEDI in the U.S. and Canada. We will continue to supply commercial product to Sobi and manage regulatory and manufacturing processes, as well as relationships with key opinion
    leaders. We will also continue to lead the TEGSEDI global commercial strategy. Sobi will otherwise have responsibility for commercializing TEGSEDI in the U.S. and Canada.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;In connection with restructuring our North American TEGSEDI operations, or Restructured North American TEGSEDI Operations,
    we enacted a plan to reorganize our Akcea workforce in North America to better align with the needs of our business and to focus on our wholly owned pipeline.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;The following table summarizes the severance expenses related to our
    Restructured North American TEGSEDI Operations that we recognized for the period indicated (in millions):&lt;/div&gt;

&lt;div style="text-align: justify;"&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;"&gt;


  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;

        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Year Ended&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;December 31, 2021&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 88%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;R&amp;amp;D expenses&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;2.3&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 88%; padding-bottom: 2px;" valign="bottom"&gt;
          &lt;div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;SG&amp;amp;A expenses&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;7.1&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 88%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Total&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;9.4&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;We recognized all severance expenses related to our Restructured North American
    TEGSEDI Operations during the three months ended June 30, 2021.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;The following table summarizes the severance reserve amounts related to our
    Restructured North American TEGSEDI Operations that we included in accrued compensation for the period indicated (in millions):&lt;/div&gt;

&lt;div style="text-align: justify;"&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;"&gt;


  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;

        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Year Ended&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;December 31, 2021&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 88%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Beginning balance as of January 1, 2021&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x2014;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 88%;" valign="bottom"&gt;
          &lt;div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Net amount expensed during the year&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;9.4&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 88%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Amounts paid during the year&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(9.4&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 88%; padding-bottom: 4px;" valign="bottom"&gt;
          &lt;div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Ending balance as of December 31, 2021&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x2014;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;
</us-gaap:RestructuringAndRelatedActivitiesDisclosureTextBlock>
    <ions:RestructuringReserveRestructuringChargesNetOfReserveAdjustments
      contextRef="c20200101to20211231_RestructuringCostAndReserveAxis_UpdatedEuropeanDistributionModelEmployeeSeveranceAndRetentionMember"
      decimals="-5"
      id="Fact_255deee8e5ea4dea982e26bddc094e71"
      unitRef="U001">14200000</ions:RestructuringReserveRestructuringChargesNetOfReserveAdjustments>
    <ions:RestructuringReserveRestructuringChargesNetOfReserveAdjustments
      contextRef="c20210101to20211231_RestructuringCostAndReserveAxis_UpdatedEuropeanDistributionModelEmployeeSeveranceAndRetentionMember"
      decimals="-5"
      id="Fact_286ef7c4c3864cf693bd0a9e320cc095"
      unitRef="U001">1700000</ions:RestructuringReserveRestructuringChargesNetOfReserveAdjustments>
    <ions:RestructuringReserveRestructuringChargesNetOfReserveAdjustments
      contextRef="c20200101to20201231_RestructuringCostAndReserveAxis_UpdatedEuropeanDistributionModelEmployeeSeveranceAndRetentionMember"
      decimals="-5"
      id="Fact_3d03331e3cbe4b0eab5e2342db5f3416"
      unitRef="U001">12500000</ions:RestructuringReserveRestructuringChargesNetOfReserveAdjustments>
    <us-gaap:ScheduleOfRestructuringAndRelatedCostsTextBlock
      contextRef="c20210101to20211231_RestructuringCostAndReserveAxis_RestructuredEuropeanOperationsMember"
      id="Text_f2df1e72e7314af39e867699554af81d">
&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;The following table summarizes the
    severance and retention expenses related to our restructured European operations that we recognized for the periods indicated (in millions):&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;"&gt;


  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;

        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Year Ended&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;December 31, 2021&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: top; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Year Ended&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;December 31, 2020&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 76%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;R&amp;amp;D expenses&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;0.6&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;4.2&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 76%; padding-bottom: 2px;" valign="bottom"&gt;
          &lt;div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;SG&amp;amp;A expenses&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;1.1&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;8.3&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 76%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Total&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;1.7&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;12.5&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;The following table summarizes the severance and retention reserve amounts related to our restructured European operations
    that we included in accrued compensation for the period indicated (in millions):&lt;/div&gt;

&lt;div style="text-align: justify;"&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;"&gt;


  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;

        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Year Ended&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;December 31, 2021&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 88%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Beginning balance as of January 1, 2021&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;12.4&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 88%;" valign="bottom"&gt;
          &lt;div style="text-align: left; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Amount expensed during the year&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;2.6&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 88%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: left; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Reserve adjustments during the year&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(0.9&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 88%;" valign="bottom"&gt;
          &lt;div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Net amount expensed during the year&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;1.7&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 88%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Amounts paid during the year&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(14.1&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 88%; padding-bottom: 4px;" valign="bottom"&gt;
          &lt;div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Ending balance as of December 31, 2021&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x2014;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;
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    <us-gaap:ScheduleOfRestructuringAndRelatedCostsTextBlock
      contextRef="c20210101to20211231_RestructuringCostAndReserveAxis_RestructuredNorthAmericanTegsediOperationsMember"
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&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;The following table summarizes the severance expenses related to our
    Restructured North American TEGSEDI Operations that we recognized for the period indicated (in millions):&lt;/div&gt;

&lt;div style="text-align: justify;"&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;"&gt;


  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;

        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Year Ended&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;December 31, 2021&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 88%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;R&amp;amp;D expenses&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;2.3&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 88%; padding-bottom: 2px;" valign="bottom"&gt;
          &lt;div style="text-align: justify; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;SG&amp;amp;A expenses&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;7.1&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 88%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Total&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;9.4&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;The following table summarizes the severance reserve amounts related to our
    Restructured North American TEGSEDI Operations that we included in accrued compensation for the period indicated (in millions):&lt;/div&gt;

&lt;div style="text-align: justify;"&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;"&gt;


  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;

        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Year Ended&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;December 31, 2021&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 88%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Beginning balance as of January 1, 2021&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x2014;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 88%;" valign="bottom"&gt;
          &lt;div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Net amount expensed during the year&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;9.4&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 88%; padding-bottom: 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Amounts paid during the year&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(9.4&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 88%; padding-bottom: 4px;" valign="bottom"&gt;
          &lt;div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Ending balance as of December 31, 2021&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x2014;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;
</us-gaap:ScheduleOfRestructuringAndRelatedCostsTextBlock>
    <us-gaap:RestructuringCharges
      contextRef="c20210101to20211231_IncomeStatementLocationAxis_ResearchDevelopmentAndPatentExpensesMember_RestructuringCostAndReserveAxis_RestructuredNorthAmericanTegsediOperationsMember"
      decimals="-5"
      id="Fact_af55dde53acc4ad79c91fa58bb7992ee"
      unitRef="U001">2300000</us-gaap:RestructuringCharges>
    <us-gaap:RestructuringCharges
      contextRef="c20210101to20211231_IncomeStatementLocationAxis_SellingGeneralAndAdministrativeExpensesMember_RestructuringCostAndReserveAxis_RestructuredNorthAmericanTegsediOperationsMember"
      decimals="-5"
      id="Fact_125a7995b2084fc681531cbc38a2ed21"
      unitRef="U001">7100000</us-gaap:RestructuringCharges>
    <us-gaap:RestructuringCharges
      contextRef="c20210101to20211231_RestructuringCostAndReserveAxis_RestructuredNorthAmericanTegsediOperationsMember"
      decimals="-5"
      id="Fact_eabbcfa223474dff907437a5eb0f17e4"
      unitRef="U001">9400000</us-gaap:RestructuringCharges>
    <us-gaap:RestructuringReserve
      contextRef="c20201231_RestructuringCostAndReserveAxis_RestructuredNorthAmericanTegsediOperationsMember"
      decimals="-6"
      id="Fact_dc999c1500104db19468603b328342c4"
      unitRef="U001">0</us-gaap:RestructuringReserve>
    <us-gaap:RestructuringCharges
      contextRef="c20210101to20211231_RestructuringCostAndReserveAxis_RestructuredNorthAmericanTegsediOperationsMember"
      decimals="-5"
      id="Fact_0c7a5220424847c799e6df1f74c0c897"
      unitRef="U001">9400000</us-gaap:RestructuringCharges>
    <us-gaap:PaymentsForRestructuring
      contextRef="c20210101to20211231_RestructuringCostAndReserveAxis_RestructuredNorthAmericanTegsediOperationsMember"
      decimals="-5"
      id="Fact_260154de61f54ac5babc0a112b5b0236"
      unitRef="U001">9400000</us-gaap:PaymentsForRestructuring>
    <us-gaap:RestructuringReserve
      contextRef="c20211231_RestructuringCostAndReserveAxis_RestructuredNorthAmericanTegsediOperationsMember"
      decimals="-6"
      id="Fact_4723e043c9f3473a9b3b847984c59b4f"
      unitRef="U001">0</us-gaap:RestructuringReserve>
    <us-gaap:PensionAndOtherPostretirementBenefitsDisclosureTextBlock
      contextRef="c20210101to20211231"
      id="Text_44a1974bfba9485682c02d2913778f03">
&lt;div style="text-align: justify; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;9. Employment Benefits&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;We have employee 401(k) salary deferral plans covering all employees. Employees could make contributions by withholding a
    percentage of their salary up to the IRS annual limits of $20,500 and $27,000 in 2021 for employees under 50 years old and employees 50 years old or over,
    respectively. We made approximately $5.5 million, $5.7
    million and $6.4 million in matching contributions for the years ended December 31, 2021, 2020 and 2019, respectively.&lt;/div&gt;
</us-gaap:PensionAndOtherPostretirementBenefitsDisclosureTextBlock>
    <us-gaap:DefinedContributionPlanMaximumAnnualContributionsPerEmployeeAmount
      contextRef="c20210101to20211231_RangeAxis_MinimumMember"
      decimals="0"
      id="Fact_06c142c7ec1040e0b05c4b2596dfe112"
      unitRef="U001">20500</us-gaap:DefinedContributionPlanMaximumAnnualContributionsPerEmployeeAmount>
    <us-gaap:DefinedContributionPlanMaximumAnnualContributionsPerEmployeeAmount
      contextRef="c20210101to20211231_RangeAxis_MaximumMember"
      decimals="0"
      id="Fact_2703ad6213db4e249c38d0794a2c6418"
      unitRef="U001">27000</us-gaap:DefinedContributionPlanMaximumAnnualContributionsPerEmployeeAmount>
    <us-gaap:DefinedContributionPlanCostRecognized
      contextRef="c20210101to20211231"
      decimals="-5"
      id="Fact_345fd7748408424580894d7cb0e0e108"
      unitRef="U001">5500000</us-gaap:DefinedContributionPlanCostRecognized>
    <us-gaap:DefinedContributionPlanCostRecognized
      contextRef="c20200101to20201231"
      decimals="-5"
      id="Fact_47a2898dc66b4221ba3a2d92c2c0643a"
      unitRef="U001">5700000</us-gaap:DefinedContributionPlanCostRecognized>
    <us-gaap:DefinedContributionPlanCostRecognized
      contextRef="c20190101to20191231"
      decimals="-5"
      id="Fact_0c0b367e1550466b886c0390a13e1e0f"
      unitRef="U001">6400000</us-gaap:DefinedContributionPlanCostRecognized>
    <us-gaap:LegalMattersAndContingenciesTextBlock
      contextRef="c20210101to20211231"
      id="Text_656730b2a28e4e958b751e639ff66fd5">
&lt;div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;10. Legal Proceedings&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;From time to time, we are involved in legal proceedings arising in the ordinary course of our business. Periodically, we
    evaluate the status of each legal matter and assess our potential financial exposure. If the potential loss from any legal proceeding is considered probable and the amount can be reasonably estimated, we accrue a liability for the estimated loss.
    Significant judgment is required to determine the probability of a loss and whether the amount of the loss is reasonably estimable. The outcome of any proceeding is not determinable in advance. As a result, the assessment of a potential liability and
    the amount of accruals recorded are based only on the information available to us at the time. As additional information becomes available, we reassess the potential liability related to the legal proceeding, and may revise our estimates.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;On August 5, 2021, &lt;/span&gt;four&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt; purported former stockholders of Akcea filed an action in the Delaware
      Court of Chancery captioned John Makris, et al. v. Ionis Pharmaceuticals, Inc., et al., C.A. No. 2021-0681, or the &#x201c;Delaware Action.&#x201d;&#160; The plaintiffs in the Delaware Action assert claims against (i) former members of Akcea&#x2019;s board of directors; and
      (ii) Ionis, or collectively, the &#x201c;Defendants.&#x201d; The plaintiffs assert putatively direct claims on behalf of a purported class of former Akcea stockholders. The plaintiffs in the Delaware Action assert that the Defendants breached their fiduciary
      duties in connection with the October 2020 take-private transaction that we and Akcea entered into, in which Akcea became a wholly-owned subsidiary of Ionis. We believe that the claims asserted in the Delaware Action are without merit and filed a
      motion to dismiss the claims in November 2021. Briefing on the motion to dismiss is ongoing, and pursuant to an agreed-upon scheduling order that has been entered by the Court, argument on the motion to dismiss is expected later in the first quarter
      of 2022.&lt;/span&gt;&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;On January 19, 2022, a purported stockholder of Ionis filed a stockholder derivative complaint in the Delaware Court of Chancery captioned
    Leo Shumacher, et al. v. Joseph Loscalzo, et al., C.A. No. 2022-0059, or the &#x201c;Action.&#x201d; The complaint names as defendants the current members of Ionis&#x2019; board of directors, collectively the Directors. The company is a nominal defendant. Plaintiff asserts
    a breach of fiduciary duty claim against the Directors for awarding and receiving allegedly excessive compensation. Plaintiff also asserts an unjust enrichment claim against the non-employee Directors as a result of the compensation they received. The
    complaint seeks, among other things, damages, restitution, attorneys&#x2019; fees and costs, and such other relief as deemed just and proper by the court. Defendants have not yet responded to the complaint in this Action.&lt;/div&gt;
</us-gaap:LegalMattersAndContingenciesTextBlock>
    <us-gaap:LossContingencyNumberOfPlaintiffs
      contextRef="c20210805to20210805_LitigationCaseAxis_JohnMakrisEtAlVIonisPharmaceuticalsIncEtAlMember"
      decimals="INF"
      id="Fact_7c35b15c9ad84e4db79ca2e02b038551"
      unitRef="U021">4</us-gaap:LossContingencyNumberOfPlaintiffs>
    <us-gaap:QuarterlyFinancialInformationTextBlock
      contextRef="c20210101to20211231"
      id="Text_4be6328593df49c295c60f8f5c9d4bc0">
&lt;div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;11. Fourth Quarter Financial Data (Unaudited)&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;The following financial information reflects all normal recurring adjustments, which are,
    in the opinion of management, necessary for a fair statement of the results of the interim periods. Summarized fourth quarter data for 2021
    and 2020 are as follows (in thousands, except per share data).&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;"&gt;


  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; border-bottom: #000000 2px solid;" valign="bottom"&gt;
          &lt;div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Three Months Ended December 31,&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;2021&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;2020&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 76%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Revenue&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;440,006&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;290,281&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 76%;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Operating expenses&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;219,403&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;312,945&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 76%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Income (loss) from operations&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;220,603&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(22,664&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 76%;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Net income (loss)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;224,613&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(355,687&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 76%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Net income (loss) attributable to Ionis Pharmaceuticals, Inc. common stockholders&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;224,613&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(354,532&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 76%;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Basic net income (loss) per share (1) (2)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;1.59&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(2.54&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 76%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Diluted net income (loss) per share (1) (3)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;1.41&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(2.54&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;________________&lt;/div&gt;

&lt;table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;"&gt;


  &lt;tr&gt;

    &lt;td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(1)&lt;/td&gt;

    &lt;td style="width: auto; vertical-align: top; text-align: left;"&gt;
          &lt;div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt;We &lt;/span&gt;compute net income (loss) per share independently for each quarter during &lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt;the year.&lt;/span&gt;&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;"&gt;


  &lt;tr&gt;

    &lt;td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(2)&lt;/td&gt;

    &lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;As discussed in Note 1, &lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;"&gt;Organization and Significant Accounting Policies, &lt;/span&gt;we compute basic net income (loss) per share by dividing the total net income (loss)
            attributable to our common stockholders by our weighted-average number of common shares outstanding during the period. Our basic net income per share for the fourth quarter of 2021 was $1.59.&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="text-align: justify; margin-left: 18pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Our basic net loss per share calculation for the fourth quarter of 2020 considered our net loss for Ionis on a stand-alone
    basis plus our share of Akcea&#x2019;s net loss for the period. To calculate the portion of Akcea&#x2019;s net loss attributable to our ownership, we multiplied Akcea&#x2019;s loss per share by the weighted average shares we owned in Akcea during the period. As a result of
    this calculation, our total net loss available to Ionis common stockholders for the calculation of net loss per share is different than net loss attributable to Ionis Pharmaceuticals, Inc. common stockholders in the consolidated statements of
    operations.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="text-align: justify; margin-left: 18pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Our basic net loss per share for the fourth quarter of 2020 was calculated as follows (in thousands, except per share amounts):&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;"&gt;


  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; border-bottom: #000000 2px solid; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Three Months Ended December 31, 2020&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Weighted&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Average Shares&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Owned in Akcea&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Akcea&lt;/span&gt;&#x2019;&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;s&lt;/span&gt;&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Net Loss&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Per Share&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Basic Net Loss&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Per Share&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Calculation&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 64%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Akcea&#x2019;s net loss in the pre-merger period attributable to our ownership&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;77,095&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(0.05&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(3,603&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 64%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Akcea&#x2019;s net loss in the post-merger period attributable to our ownership&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(85,987&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 64%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Akcea&#x2019;s total net loss attributable to our ownership&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(89,590&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 64%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Ionis&#x2019; stand-alone net loss&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(266,418&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 64%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Net loss available to Ionis common stockholders&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(356,008&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 64%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Weighted average shares outstanding&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;139,956&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 64%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Basic net loss per share&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(2.54&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;"&gt;


  &lt;tr&gt;

    &lt;td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(3)&lt;/td&gt;

    &lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;We had net income available
            to Ionis common stockholders for the fourth quarter of 2021. As a result, we computed diluted net income per share using the weighted-average number of common shares and dilutive common equivalent shares outstanding during the period as follows (in thousands except per share amounts):&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;"&gt;


  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; border-bottom: #000000 2px solid;" valign="bottom"&gt;
          &lt;div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Three Months Ended December 31, 2021&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Income&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;(Numerator)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Shares&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;(Denominator)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Per-Share&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Amount&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 64%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Net income available to Ionis common stockholders&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;224,612&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;141,205&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;1.59&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 64%;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Effect of dilutive securities:&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 64%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9pt; margin-left: 21pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Shares issuable upon exercise of stock options&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x2014;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;46&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 64%;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9pt; margin-left: 21pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Shares issuable upon restricted stock award issuance&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x2014;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;1,065&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 64%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9pt; margin-left: 21pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Shares issuable related to our ESPP&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x2014;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;34&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 64%;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9pt; margin-left: 21pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Shares issuable related to our &lt;span style="text-indent: 0pt;"&gt;0 percent&lt;/span&gt; convertible notes&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;777&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;10,936&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 64%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9pt; margin-left: 21pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Shares issuable related to our &lt;span style="text-indent: 0pt;"&gt;0.125 percent&lt;/span&gt; convertible notes&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;716&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;6,590&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 64%; padding-bottom: 2px;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9pt; margin-left: 21pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Shares issuable related to our &lt;span style="text-indent: 0pt;"&gt;1 percent&lt;/span&gt; convertible notes&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;105&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;464&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 64%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Income available to Ionis common stockholders, plus assumed conversions&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;226,210&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;160,340&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;1.41&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;
</us-gaap:QuarterlyFinancialInformationTextBlock>
    <us-gaap:ScheduleOfQuarterlyFinancialInformationTableTextBlock
      contextRef="c20210101to20211231"
      id="Text_53a7dc3cb94e432bbe1ab7ec6da16d34">
&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;The following financial information reflects all normal recurring adjustments, which are,
    in the opinion of management, necessary for a fair statement of the results of the interim periods. Summarized fourth quarter data for 2021
    and 2020 are as follows (in thousands, except per share data).&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;"&gt;


  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; border-bottom: #000000 2px solid;" valign="bottom"&gt;
          &lt;div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Three Months Ended December 31,&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;2021&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;2020&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 76%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Revenue&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;440,006&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;290,281&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 76%;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Operating expenses&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;219,403&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;312,945&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 76%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Income (loss) from operations&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;220,603&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(22,664&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 76%;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Net income (loss)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;224,613&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(355,687&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 76%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Net income (loss) attributable to Ionis Pharmaceuticals, Inc. common stockholders&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;224,613&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(354,532&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 76%;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Basic net income (loss) per share (1) (2)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;1.59&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(2.54&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 76%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Diluted net income (loss) per share (1) (3)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;1.41&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(2.54&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;________________&lt;/div&gt;

&lt;table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;"&gt;


  &lt;tr&gt;

    &lt;td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(1)&lt;/td&gt;

    &lt;td style="width: auto; vertical-align: top; text-align: left;"&gt;
          &lt;div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt;We &lt;/span&gt;compute net income (loss) per share independently for each quarter during &lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; color: #000000;"&gt;the year.&lt;/span&gt;&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;"&gt;


  &lt;tr&gt;

    &lt;td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(2)&lt;/td&gt;

    &lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;As discussed in Note 1, &lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;"&gt;Organization and Significant Accounting Policies, &lt;/span&gt;we compute basic net income (loss) per share by dividing the total net income (loss)
            attributable to our common stockholders by our weighted-average number of common shares outstanding during the period. Our basic net income per share for the fourth quarter of 2021 was $1.59.&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="text-align: justify; margin-left: 18pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Our basic net loss per share calculation for the fourth quarter of 2020 considered our net loss for Ionis on a stand-alone
    basis plus our share of Akcea&#x2019;s net loss for the period. To calculate the portion of Akcea&#x2019;s net loss attributable to our ownership, we multiplied Akcea&#x2019;s loss per share by the weighted average shares we owned in Akcea during the period. As a result of
    this calculation, our total net loss available to Ionis common stockholders for the calculation of net loss per share is different than net loss attributable to Ionis Pharmaceuticals, Inc. common stockholders in the consolidated statements of
    operations.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="text-align: justify; margin-left: 18pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Our basic net loss per share for the fourth quarter of 2020 was calculated as follows (in thousands, except per share amounts):&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;"&gt;


  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; border-bottom: #000000 2px solid; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Three Months Ended December 31, 2020&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Weighted&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Average Shares&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Owned in Akcea&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Akcea&lt;/span&gt;&#x2019;&lt;span style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;s&lt;/span&gt;&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Net Loss&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Per Share&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Basic Net Loss&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Per Share&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Calculation&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 64%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Akcea&#x2019;s net loss in the pre-merger period attributable to our ownership&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;77,095&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(0.05&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(3,603&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 64%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Akcea&#x2019;s net loss in the post-merger period attributable to our ownership&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(85,987&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 64%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Akcea&#x2019;s total net loss attributable to our ownership&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(89,590&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 64%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Ionis&#x2019; stand-alone net loss&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(266,418&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 64%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Net loss available to Ionis common stockholders&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(356,008&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 64%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Weighted average shares outstanding&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;139,956&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 64%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Basic net loss per share&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(2.54&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;"&gt;


  &lt;tr&gt;

    &lt;td style="width: 18pt; vertical-align: top; align: right; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;(3)&lt;/td&gt;

    &lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;We had net income available
            to Ionis common stockholders for the fourth quarter of 2021. As a result, we computed diluted net income per share using the weighted-average number of common shares and dilutive common equivalent shares outstanding during the period as follows (in thousands except per share amounts):&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000; width: 100%;"&gt;


  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; border-bottom: #000000 2px solid;" valign="bottom"&gt;
          &lt;div style="text-align: left; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Three Months Ended December 31, 2021&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Income&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;(Numerator)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Shares&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;(Denominator)&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Per-Share&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Amount&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 64%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Net income available to Ionis common stockholders&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;224,612&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;141,205&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;1.59&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 64%;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Effect of dilutive securities:&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 64%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9pt; margin-left: 21pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Shares issuable upon exercise of stock options&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x2014;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;46&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 64%;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9pt; margin-left: 21pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Shares issuable upon restricted stock award issuance&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x2014;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;1,065&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 64%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9pt; margin-left: 21pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Shares issuable related to our ESPP&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&#x2014;&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;34&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 64%;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9pt; margin-left: 21pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Shares issuable related to our &lt;span style="text-indent: 0pt;"&gt;0 percent&lt;/span&gt; convertible notes&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;777&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;10,936&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 64%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9pt; margin-left: 21pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Shares issuable related to our &lt;span style="text-indent: 0pt;"&gt;0.125 percent&lt;/span&gt; convertible notes&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;716&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;6,590&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 64%; padding-bottom: 2px;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9pt; margin-left: 21pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Shares issuable related to our &lt;span style="text-indent: 0pt;"&gt;1 percent&lt;/span&gt; convertible notes&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;105&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;464&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 64%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt; color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Income available to Ionis common stockholders, plus assumed conversions&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;226,210&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;160,340&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;1.41&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;
</us-gaap:ScheduleOfQuarterlyFinancialInformationTableTextBlock>
    <us-gaap:Revenues
      contextRef="c20211001to20211231"
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      id="Fact_284eab838adc45f1bab65fa3ed3e8a21"
      unitRef="U001">440006000</us-gaap:Revenues>
    <us-gaap:Revenues
      contextRef="c20201001to20201231"
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      id="Fact_20e60632220f4799962c4c0ff5f00ab5"
      unitRef="U001">290281000</us-gaap:Revenues>
    <us-gaap:CostsAndExpenses
      contextRef="c20211001to20211231"
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      id="Fact_b6f8e9fbc8074a218922e8576d906d68"
      unitRef="U001">219403000</us-gaap:CostsAndExpenses>
    <us-gaap:CostsAndExpenses
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      id="Fact_ef4a183f40c64bdd8dd30738366a5262"
      unitRef="U001">312945000</us-gaap:CostsAndExpenses>
    <us-gaap:OperatingIncomeLoss
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      unitRef="U001">220603000</us-gaap:OperatingIncomeLoss>
    <us-gaap:OperatingIncomeLoss
      contextRef="c20201001to20201231"
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      id="Fact_e656146c3d254200b1d7c79c8135fb39"
      unitRef="U001">-22664000</us-gaap:OperatingIncomeLoss>
    <us-gaap:ProfitLoss
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      decimals="-3"
      id="Fact_64bf3d68a9a94552bd3463e1e35b0df2"
      unitRef="U001">224613000</us-gaap:ProfitLoss>
    <us-gaap:ProfitLoss
      contextRef="c20201001to20201231"
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      id="Fact_af25cdfae24542caac610d75303df0eb"
      unitRef="U001">-355687000</us-gaap:ProfitLoss>
    <us-gaap:NetIncomeLoss
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      id="Fact_1e76c1964074458397b0d306a622dd8c"
      unitRef="U001">224613000</us-gaap:NetIncomeLoss>
    <us-gaap:NetIncomeLoss
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      id="Fact_7fcd3e2599a04e4e855a4af0afbf502f"
      unitRef="U001">-354532000</us-gaap:NetIncomeLoss>
    <us-gaap:EarningsPerShareBasic
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      id="Fact_cd1a45a0547d47c59adf0ba90c1e5105"
      unitRef="U004">1.59</us-gaap:EarningsPerShareBasic>
    <us-gaap:EarningsPerShareBasic
      contextRef="c20201001to20201231"
      decimals="2"
      id="Fact_bdec6ddb89aa427eb5832c982172b15b"
      unitRef="U004">-2.54</us-gaap:EarningsPerShareBasic>
    <us-gaap:EarningsPerShareDiluted
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end
</TEXT>
</DOCUMENT>
</SEC-DOCUMENT>
